Assn of American Physicians & Surgeons.

AAPS 71st Annual Meeting: Summit to Save American Medicine Sep 4, 2014 - Sep 6, 2014 Charleston, South Carolina Join your colleagues for this historic meeting in this historic city. General Session convenes at 2pm on Thursday September 4, 2014 and adjourns at Noon on Saturday, September 6, 2014.

ZIKA VIRUS: First time in Europe A SEXUALLY TRANSMITTED DISEASE

PRO/EDR> Zika virus - Germany ex Thailand Inbox x promed@promedmail.org 20:24 (12 hours ago) to promed-post, promed-edr-post ZIKA VIRUS - GERMANY ex THAILAND ******************************** A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Fri 27 Dec 2013 From: Jonas Schmidt-Chanasit [edited] A previously healthy 53-year-old man consulted at the Saarland University Medical Center on 22 Nov 2013 after returning from travel to Thailand. During his 3-week round trip (31 Oct-20 Nov 2013), including visits to Phuket, Krabi, Ko Jum, and Ko Lanta, he developed joint pain and swelling on his left ankle and foot on 12 Nov 2013 after several mosquito bites, followed by a maculopapular rash on his rear and front trunk that spread to the face and the upper as well as lower extremities over the next 4 days before fading. Accompanying symptoms were malaise, fever, and shivering, of which the latter 2 appeared only for one day. He and his travel partner, who never had any comparable symptoms, were using insect repellent during travel. Upon presenting in Germany, which was intended as a check for tropical diseases and included taking blood samples, no clinical signs could be found, and the only subjective complaint was continuing tiredness. Initially, the 1st serum sample collected 10 days after disease onset gave a positive result in the dengue IgM antibody tests (IFA and rapid test), although tests for dengue IgG antibody (IFA and rapid test) and dengue NS 1 antigen (ELISA and rapid test) were negative. However, the isolated positive result for dengue IgM antibodies prompted us to investigate a probable flavivirus etiology through a serological approach. Serological tests for Japanese encephalitis virus, West Nile virus, yellow fever virus, tick-borne encephalitis virus, and Zika virus were performed by the WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research (WHOCC), Hamburg, Germany. IFAs gave positive results for Zika virus IgG and IgM antibodies, demonstrating an acute or recent Zika virus [ZIKV] infection of the patient. In contrast, IFAs gave negative results for the other flaviviruses tested as well as for chikungunya virus. Real-Time RT-PCR for ZIKV RNA (in-house) was negative. The presence of ZIKV-specific neutralizing antibodies was confirmed by a virus neutralization assay, and an IgM titer decrease in IFA was demonstrated in the 2nd serum sample collected 31 days after disease onset. This is the 1st laboratory confirmed case of ZIKV reported in Germany and Europe and the 2nd case reported from Thailand. Thus, differential diagnosis in febrile returning travelers from the south of Thailand (Phuket, Krabi, Ko Jum, and Ko Lanta) should include Zika virus infection. -- Jonas Schmidt-Chanasit, Petra Emmerich, Dennis Tappe, Martin Gabriel, Stephan Gunther: Bernhard Nocht Institute for Tropical Medicine, WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research, National Reference Centre for Tropical Infectious Diseases, Hamburg, Germany. Jorgen Rissland, Gerhard Held, Sigrun Smola: Saarland University Medical Center, Homburg/Saar, Germany [ProMED thanks Jonas Schmidt-Chanasit and colleagues for sending in this interesting, firsthand report. This is the 2nd ProMED-mail report of a Zika virus infection originating in Thailand. The virus was 1st isolated in 1947 from sentinel rhesus monkey serum in Uganda. Fortunately, the probability of ongoing transmission from this case in Germany is nil. This is another example of long-distance international travel involving an individual who acquired a tropical arbovirus disease who was seen in a temperate zone clinic halfway around the world. The above case is an excellent example of a thorough laboratory approach to establishing a diagnosis of a disease exotic to Germany. It also underscores the importance of taking a good travel history for these types of cases. It also indicates that Zika virus transmission is active in Thailand and could be confused easily with a dengue virus infection without comprehensive laboratory testing. This report along with the earlier one this year [2013] make one wonder how many Zika virus infections in Thailand and other Southeast Asian countries are mistakenly diagnosed as dengue virus infections.

BMJ:COITUS PORTALIS

Like a virgin (mother): analysis of data from a longitudinal, US population representative sample survey BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f7102 (Published 17 December 2013) Cite this as: BMJ 2013;347:f7102 Amy H Herring, professor12,DEPT.BIOSTATISTICS,U.NORTH CAROLINA Samantha M Attard, PhD candidate23, Penny Gordon-Larsen, professor23, William H Joyner, the reverend4, Carolyn T Halpern, professor25 Author Affiliations Correspondence to: A H Herring amy_herring@unc.edu Abstract Objective To estimate the incidence of self report of pregnancy without sexual intercourse (virgin pregnancy) and factors related to such reporting, in a population representative group of US adolescents and young adults. Design Longitudinal, population representative sample survey. Setting Nationally representative, multiethnic National Longitudinal Study of Adolescent Health, United States. Participants 7870 women enrolled at wave I (1995) and completing the most recent wave of data collection (wave IV; 2008-09). Main outcome measures Self reports of pregnancy and birth without sexual intercourse. Results 45 women (0.5%) reported at least one virgin pregnancy unrelated to the use of assisted reproductive technology. Although it was rare for dates of sexual initiation and pregnancy consistent with virgin pregnancy to be reported, it was more common among women who signed chastity pledges or whose parents indicated lower levels of communication with their children about sex and birth control. Conclusions Around 0.5% of women consistently affirmed their status as virgins and did not use assisted reproductive technology, yet reported virgin births. Even with numerous enhancements and safeguards to optimize reporting accuracy, researchers may still face challenges in the collection and analysis of self reported data on potentially sensitive topics.

SWEDEN:PANDEMRIX & NARCOLEPSY

to promed-post, promed-edr-post INFLUENZA (71): SWEDEN, PANDEMRIX VACCINE AND NARCOLEPSY ******************************************************** A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Thu 19 Dec 2013 Source: The Local (Sweden) [edited] Scientists believe they have found the cause of the narcolepsy cases uncovered after Sweden's inoculation drive against swine flu [influenza H1N1 pdm09]. The jab may have set off an auto-immune response that caused brain damage. The Pandemrix vaccine likely "fooled" the brain to attack cells in the brain that regulate sleeping patterns. The cells in question produce a protein called hypocretin, which regulates whether a person is awake or asleep. Sweden offered its citizens the vaccine against swine flu during the epidemic in 2009-2010, which claimed between 9 to 31 Swedes' lives. Experts at the time said they feared the disease would be as big a killer as the Spanish flu in the late 1910s, when an estimated 3-5 percent of the world's population succumbed. Since the inoculation drive, however, more than 100 Swedes -- many of them teenagers -- have developed narcolepsy. The Swedish Medical Products Agency (Lakemedelsverket) ordered a massive study to determine whether the vaccine had any connection to narcolepsy. It compared 3.3 million vaccinated Swedes with 2.5 million who were not vaccinated. "We can see that over the whole study period, we have 126 cases of those vaccinated getting narcolepsy," Ingemar Person, professor behind the study, said in a statement on Tuesday [17 Dec 2013]. "There were 20 cases among those not vaccinated. We're talking about a 3-fold increase in risk." The scientists at the Stanford School of Medicine have now said that a part of the vaccine had some similarities to parts of hypocretin that trigger the immune system. The scientists said that the ensuing reaction meant the body's own immune system could not see the difference between the hypocretin and the parts of the flu virus that the body was meant to attack. The end result: The body attacked the part of the brain that regulates sleeping patterns. "We have long thought that auto-immune diseases don't afflict the brain, but that is obviously not correct," according to the Stanford researcher Emmanuel Mignot. Narcolepsy is a chronic nervous system disorder that causes excessive drowsiness, often causing people to fall asleep uncontrollably and, in more severe cases, to suffer hallucinations or paralysing physical collapses called cataplexy. Sweden was not alone in facing narcolepsy cases after the jab drive. In Finland, 79 children aged 4 to 19 developed narcolepsy after receiving the Pandemrix vaccine in 2009 and 2010, while in Sweden, the number was close to 200, according to figures in the 2 countries released last year [2012]. Sweden has more than 9 million citizens, while Finland has some 5 million, making the cases approximately proportionate to population size. In the past years, the Finnish and Swedish governments have both agreed to provide financial compensation for the affected children after their own national research showed a link between the inoculation and narcolepsy.

Primary Aldosteronism:a Potassium channelopathy?

Endocrinology. 2013 Nov 18. [Epub ahead of print] Minireview: Potassium Channels and Aldosterone Dysregulation. Is Primary Aldosteronism a Potassium Channelopathy? Gomez-Sanchez Celso E,(Univ.MISSISSIPPI,JACKSON) Oki K. Primary aldosteronism is the most common form of secondary hypertension and has significant cardiovascular consequences. Aldosterone-producing adenomas (APAs) are responsible for half the cases of primary aldosteronism, and about half have mutations of the G protein-activated inward rectifying potassium channel Kir3.4. Under basal conditions, the adrenal zona glomerulosa cells are hyperpolarized with negative resting potentials determined by membrane permeability to K+ mediated through various K+ channels, including the leak K+ channels TASK-1, TASK-3, and TREK1, and G protein inward rectifying potassium channel Kir3.4. Angiotensin II decreases the activity of the leak K+ channels and Kir3.4 channel and decreases the expression of the Kir3.4 channel, resulting in membrane depolarization, increased intracellular calcium, calcium-calmodulin pathway activation, and increased expression of CYP11B2, the last enzyme for aldosterone production. Somatic mutations of the selectivity filter of the Kir3.4 channel in APA results in loss of selectivity for K+ and entry of sodium, resulting in membrane depolarization, calcium mobilization, increased CYP11B2 expression, and hyperaldosteronism. Germ cell mutations cause familial hyperaldosteronism type 3, which is associated with adrenal zona glomerulosa hyperplasia, rather than adenoma. Less commonly, somatic mutations of the sodium-potassium ATPase, calcium ATPase, or the calcium channel Cav1.3 have been found in some APAs. The regulation of aldosterone secretion is exerted to a significant degree by activation of membrane K+ and calcium channels or pumps, so it is not surprising that the known causes of disorders of aldosterone secretion in APA have been channelopathies, which activate mechanisms that increase aldosterone synthesis. PMID: 24248457 [PubMed - as supplied by publisher]

UK NEW STATESMAN: FEMALE GENITAL MUTILATION

Syndicate contentRSS A London clinic fighting back against female genital mutilation By Natasha Tsangarides Published 21 December 2013 10:17 The West London clinic offers a vital service for FGM survivors. Maryam has just had “reversal” surgery, a procedure to open up the vagina, which had been sewn up during FGM. “It’s amazing, I didn’t realize I wouldn’t feel pain,” she said. “My legs were shaking from fear but I didn’t feel a thing.” Maryam was 10-years-old when she was “cut” in Somalia. “I remember the day,” she recalled. “My mum sent me to the shop to get a needle and thread. I knew what was going on. The old lady had already done it to girls on my street that day. I felt ashamed if I didn’t do it. “Recently I got married. I suffered with sex. There’s no reason for my vagina to be closed. My husband is Somali so he expected I would be cut. When my husband realised I was closed though, he was disappointed. He said, ‘You’d better open this up’. He’s going to be happy now.” The West London African Women’s Community Clinic, based at Charing Cross hospital, runs an FGM service every Wednesday afternoon. The clinic is a pioneering centre set up in 2010 to deliver services for women suffering the consequences of FGM. Treating women mostly from the Somali community, the clinic is breaking the taboo surrounding the procedure. This November, several campaigns have been launched nationally in order to raise awareness and eliminate the practice of FGM in the UK. What is the scale of the problem and who is affected by it? What are the health consequences for victims of FGM? With the practice happening behind closed doors, can it really be eliminated in the UK? FGM involves cutting female genital organs for non-medical reasons. In the UK, over 20,000 girls are at risk and 66,000 women are living with the consequences of FGM, according to a study carried out by the anti-FGM charity, Forward. A cultural practice, FGM developed to preserve women’s virginity and control sexuality. It is prevalent in 28 countries in Africa and in parts of Asia and the Middle East. 97% of women in Somalia undergo the horrific procedure, typically between the ages of 5 and 9 years old, according to a 2007 study by the London School of Hygiene and Tropical Medicine. The study estimated that 15,272 Somali women aged between 15 and 49 are living with FGM in England and Wales. Somalis comprise one of the largest ethnic groups in Hammersmith and Fulham. The 2011 census shows that 45% of the population in White City is foreign-born. The majority (636 people) come from Somalia, of which just over half are women. With the practice so ingrained in Somali culture, migration to the UK has not stamped it out. Some second-generation girls born in the UK are being sent back to their parent’s countries of origin or, probably less commonly, having the procedure done here. Freedom of Information requests submitted by the Evening Standard show that 2,115 FGM patients were seen at London hospitals between 2010 and summer this year. The West London African Women’s Service provides gynaecology, maternity and sexual health care for women who have undergone FGM. It is delivered at two sites: at Chelsea and Westminster Hospital as well as the community clinic at the West London Centre for Sexual Health, Charing Cross Hospital. Between June 2011 and August 2013, 662 women with FGM have accessed the service, of whom 432 attended the community clinic. The impact of the service has not gone unnoticed. In 2012, it won two all-party parliamentary maternity awards for most marked improvement in a service to address health inequalities and the best example of a service to address complex needs, and this year it also won the accolade of ‘Adult Sexual Health Service of the Year’ by the UK Sexual Health Awards. Sagal Osman, an anti-FGM campaigner from White City, helps local West London women access the clinic. Originally from Somalia and a survivor of FGM, Sagal developed relationships with practitioners at Charing Cross hospital and secured regular clinics for FGM patients at the West London African Women’s Community Clinic. Sagal said: “At the moment I have five new patients every week and I have a waiting list of about 50 people. Most patients are Somalis. It’s probably the hardest community to reach. But over the years trust has been built.” Women come to the clinic for a variety of reasons, typically stemming from the long-term consequences associated with FGM. These include recurrent urinary infections, painful scarring, severe menstrual cramps, wound infections, fertility problems, complications in pregnancy and even renal impairment or failure. Dr Naomi Low-Beer, Consultant Gynaecologist at Chelsea and Westminster Hospital, and lead doctor for the FGM service at the West London clinic, performs the invaluable reversal surgery. She explained: “With the most severe type of FGM, the clitoris and labia have been totally removed, the vaginal opening closed, with a tiny passage left for urine and menstrual blood. This makes sex painful or impossible. “Women with this type of FGM do benefit from surgery. It is often referred to as ‘reversal’, but rather than reversing the FGM the surgery opens the vagina so that women can have sex without pain. Otherwise, it can take months and months of painful attempts at penetration. A number of women come in to have the surgery pre-marriage or before their first relationship, and others come because they are suffering from repeated urine and vaginal infections or very painful periods. The surgery can help women with these problems too. It can be safely performed under local anaesthetic in the outpatient clinic. In offering this service, you feel like you’re making a difference.” Naomi works closely with an all-female team of committed specialists, including an obstetrician, FGM specialist midwife, doctors specialising in HIV and Sexual Health, and of course Sagal Osman, anti-FGM campaigner and health advocate. Between them they provide comprehensive specialist care for women with FGM. Between June 2011 and August 2013, of the 662 women attending the West London African Women’s Service 69 women had de-infibulations, otherwise known as reversal surgery, of whom 37 had this performed at the West London clinic. Alia*, draped head-to-foot in black, sits nervously in the clinic’s waiting room. Having had reversal surgery four weeks ago, she is at the clinic to treat syphilis and Hepatitis B, infections commonly attributed to dirty tools used during FGM. Despite having the infections, Alia is optimistic following the successful surgery. She says, “I feel better and I feel like my life has changed.” Tending to the needs of women suffering the after-effects of FGM is only one part of the problem. Preventing it from happening is something campaigners, frontline workers and the government have been battling with for almost thirty years. In July this year, Hammersmith and Fulham Council passed a special motion that proposes to raise awareness and end all forms of FGM in the borough. Councillor Helen Binmore said: “We have just set up a strategic board and hope that our coordinated multi-agency approach will help improve how agencies, services and professionals respond to this issue and offer protection to women and girls from FGM.” Efua Dorkenoo OBE is Advocacy Director at Equality Now, an international human rights organisation. She said: “Parents know about the health consequences but it still goes on. Parents need to know that professionals are keeping an eye on their children and that they will report FGM happening and that there can be prosecutions.” FGM has been a criminal offence since 1985 and the 2003 Female Genital Mutilation Act made it illegal for British citizens and permanent residents to practice FGM within and outside the UK. To date, there have been no prosecutions. By comparison, France has convicted around 100 parents and practitioners. Misplaced cultural sensitivities, a failure to see FGM as a child protection issue and a lack of accountability have so far impeded successful prosecutions taking place, Mrs Dorkenoo said. “The issue needs to be brought into the mainstream as a child abuse issue through a combination of education, protection and prosecutions.” Momentum is growing in the campaign to raise awareness and eliminate FGM with the government making it a national priority. Last month, the London Metropolitan Police have, for the first time, arrested two people suspected of performing FGM on a five-week old girl. The case is under investigation and a successful prosecution would be a landmark victory and an important step to achieving the goal of eliminating FGM.

INDIA : increased incidence MYCOBACTERIUM LEPRAE

LEPROSY - INDIA (05): (ANDHRA PRADESH) INCREASED INCIDENCE ********************************************************** A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Sat 21 Dec 2013 Source: The Times of India Times News Network (TNN) [edited] Leprosy is increasing alarmingly in Andhra Pradesh with the government doing little to check the bacterial infection from spreading, experts said as a staggering 8285 cases were reported in the state during 2012-13. As many as 239 new cases were detected in Hyderabad in the same period. Health department officials said Andhra Pradesh now figures among the top 12 states with the highest caseloads of leprosy in the country. The proportion of new paediatric cases in the state was also among the highest in the country, experts said. Data from the National Leprosy Eradication Programme shows that out of the total new cases, a substantial 911 cases (11.34 per cent) are of children, officials said. Experts said the numbers have gone up particularly in the last 2 years. During 2011-12, 7820 cases were detected, they pointed out and attributed the situation to the state government's apathy towards the health issue, so much so that it is now regaining ground. "We could not identify these cases well in time," said Dr Michael Sukumar, a WHO consultant who is working with the state leprosy cell [in Hyderabad], underscoring a situation when agencies are sometimes helpless when local governments fail to read health warnings.

SWITZERLAND:PRESERATIVE-FREE EYE DROPS.

Consider using preservative-free topical medication in patients with ocular surface disease Publishing date: December 2013 The Science behind the Tip Many glaucoma drops contain a preservative agent to minimise the risk of microbial contamination. Benzalconium chloride, a cationic surfactant, is the most widely used preservative, but even in doses of 0.002% to 0.004% can result in toxic effects on the surface of the eye and ocular inflammation. (1) Symptoms and signs of ocular surface disease (OSD) are found in 48-60% of patients on topical glaucoma medication (2) (3). This is a multifactorial condition which leads to adverse local reactions, reduced visual acuity, reduced quality of life and reduced compliance with prescribed therapy. (1). Risk factors associated with OSD include the number of preserved drops used and duration of therapy. (4) An improvement of symptoms is found if these patients are switched to preservative-free topical medication. (1) Contributor: Frances Meier-Gibbons, Switzerland References 1. Baudouin C, Labbé A, Liang H et al Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res 2010; 29 (4) 312-334. 2. Leung EW, Medeiros FA, Weinreb RN. Prevalance of ocular surface disease in glaucoma patients. J Glaucoma 2008; 17 (5) 350-355. 3. Fechtner RD, Godfrey DG, Budenz D et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure lowering medications. Cornea 2010;? 29: 618-621. 4. Rossi GC, Pasinetti GM, Scudeller L et al. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. Eur J Ophthalmol 2013; 23 (3) 296-302. Tip Editors: John Salmon and John Thygesen Reviewers: Roger Hitchings and Anders Heijl

SWISS MED. WKLY: PLATELET TRANSFUSION

Review article | Published 13 December 2013, doi:10.4414/smw.2013.13885 Cite this as: Swiss Med Wkly. 2013;143:w13885 Platelet transfusion: basic aspects Andreas Holbroa, Laura Infantia, Jörg Sigleb, Andreas Busera a Blood Transfusion Centre, Swiss Red Cross, Basel, Switzerland b Blood Transfusion Centre, Swiss Red Cross, Aarau, Switzerland Summary Platelet transfusions have been shown to prevent major haemorrhage and improve survival in thrombocytopenic patients. Since then, advances in the preparation of platelet components, including the introduction of pathogen reduction techniques, have been achieved. The number of transfused platelet components is still growing owing to the increasing number of patients treated for haemato-oncological diseases. Additionally, indications have been extended, for example to patients with drug-induced platelet dysfunction. This review focuses on current platelet component production and storage techniques, including pathogen reduction, indications for platelet transfusion and safety issues including alloimmunisation and management of platelet refractoriness. Key words: platelets; transfusion; refractoriness, safety Introduction Platelet (PLT) transfusions were shown to reduce mortality from haemorrhage in patients with leukaemia in the 1950s [1]. Since then, although their use has grown and continues to grow [2, 3], a number of questions related to optimal preparation and storage of PLT components, and the indications, safety and efficacy of PLT transfusion have arisen. Nowadays PLT transfusions are an essential part of the supportive care of thrombocytopenic patients, such as those with haematological diseases. Additionally, inborn and acquired – mainly drug-induced – platelet dysfunctions can be overcome through transfusion of PLT components. In this review we provide an overview of the basic aspects of PLT transfusions and indicate the still open questions related to this practice. History The discovery of blood circulation by William Harvey in 1628 was the premise for transfusion medicine [4]. Afterwards, the first animal-to-animal transfusions were performed, soon leading to early experiments with animal-to-men transfusions in the mid of the 17th century. The first men-to-men transfusions were performed in 1818 [5]. In 1900, the discovery of the ABO blood group by Landsteiner was the cornerstone for further improvements in transfusion medicine [6]. As major and fatal haemorrhage due to thrombocytopenia was a leading cause of death in children with acute lymphoblastic leukaemia, major efforts were undertaken to improve the supportive care of thrombocytopenic patients [7]. The first studies of PLT transfusions showed not only feasibility but also efficacy in preventing major haemorrhage in thrombocytopenic patients, thus improving overall survival [1, 8]. PLT component production and clinical use were further improved by technical developments, improvements in apheresis techniques, development of PLT additive solutions and studies on storage conditions [9–12]. In the last few years, pathogen reduction techniques have been successfully implemented for PLT components and have reduced, in particular, the risks of morbidity and mortality due to bacterial contamination, one of the most feared consequences for the transfusion recipient [13, 14]. Nowadays, more than 4 million PLT components are transfused worldwide each year [2, 15]. Platelet components: manufacturing, storage and pathogen reduction Manufacturing of platelet components PLT components can be obtained either from whole blood donations or by single-donor apheresis. Both techniques have advantages and disadvantages (table 1) [16, 17]. PLT components derived from whole blood donations are produced by pooling either platelet rich plasma or buffy coats from multiple donors, using different sequential centrifugation steps [18]. The buffy coat pooling technique is the one most widely used in Europe. Whole blood donations are selected and centrifuged (hard spin) to separate plasma and red blood cells from the buffy coat layer containing leucocytes and PLTs. Four to six buffy coats of the same ABO blood group are pooled and a second centrifugation is performed (soft spin) to separate leucocytes and residual red blood cells from the PLTs. The remaining PLTs are resuspended in plasma or in a mixture of additive solution and plasma (about 2:1). For the production of single-donor apheresis PLT concentrates, various blood-separating devices are in use and licensed. Donor availability is a major limitation of this process. Although specific adverse effects of PLT apheresis are well described [19, 20], PLT apheresis is considered safe and can be safely performed even in donors with mild anaemia and low iron stores [21]. In Europe, virtually all PLT components are leucocyte-depleted in order to reduce side effects [22]. Overall, the properties and efficacy of the above-described PLT preparations are similar [23–27], although some centres still prefer single donor apheresis components for patients with haematological diseases in order to reduce donor exposure. Specifications of the final PLT product are stipulated by various regulations (Standards for Blood Banks and Transfusion Services, 26th edition. Bethesda, Maryland, AABB, 2009 and Guide to the Preparation, Use and Quality Assurance of Blood Components, 16th edition, Strasbourg, Council of Europe Publishing, 2010). In Switzerland the minimal PLT content has to be >2.4 x 1011/unit, and the number of residual leucocytes and red blood cells has to be <1 x 106/unit and <5 x 109/unit, respectively. Platelet storage In contrast to red blood cell concentrates, PLT components are stored at 22±2 °C under gentle agitation. Studies have shown a better transfusion response if they are stored at room temperature [10]. Because possibly contaminating bacteria can grow well under these conditions, duration of storage is limited to 4–7 days, depending on whether bacterial detection methods or pathogen reduction are used. The introduction of pathogen reduction techniques might solve this problem, but possibly at the price of a slight impairment of PLT function. After the introduction of universal pathogen reduction in Switzerland, PLT storage is now limited to a maximum of 7 days. PLT concentrates have to be agitated during storage in order to assure optimal oxygen and carbon dioxide exchange through the storage bag and to avoid a fall of pH, which would compromise PLT recovery and survival after transfusion [28]. Once delivered by the blood bank, PLT components can be kept safely at room temperature and removed from the rotator for at least 6 hours [29]. The short storage period of PLT components requires optimal inventory management by blood banks, best achieved through a close cooperation with the clinicians. Pathogen reduction Figure 1 Figure 1 Pathogen reduction with the INTERCEPT® method. Schematic representation of the mode of action of INTERCEPT®. Amotosalen intercalates within DNA/RNA. DNA/RNA crosslinks upon UVA irradiation. This blocks reproduction of pathogens and leucocytes. Courtesy of Cerus Corporation, Concord, CA, USA. Various pathogen reduction techniques have been developed in recent years [13]. In Switzerland, the amotosalen/UVA based INTERCEPT® (Intercept Blood System, Cerus Corporation, Concord, CA, USA) has been introduced nationwide and deemed mandatory in 2011. Amotosalen, a psoralen derivative, is added to PLT concentrates, binds to deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and – upon activation by ultraviolet-A (UVA) irradiation – crosslinks DNA and RNA. An absorbing device then removes residual amotosalen. With this technique, replication of viruses, bacteria, protozoa and residual leucocytes is reduced (fig. 1). To date, amotosalen, at the concentrations used, is reported to be nontoxic and nonmutagenic [30–33]. Concerns regarding the efficacy of pathogen-reduced PLT components in preventing bleeding have arisen. Studies showed discrepancies in PLT recovery, measured as the platelet corrected count increment (CCI; see below): some studies showed lower CCI of pathogen-reduced PLT compared with standard PLT components [34–36]. Other trials could not detect any significant difference [32, 37]. However, in all these studies the standard PLT components used for comparison were prepared in different additive solutions or in plasma, and were partly gamma irradiated, raising concerns about the influence of product factors on CCI. Our own study comparing single-donor apheresis PLTs treated with amotosalen/UVA versus gamma-irradiated PLTs, both resuspended in the same additive solution (PAS III), showed no significant differences in CCI [38]. Clinical endpoints, measured as incidence and severity of World Health Organisation (WHO) grade 2 bleeding complications, were shown to occur slightly more frequently in patients supported with pathogen-reduced PLT [36]. However, there was no significant difference in severe bleeding complications, thus arguing in favour of pathogen-reduced PLT components, which are associated with improved safety concerning microbial contamination [39]. Two different meta-analyses [40, 41] reached conclusions different from the available studies as to the risk of WHO grade 2 bleeding. However, WHO grade 2 bleeding might not be the right surrogate outcome in PLT transfusions studies [42]. Since the nationwide introduction of pathogen reduction of PLT components in Switzerland in 2011, no transfusion-transmitted infection related to bacterial contamination has been reported to the national haemovigilance office, whereas the incidence of mortality due to bacterially contaminated PLT transfusions was estimated to be 1.5 cases/year before implementation of this method [3]. Two other methods are also on the way; however they are not yet licensed for use in Switzerland. Mirasol® (Terumo BCT, Tokyo, Japan) uses riboflavin, which associates with DNA/RNA and mediates an oxygen-independent electron transfer upon UV exposure causing irreversible damage to nucleic acids [43, 44]. Theraflex® (Macopharma, Tourcoing, France) uses UVC without any additional photochemically active compound [45]. The clinical experience with PLT components treated with these methods is still limited. Table 1: Comparison of platelet components produced from whole blood donations or by apheresis. Advantages Disadvantages Whole-blood derived PLTs Availability PLT dose modification Avoids product waste No additional donor risk Multiple donor exposure Difficult HLA/HPA matching Apheresis PLTs Less donor exposure Automation and standardisation HLA/HPA matching Donor availability Higher production costs Limited PLT dose Donor risk from apheresis procedure HLA = human leucocyte antigen; HPA = human platelet antigen; PLT = platelet Indications for platelet transfusions PLTs can be transfused in order to prevent bleeding (prophylactic indication) or to stop bleeding (therapeutic indication) both in thrombocytopenic and in patients with normal PLT counts. The vast majority of PLT transfusions are performed in thrombocytopenic haemato-oncological patients. Drug-induced PLT dysfunctions, such as in patients undergoing major cardiovascular surgery or, less frequently, due to inborn defects, are further indications for PLT transfusions. In patients with thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT), PLT transfusions are in general indicated only in the case of severe bleeding. For prophylactic PLT transfusions, many studies have shown that in patients with chronic stable thrombocytopenia a lower threshold of 5–10 x 109/l is safe [46, 47]. Today this threshold is widely accepted by clinicians and is generally indicated as standard in the various published guidelines for PLT transfusion [48, 49]. Based on the available studies and guidelines, every institution should establish its own transfusion triggers in collaboration with the blood bank and transfusion specialists. The efficacy of prophylactic PLT transfusions in thrombocytopenic patients has been evaluated in studies comparing prophylactic and therapeutic PLT transfusions regimens in haemato-oncological patients. A recent trial showed an increase in severe and fatal haemorrhage in patients with acute leukaemia who received therapeutic rather than prophylactic transfusions [50]. This finding was confirmed by another recent noninferiority study in haematological patients, who did not receive prophylactic PLT transfusions when morning PLT counts were less than 10 x 109/l, but only in the case of bleeding [51]. Factors affecting efficacy of platelet transfusions Assessment of PLT transfusion efficacy is a major challenge. Several criteria have been developed and evaluated, most of them including the post-transfusion PLT count (fig. 2). Figure 2 Figure 2 Methods for assessment of platelet transfusion efficacy. Clinical endpoints (i.e. bleeding) are the most important method for evaluating effectiveness of PLT transfusions. Different scores have been developed with the goal of objectively assessing bleeding, but lack of standardisation of these methods is still a major problem [52, 53]. It has to be emphasised that CCI, the most widely used marker for measuring efficacy of PLT transfusions, does not necessarily correlate with clinical bleeding (see below, “platelet transfusion refractoriness”). Various factors have a direct or indirect influence on the efficacy of PLT transfusions: Product factors Platelet dose In Switzerland the standard therapeutic adult dose is more than 2.4 x 1011 PLTs per unit. This varies according to different guidelines and national transfusion policies. However, PLT dose per unit has no effect on the incidence of bleeding in patients undergoing haematopoietic stem-cell transplantation or chemotherapy for haematological cancers or solid tumours [54]. ABO compatibility ABO mismatched transfusions have a lower PLT recovery than ABO-compatible PLT transfusions [55]. Guidelines recommend that, whenever possible, PLT units issued for transfusion should be of the same ABO blood group as the patient’s. Other Other product factors include storage time, resuspension of PLT in additive solutions vs plasma, PLT irradiation and pathogen reduction. Interestingly, ABO blood group, PLT storage time and PLT source, which all have a moderate impact on CCI, had no impact on clinical bleeding [39]. Patient factors Patient’s gender, height and weight, several clinical conditions (listed in table 2), and drugs all have an impact on transfusion efficacy (see below, “platelet transfusion refractoriness”). On the basis of standard CCI or percent PLT recovery calculations, male patients showed inferior recovery rates, irrespective of donor sex. However, using an adjusted percent of platelet recovery, which takes into account differences in blood volume between males and females (according to Nadler’s formula), neither donor nor recipient sex played any role in PLT recovery after transfusion in non-HLA-immunised patients [56]. Table 2: Factors associated with platelet transfusion refractoriness. A. Nonimmune factors: – Clinical factors: fever, infection/sepsis, splenomegaly, DIC, GVHD, bleeding – Drugs*: vancomycin, heparin, GPIIb/IIIa antagonists, ... – Product factors: storage duration, platelet dose, ABO compatibility, use of additive solution, irradiation, pathogen reduction – Patient factors: sex, weight/height, history of pregnancy and transfusions B. Immune factors: – ABO incompatibility – HLA-antibodies – HPA antibodies DIC = disseminated intravascular coagulation; GVHD = graft-versus-host disease; HLA = human leucocyte antigen; HPA = human platelet antigen * See also reference [58]. Platelet transfusion refractoriness Figure 3 Figure 3 Proposed algorithm for the management of patients with platelet transfusion refractoriness. DIC = disseminated intravascular coagulation; GVHD = graft-versus-host disease; HLA = human leucocyte antigen; HPA = human platelet antigen; PLT = platelet components Definitions: – HLA-identical: same class I HLA antigens (HLA-A and HLA-B) patient and donor – HLA-compatible: according to HLA matchmaker (see text) – HLA-permissive: recipient has no HLA antibodies against donor HLA antigens As described above, assessment of PLT transfusion efficacy is very important. Fig. 2 shows different criteria for evaluating PLT transfusion efficacy. Platelet transfusion refractoriness is defined as an insufficient post-transfusion PLT count increment. Usually it is defined as two or more consecutive CCIs of <7.5 at 1 hour or a CCI <4.5 18‒24 hours after transfusion of ABO-identical PLT concentrates less than 3 days old (fig. 2) [57]. However, in daily routine practice the provision of these products (ABO-compatible and younger than 3 days) may be difficult and they are not always readily available. Nonimmune and immune factors are associated with PLT transfusion refractoriness (table 2) [58, 59]. Nonimmune factors lead to increased PLT consumption. Bleeding, infection/sepsis, splenomegaly and graft-versus-host disease (GVHD) in patients receiving allogeneic haematopoietic stem-cell transplantation are the most common nonimmune causes for refractoriness to PLT transfusions. Drugs are also an important cause and should be considered in the evaluation of patients with PLT transfusion refractoriness. Immune factors are responsible for PLT transfusion refractoriness in approximately 20% of cases, with HLA antibodies being most commonly involved [58]. Less frequently, human platelet antigen (HPA) antibodies – or a combination of HLA and HPA antibodies – cause transfusion refractoriness. Minor histocompatibility antigens play an important role in haematopoietic stem-cell transplantation [60]. H-Y proteins are ubiquitously expressed Y chromosome-encoded minor histocompatibility antigens. These antigens however have no influence on the outcome of PLT transfusions [56]. In refractory patients, nonimmune aetiologies have first to be excluded (table 2 and fig. 3). If immune PLT transfusion refractoriness is suspected, a search for HLA-antibodies should be initially performed. If HLA antibodies are detected, various options for the selection of suitable PLT units are available. All of them require HLA class I typing of PLT donors: (A) Selection of HLA-identical PLT components from HLA-matched apheresis donors (B) Selection of HLA-compatible PLT products according to cross-reactive groups (CREGs) or in silico matching (HLA matchmaker). HLA matchmaker is a computer algorithm that identifies compatibility at the epitope level, which is determined by short sequences of polymorphic amino acids [61, 62]. (C) Selection of HLA-permissive PLT products, avoiding the recipient HLA antibody specificities by selection of donors lacking the corresponding antigens. Provision of HLA permissive PLT products is especially useful if HLA typing of the recipient is not available. It is important to note that the presence of HLA-antibodies is – on the other hand - not always associated with PLT transfusion refractoriness. An in-vitro method to test compatibility is a PLT crossmatch, i.e., testing the patient`s serum against donor PLTs. Fig. 3 shows a proposed algorithm, which may help in the case of PLT transfusion refractoriness [63]. Safety of platelet transfusions PLT transfusions can be associated with various transfusion reactions (see table 3) [64]. Febrile transfusion reactions are the most frequently observed side effects after PLT transfusions [3, 65]. Immune-haemolytic complications and microbial contamination of PLT components have to be excluded. Cytokines in PLT concentrates and anti-HLA antibodies of the recipient are the main causes for febrile transfusion reactions [66]. Allergic reactions are generally mild. Foreign donor plasma antigens are responsible for these. Patients with IgA deficiency and anti-IgA antibodies are at particular risk for severe anaphylactic transfusion reactions [67, 68]. In patients with IgA deficiency, these can range from urticarial to severe anaphylactic reactions including hypotension, dyspnoea and shock [69]. Haemolysis due to donor isohaemagglutinins (anti-A and anti-B) can occur after PLT transfusions [70, 71]. As already mentioned above, the risk of microbial contamination of PLT components can be reduced by pathogen reduction techniques [13]. Before the introduction of universal pathogen reduction in Switzerland, bacterial contamination occurred with an incidence of 1:3,000–1:10,000 [14]. Sepsis due to bacterial contamination is one of the most feared transfusion reactions as it can be fatal. Transfusion related lung injury (TRALI) is a severe pulmonary transfusion complication, caused by HLA and human neutrophil antibodies against recipient antigens [72]. Storage of PLT in PAS has shown to reduce the incidence of TRALI [73, 86]. Transfusion associated circulatory overload (TACO) is seldom associated with isolated PLT transfusions. It occurs after rapid transfusion of large volumes of blood, as in cases of massive transfusion. Older patients and patients with cardiovascular diseases and renal failure are at increased risk of TACO [74]. Transfusion associated graft-versus-host disease (taGVHD) occurs in severely immunosuppressed patients after engraftment of donor lymphocytes and is often fatal. It can be prevented by gamma irradiation of PLT concentrates (25–30 Gy). Pathogen reduction techniques are equivalent to gamma irradiation in this respect [75]. Alloimmunisation can be a problem in patients receiving multiple transfusions. It is related to residual red blood cells and leucocytes in the PLT components, as well as PLT antigens. PLTs express carbohydrate blood groups like ABO, P, I and Lewis antigens [76]. Additionally HLA class I molecules are expressed, as PLT contain messenger RNA for the synthesis of these molecules [77]. PLT-specific antigens (HPAs) are glycoproteins involved in haemostasis [78]. Both HLA and HPA can stimulate the production of alloantibodies and thus cause PLT transfusion refractoriness. Additionally, HPA can cause neonatal alloimmune thrombocytopenia (NAIT), caused by maternal alloantibodies against paternally inherited HPA of the foetus. These HPA alloantibodies pass the placenta and are responsible for severe thrombocytopenia in the foetus and the newborn [79]. Although PLT express HLA class I antigens, the main cause for the development of HLA antibodies in chronically transfused patients are leucocytes contaminating PLT products. Universal leucoreduction is thus an efficient measure for the prevention of HLA immunisation [80–82]. Additionally, a careful evaluation of transfusion indications in order to avoid unnecessary exposure to antigens is of primary importance. Besides transfusions, HLA and HPA antibodies can develop during pregnancy, which is the most important cause of alloimmunisation [83]. Alloimmunisation against rhesus (Rh) D antigen can also occur following PLT transfusions, although PLTs do not express Rh antigens. Alloimmunisation against red blood cell antigens due to PLT transfusions are related to residual red blood cells in PLT products. Transfusion of Rh D negative PLT components is therefore especially important in Rh D negative female recipients of childbearing age [84]. In the case of transfusion of Rh D positive PLT concentrates to a Rh D negative recipient, which is sometimes unavoidable because of inventory shortages, administration of Rh immunglobulin has to be considered (120–300 μg IV). Table 3: Transfusion reactions after platelet transfusion. Cause Prevention Febrile transfusion reaction Cytokines; recipient HLA antibodies Leucocyte reduction Allergy/anaphylaxis Anti-IgA antibodies in patients, donor plasma antigens Antihistamines, steroids, washed PLT products Haemolysis Donor isohaemagglutinins ABO identical transfusion, washed PLT products, use of PAS Microbial contamination Viruses, bacteria, parasites, fungi Donor selection and testing, pathogen reduction, leucocyte reduction (CMV), limitation of storage duration Transfusion associated lung injury (TRALI) Donor HLA and HNA antibodies Male donors, exclusion of donors with HLA and/or HNA antibodies Transfusion associated circulatory overload (TACO) Volume overload Identify patients at risk (neonates, old patients, patients with cardiac and renal diseases), diuretics Transfusion associated GVHD Donor lymphocytes in immunosuppressed patients Gamma irradiation (25‒30 Gy), pathogen reduction Alloimmunisation HLA antigens on residual leucocytes HPA antigens on PLT Residual RBC in PLT component Leucocyte reduction, donor selection, Anti-D prophylaxis CMV = cytomegalovirus; GVHD = graft-versus-host disease; Gy = Gray (J/kg); HLA = human leucocyte antigen; HNA = human neutrophil antigen; PAS = platelet additive solutions; PLT = platelets; RBC = red blood cell Future directions As demand for PLT transfusions will continue to increase, donor availability poses a major challenge for blood banks. For optimal management of PLT supply, a close collaboration between clinicians, blood banks and transfusion specialists is mandatory. Alternative pathogen reduction techniques are under development and may contribute substantially to safer PLT transfusions. Additionally, studies on alternatives to PLT transfusions and other methods to improve haemostasis in bleeding patients are under investigation. Until then, a personalised and individualised patient transfusion management is the safest and most efficient approach to patients requiring PLT support. Development of PLTs from haematopoietic stem cells, human embryonic stem cells and human induced pluripotent stem cells and expansion of ex-vivo generated PLT are further exciting fields of research [85]. Funding / potential competing interests: No financial support and no other potential conflict of interest relevant to this article was reported. Correspondence: Andreas Holbro, MD, Blood Transfusion Centre, Swiss Red Cross, Hebelstrasse 10, CH-4031 Basel, Switzerland, andreas.holbro[at]usb.ch

BREAKTHROUGH PRIZES ($3-million each)

The Breakthrough Prize in Life Sciences Foundation announced that Howard Hughes Medical Institute (HHMI) investigator Richard P. Lifton of Yale University is among the six scientists awarded the Life Sciences Prize for excellence in research aimed at curing intractable diseases and extending human life. The Breakthrough Prizes recognize pioneering work in physics and genetics, cosmology, and neurology and mathematics. Each prize carries an award of $3 million. Lifton, who has been an HHMI investigator since 1994, uses genetic approaches to identify the genes and pathways that contribute to common human diseases, including cardiovascular, renal, and bone disease. He was honored by the foundation for the discovery of genes and biochemical mechanisms that cause hypertension. More than two decades ago, when Lifton first proposed using genetic methods to study the causes of high blood pressure, his approach was not uniformly accepted. Such a complicated condition, critics thought, would not lend itself to traditional genetic tactics, which try to link a disease to alterations in a single gene. Since then, Lifton has proved his detractors wrong many times over. Lifton has identified more than 20 genes associated with blood pressure, cardiovascular disease, and bone density, and he has characterized mutations that cause either extreme hypertension (high blood pressure) or hypotension (low blood pressure) in people. More significantly, he has shown that severe blood pressure problems can be caused by mutations in genes that regulate the amount of sodium chloride the kidney allows to flow into the blood. When these genes falter in severe hypertension cases, salt levels rise, blood volume increases, the heart pumps harder, and blood pressure surges. With excessive hypotension, the opposite occurs. Today, his findings have changed how doctors treat hypertension, which affects approximately one billion people worldwide and is the most prevalent cardiovascular disease risk factor. The foundation also recognized HHMI alumni investigator James Allison at the University of Texas MD Anderson Cancer Center for the discovery of T cell checkpoint blockade as effective cancer therapy. Allison was an HHMI investigator from 2004-2012. The six winners of the 2014 Breakthrough Prize in Life Sciences are: • James Allison, MD Anderson Cancer Center, for the discovery of T cell checkpoint blockade as effective cancer therapy. • Mahlon DeLong, Emory University, for defining the interlocking circuits in the brain that malfunction in Parkinson's disease. This scientific foundation underlies the circuit-based treatment of Parkinson's disease by deep brain stimulation. • Michael Hall, University of Basel, for the discovery of Target of Rapamycin (TOR) and its role in cell growth control. • Robert Langer, David H. Koch Institute Professor at the Massachusetts Institute of Technology, for discoveries leading to the development of controlled drug-release systems and new biomaterials. • Richard Lifton, Yale University; Howard Hughes Medical Institute, for the discovery of genes and biochemical mechanisms that cause hypertension. • Alexander Varshavsky, California Institute of Technology, for discovering critical molecular determinants and biological functions of intracellular protein degradation. Prize recipients are invited to serve on the selection committee to select recipients of future prizes. Last year, HHMI investigators Cornelia I. Bargmann at the Rockefeller University, Charles L. Sawyers at Memorial Sloan-Kettering Cancer Center and Bert Vogelstein at Johns Hopkins University School of Medicine were awarded the Breakthrough Prize in Life Sciences. Founded in 2013, the Breakthrough Prize in Life Sciences Foundation is a not-for-profit corporation dedicated to advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career. The Foundation was founded by Sergey Brin and Anne Wojcicki, Mark Zuckerberg and Priscilla Chan, Jack Ma and Cathy Zhang, and Yuri and Julia Milner, and is chaired by Arthur Levinson, who is also chairman of Genenand Apple.

St.MARTIN.(FRENCH part of island) CHIKUNGUNYA VIRUS

Notice to Public Health Officials and Clinicians: Recognizing, Managing, and Reporting Chikungunya Virus Infections in Travelers Returning from the Caribbean Summary On December 7, 2013, the World Health Organization (WHO) reported the first local (autochthonous) transmission of chikungunya virus in the Americas. As of December 12th, 10 cases of chikungunya have been confirmed in patients who reside on the French side of St. Martin in the Caribbean. Laboratory testing is pending on additional suspected cases. Onset of illness for confirmed cases was between October 15 and December 4. At this time, there are no reports of other suspected chikungunya cases outside St. Martin. However, further spread to other countries in the region is possible. Chikungunya virus infection should be considered in patients with acute onset of fever and polyarthralgia, especially those who have recently traveled to the Caribbean. Healthcare providers are encouraged to report suspected chikungunya cases to their state or local health department to facilitate diagnosis and to mitigate the risk of local transmission. Background Chikungunya virus is a mosquito-borne alphavirus transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes. Humans are the primary reservoir during epidemics. Outbreaks have been documented in Africa, Southern Europe, Southeast Asia, the Indian subcontinent, and islands in the Indian and Pacific Oceans. Prior to the cases on St. Martin, the only chikungunya cases identified in the Americas were in travelers returning from endemic areas. Clinical Disease A majority of people infected with chikungunya virus become symptomatic. The incubation period is typically 3–7 days (range, 2–12 days). The most common clinical findings are acute onset of fever and polyarthralgia. Joint pains are often severe and debilitating. Other symptoms may include headache, myalgia, arthritis, or rash. Persons at risk for more severe disease include neonates (aged <1 month) exposed intrapartum, older adults (e.g., ≥ 65 years), and persons with underlying medical conditions (e.g., hypertension, diabetes, or cardiovascular disease). Diagnosis Chikungunya virus infection should be considered in patients with acute onset of fever and polyarthralgia who recently returned from the Caribbean. Laboratory diagnosis is generally accomplished by testing serum to detect virus, viral nucleic acid, or virus-specific immunoglobulin M (IgM) and neutralizing antibodies. During the first week of illness, chikungunya virus infection can often be diagnosed by using viral culture or nucleic acid amplification on serum. Virus-specific IgM and neutralizing antibodies normally develop toward the end of the first week of illness. To definitively rule out the diagnosis, convalescent-phase samples should be obtained from patients whose acute-phase samples test negative. Chikungunya virus diagnostic testing is performed at CDC, two state health departments (California and New York), and one commercial laboratory (Focus Diagnostics). Healthcare providers should contact their state or local health department to facilitate testing. Treatment No specific antiviral treatment is available for chikungunya fever. Treatment is generally palliative and can include rest, fluids, and use of analgesics and antipyretics. Because of similar geographic distribution and symptoms, patients with suspected chikungunya virus infections also should be evaluated and managed for possible dengue virus infection. People infected with chikungunya or dengue virus should be protected from further mosquito exposure during the first few days of illness to prevent other mosquitoes from becoming infected and reduce the risk of local transmission. Prevention No vaccine or preventive drug is available. The best way to prevent chikungunya virus infection is to avoid mosquito bites. Use air conditioning or screens when indoors. Use insect repellents and wear long sleeves and pants when outdoors. People at increased risk for severe disease should consider not traveling to areas with ongoing chikungunya outbreaks.

TORONTO: MEDICAL SERVICES for visitors.

FROM PHYSICIAN CONTRIBUTOR IN TORONTO AVOID LOCAL ER DEPTS. WAITING TIME 4-6 hrs. Nurse triage. ADVISE LIMO RIDE ($400)1.5 - 2 hr. to Mount St.Mary Hospital,Lewiston, NY. Quick access to Specialists, MRI etc. For general medical advice CLEVELAND CLINIC CANADA, (30,000 sq.ft.)@ BROOKFIELD PLACE, 181 BAY ST. (also entrance YONGE ST.) 416-507-6600 Same building as Hockey Hall of Fame & MARCHE Swiss Restaurant. Connected to USA Cleveland clinics. (Near Fairmont ROYAL YORK Hotel.) MEDCAN Private clinic,150 YORK St.(@ Adelaide)416-350-5900 (Mid-Town location)Near to HILTON & SHERATON Hotels.) No Private Hospitals in Ontario (Quebec has Private Medicine)

USA NIH Dr.Ola LANDGREN MD PhD (Karolinska,Stockholm)

C. Ola Landgren, M.D., Ph.D. Lymphoid Malignancies Branch Senior Investigator Center for Cancer Research National Cancer Institute Bulding 10, Room 13N240 Bethesda, MD 20892-1906 Phone: 301-496-0670 Fax: 301-402-0172 E-Mail: landgreo@mail.nih.gov Dr. Landgren received his M.D. in 1995 from the Karolinska Institute (Stockholm, Sweden). Following clinical training as a hematology/internal medicine specialist physician and receipt of a Ph.D. focusing on diagnostics and prognostics in Hodgkin lymphoma (2002) at Karolinska Institute in Sweden, he worked as an attending physician and conducted clinical research on lymphoproliferative malignancies and related precursors. In 2004, he came to the National Cancer Institute, Genetic Epidemiology Branch, DCEG, where he worked as an Investigator before he joined the Medicial Oncology Branch. Dr. Landgren's major research interests are in the treatment, causation, diagnostics and prognostics, and natural history of multiple myeloma and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). He also studies related hematologic malignancies and their precursors states (including chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis (MBL); Waldenstrom's macroglobulinemia and IgM MGUS), as well as myeloproliferative neoplasms. His research focuses on treatment-, host-, disease-, and immune-related factors in the pathway from precursor to full-blown malignancy, and their relation to outcome. Research Dr. Landgren's research interests include: - Examination of novel therapies for multiple myeloma and its precursor states - Identification of predictors for progression; from precursor to malignancy, and outcome - Definition of the roles for infectious antigens, inflammation, chronic immune stimulation, and immune modulation in hematopoietic carcinogenesis - Assessment and definition of host- and disease-related diagnostic/prognostic markers This page was last updated on 10/28/2013.

DAILY MAIL: Death of HPV vaccine pioneer D.Anne SZAREWSKI

Scientist who pioneered cervical cancer vaccine found dead by husband at home after he warned she was working too hard By Paul Bentley and Sara Smyth PUBLISHED: 19:35 GMT, 8 December 2013 | UPDATED: 01:51 GMT, 9 December 2013 The scientist who pioneered the cervical cancer vaccine was found dead by her husband at their £2million home after he warned she was ‘heading for a crisis’ by working too hard. In August he found her dead in their four-bedroom home in West Hampstead, North London, after he spent two hours drilling through a door she had locked from the inside. She was found with high levels of an anti-malarial drug in her bloodstream, but doctors said this was not thought to have caused her death. Dr Szarewski, who used her maiden name, was preparing for five international work trips and had been complaining that she was experiencing all-over body pains with ‘mounting intensity’. University lecturer: Dr Anne Szarewski's discovery has saved thousands of lives Mr Venter,(husband) 63, told the inquest into her death at St Pancras Coroner’s Court: ‘I was in the habit of telling her that she was heading for a crisis. I just realised she couldn’t maintain the pace that she was setting for herself.’ Dr Szarewski is credited with discovering the link between the human papillomavirus and cervical cancer, leading to a vaccine for HPV – the first-ever vaccine against any form of cancer – which is now routinely given to girls across the country. Born in London to Polish parents, she studied medicine at Middlesex Hospital before working at the Whittington Hospital in Highgate, North London. Latterly she worked as a gynaecologist at the Margaret Pike Centre in King’s Cross, was a clinical lecturer at the Wolfson Institute, Queen Mary, University of London, and also worked for Cancer Research. Her husband of ten years, a former political journalist from South Africa, told the court the couple slept in separate bedrooms because they enjoyed their own space. Mr Venter said that he woke up on August 24 after a night at the theatre and when his wife did not come down for breakfast he was initially pleased that she was having a well-deserved lie-in. When she still had not emerged at 2pm, however, he became concerned and found her bedroom door was locked. After two hours trying to open it with an electric drill, he forced his way inside. ‘As I entered the room I saw her on the bed and I realised straight away that she was dead,’ he said. The couple’s home contained two-and-a-half cupboards of medication, a collection Mr Venter described as one of his wife’s ‘charming eccentricities’. A pathologist’s report read out to the inquest found the scientist died from PANCREATITIS The anti-malaria drug Chloroquine was discovered in her blood. It is known to be highly toxic in overdose quantities. A packet was later found in the house but this is not thought to have been the cause of death and the coroner recorded a verdict of death by natural causes. Read more: http://www.dailymail.co.uk/news/article-2520360/Scientist-Anne-Szarewski-pioneered-cervical-cancer-vaccine-dead-husband-home.html#ixzz2mwLSq4XP Follow us: @MailOnline on Twitter | DailyMail on Facebook

50th anniversary of development of Measles vaccine by Duke Univ. Emeritus Prof. S.L.KATZ

Press Release Embargoed until: Thursday, December 5, 2013 at 12:00 noon ET Contact: Media Relations (404) 639-3286 Measles Still Threatens Health Security On 50th Anniversary of Measles Vaccine, Spike in Imported Measles Cases Fifty years after the approval of an extremely effective vaccine against measles, one of the world’s most contagious diseases, the virus still poses a threat to domestic and global health security. On an average day, 430 children – 18 every hour – die of measles worldwide. In 2011, there were an estimated 158,000 measles deaths. In an article published on December 5 by JAMA Pediatrics, CDC’s Mark J. Papania, M.D., M.P.H., and colleagues report that United States measles elimination, announced in 2000, has been sustained through 2011. Elimination is defined as absence of continuous disease transmission for greater than 12 months. Dr. Papania and colleagues warn, however, that international importation continues, and that American doctors should suspect measles in children with high fever and rash, “especially when associated with international travel or international visitors,” and should report suspected cases to the local health department. Before the U.S. vaccination program started in 1963, measles was a year-round threat in this country. Nearly every child became infected; each year 450 to 500 people died each year, 48,000 were hospitalized, 7,000 had seizures, and about 1,000 suffered permanent brain damage or deafness. People infected abroad continue to spark outbreaks among pockets of unvaccinated people, including infants and young children. It is still a serious illness: 1 in 5 children with measles is hospitalized. Usually there are about 60 cases per year, but 2013 saw a spike in American communities – some 175 cases and counting – virtually all linked to people who brought the infection home after foreign travel. “A measles outbreak anywhere is a risk everywhere,” said CDC Director Tom Frieden, M.D., M.P.H. “The steady arrival of measles in the United States is a constant reminder that deadly diseases are testing our health security every day. Someday, it won’t be only measles at the international arrival gate; so, detecting diseases before they arrive is a wise investment in U.S. health security. Eliminating measles worldwide has benefits beyond the lives saved each year. Actions taken to stop measles can also help us stop other diseases in their tracks. CDC and its partners are building a global health security infrastructure that can be scaled up to deal with multiple emerging health threats. Currently, only 1 in 5 countries can rapidly detect, respond to, or prevent global health threats caused by emerging infections. Improvements overseas, such as strengthening surveillance and lab systems, training disease detectives, and building facilities to investigate disease outbreaks make the world -- and the United States -- more secure. “There may be a misconception that infectious diseases are over in the industrialized world. But in fact, infectious diseases continue to be, and will always be, with us. Global health and protecting our country go hand in hand,” Dr. Frieden said. Today’s health security threats come from at least five sources: The emergence and spread of new microbes The globalization of travel and food supply The rise of drug-resistant pathogens The acceleration of biological science capabilities and the risk that these capabilities may cause the inadvertent or intentional release of pathogens Continued concerns about terrorist acquisition, development, and use of biological agents. “With patterns of global travel and trade, disease can spread nearly anywhere within 24 hours,” Dr. Frieden said. “That’s why the ability to detect, fight, and prevent these diseases must be developed and strengthened overseas, and not just here in the United States.” The threat from measles would be far greater were it not for the vaccine and the man who played a major role in creating it, Samuel L. Katz, M.D., emeritus professor of medicine at Duke University. Today, CDC is honoring Dr. Katz 50 years after his historic achievement. During the ceremony, global leaders in public health are highlighting the domestic importance of global health security, how far we have come in reducing the burden of measles, and the prospects for eliminating the disease worldwide. Measles, like smallpox, can be eliminated. However, measles is so contagious that the vast majority of a population must be vaccinated to prevent sustained outbreaks. Major strides already have been made. Since 2001, a global partnership that includes the CDC has vaccinated 1.1 billion children. Over the last decade, these vaccinations averted 10 million deaths – one fifth of all deaths prevented by modern medicine. “The challenge is not whether we shall see a world without measles, but when,” Dr. Katz said. “No vaccine is the work of a single person, but no single person had more to do with the creation of the measles vaccine than Dr. Katz,” said Alan Hinman, M.D., M.P.H., Director for Programs, Center for Vaccine Equity, Task Force for Global Health. “Although the measles virus had been isolated by others, it was Dr. Katz’s painstaking work passing the virus from one culture to another that finally resulted in a safe form of the virus that could be used as a vaccine.”

CANADA: Treponema pallidum infection in NUNAVUT:territory popn 32,000 ( Iqualuit- 7,000 )

SYPHILIS - CANADA (04): (NUNAVUT) INCREASED CASES, REQUEST FOR INFORMATION ************************************************************************** A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Thu 5 Dec 2013 Source: CBC News [edited] A syphilis outbreak in Nunavut [territory] that began last year [2012] continues to concern health officials. Nunavut health officials say there have been 74 confirmed cases of the sexually transmitted infection in Nunavut since May 2012 with new cases every week. Most are in Iqaluit [the capital city of Nunavut]. Dr. Maureen Baikie, Nunavut's chief medical officer of health, is urging people to get tested for syphilis even if they don't have symptoms, as the infection can have serious health consequences. "The important things about syphilis are, 1st of all, people can have it and not know they have it, which is why it's so important to go and get tested," said Dr. Maureen Baikie, Nunavut's chief medical officer of health. "The other thing is it can be a lifelong infection, and the longer you have it without treatment, the more serious the consequences can be." The infection is easily cured with antibiotics, but if left untreated it can cause severe damage to the heart, blood vessels and brain, and even death. Health officials are encouraging people to get tested and practice safer sex, by decreasing the number of sexual partners and using a condom during sex. -- Communicated by: ProMED-mail from HealthMap Alerts [Nunavut, the largest federal territory of Canada, is the size of Western Europe; it comprises a major portion of Northern Canada, and has an estimated population in 2010 of about 33 000, mostly Inuit (). The territorial capital Iqaluit, which had a population in 2011 of 6699, is located on the south coast of Baffin Island (). Iqaluit was founded in 1942 as an American airbase to provide a stopover and refueling site to support the war effort in Europe (). Iqaluit is only accessible by aircraft and, subject to ice conditions, by boat. Nunavut did not officially become a territory until 1999; prior to 1999, data for Nunavut was combined with Northwest Territories. In 2008, no cases of infectious syphilis (primary, secondary and early latent stages) were reported in Nunavut (); in 2012, 13 cases of infectious syphilis, all of them in Iqaluit, were reported in a prior ProMED-mail post (Syphilis - Canada (03): (NU) RFI 20120912.1291334), where we were told that "the pattern of transmission in Iqaluit has been largely the same as in other parts of Canada and other countries." The rates of infectious syphilis in Canada, as in the United States, have been increasing since about 2000. In Canada, the male-to-female rate ratio increased from 1.5:1.0 in 1999 to 6.4:1.0 in 2008, reflecting that more males than females were reported with infectious syphilis, and this disparity increased over time (). In 2008, men accounted for 86.1 percent of reported cases. Between 1999 and 2008, the rate in men increased from 0.7 to 7.3 per 100 000 and in women increased from 0.5 to 1.1 per 100 000. In men, the highest reported rate of infectious syphilis was shared between 25-29 year olds and 30-39 year olds (13.3 per 100 000) (). Together, these age groups accounted for almost 40 percent of reported cases in men in 2008. In women, the highest reported rate was in 20-24 year olds (3.6 per 100 000). In males, the greatest increase in reported rates of infectious syphilis between 1999 and 2008 was in 25-29 year olds. Most of the Canadian syphilis outbreaks have been in men who have sex with men (MSM), and other outbreaks were related to the sex trade, but some have been locally acquired infections in heterosexual persons (). In Calgary, Alberta, as in the United States, a syphilis outbreak has been associated with the acquisition of anonymous sex partners through the internet. In a ProMED-mail post in February 2013 (Syphilis - Canada: (NU) RFI 20130214.1542486), we were told that there were more than 30 cases in Iqaluit since the outbreak began in May 2012, and the outbreak was spreading to other "regions." According to the news report above, that number of cases has risen to 74 with new cases every week, again mostly occurring in Iqaluit. Some of this increase could be due to an increase in screening for syphilis, but details of the outbreak such as gender, sexual behavior, ethnicity, use of illicit drugs, or prostitution were again not given then, nor are they given in the news report above. Such information would be greatly appreciated from knowledgeable persons. Inuit comprise about 58 percent of Iqaluit's population (), and they may constitute a large portion of the syphilis cases in Iqaluit, as in the Canadian province of Alberta, where infection rates of infectious syphilis are reported to be 18.6 times higher among young Aboriginal women and 2.8 times higher in Aboriginal men compared to their Caucasian counterparts (). These young Aboriginal women are reported to be largely linked to the "street based" sex trade, are often involved with problematic substance use, and are poor. (Aboriginal peoples in Canada comprise the 1st Nations, Inuit, and Metis; Metis are people with mixed 1st Nations and European ancestry).

PHILADELPHIA: WILLS EYE HOSPITAL : FREE CME

Wills Eye Knowledge Portal www.willseyeonline.org Wills Eye Knowledge Portal Free Registration. Free CME. Sign Up Here! Experience Wills Eye education online at www.willseyeonline.org Learn from top doctors at Wills Eye Institute. Experience web-based medical education. Earn CME credits from world-renowned experts. ---------------------------------- CME Courses Strabismus Disorders 0.5 AMA PRA Credit Strabismus is a common condition in children, occurring in about 4% of children in the United States. If untreated, strabismus can lead to untreatable visual compromise once the child is grown. The treatments for strabismus have evolved with scientific studies. Given the potential to minimize a lifetime of sub-optimal vision, physicians should be aware and up-to-date on this topic as significant practice gaps exist in awareness of strabismus disorders. ------------------------------------ ALL CME COURSES ON THE WILLS EYE KNOWLEDGE PORTAL ARE FREE! ------------------------------------ Wills Eye 39th Annual Ophthalmology Review Course March 1-5, 2014 A comprehensive review of the basic principles and recent advances in ophthalmology for Residents and Fellows. Information: (215) 440-3169 Wills Eye 65th Annual Conference March 6-8, 2014 Philadelphia, PA willsconference.org This is a three day conference designed for comprehensive ophthalmologists, specialists, and allied health personnel. The conference will review clinical, diagnostic and therapeutic approaches to eye problems related to all ophthalmic sub-specialties. Follow us on Twitter Like us on Facebook View our videos on YouTube December 2013 Corneal Trauma, Abrasions, Chemical Burns, Perforating Trauma Presenter: Kristin Hammersmith, MD Dr. Hammersmith is an assistant surgeon on the Cornea Service and Director of the Cornea Fellowship Program at Wills Eye Hospital. She is also an instructor at the Jefferson Medical College of Thomas Jefferson University. Dr. Hammersmith interests include severe ocular surface diseases such as dry eye, blepharitis, ocular cicatricial pemphigoid, chemical burns, and the potential of limbal cell transplantation to help patients with these conditions. Central Retinal Venous Obstruction Presenter: Joseph I. Maguire, MD Dr. Maguire is an attending surgeon on the Retina Service at Wills Eye Hospital and an associate professor of ophthalmology at Thomas Jefferson University. He is a past Retina Service President and Scientific Director of the Eye Reseach Institute (ERI). He is currently a principal investigator in the VEGF-trap clinical trial and the National Institutes of Health sponsored AREDS 2, and has been clinical co-investigator in several completed and ongoing clinical trials evaluating novel treatments for diabetic retinopathy and AMD. Low Vision 101: Custom Refractions, Prisms, and Optics; and Low Vision 201: Rehabilitation Presenter: Scott Edmonds, OD Dr. Edmonds is Co-Director of the Low Vision and Contact Lens Service at Wills Eye Hospital. He has written and lectured extensively on clinical topics of post operative care, low vision, contact lenses, and ocular diseases as well as management topics of managed care and medicare. Dr. Edmonds has been recognized as Optometrist of the year by the Philadelphia Optometric Society, the Chester-Delaware Optometric Society, and Pennsylvania Optometric Association. IOP Variation: Should It Affect Our Management of Glaucoma? Presenter: L. Jay Katz, MD, FACS Dr. Katz is the director of the glaucoma service at the Wills Eye Hospital and professor of ophthalmology at Thomas Jefferson University. He has published more than 160 articles in peer reviewed journals and has authored, coauthored, or edited more than 30 books and book chapters. He has received numerous awards including the Physicians Recognition Award from the American Medical Association and an Honor award from the American Academy of Ophthalmology. Dr. Katz has been an investigator in several landmark multicenter trials. Additional Highlights: Importance of Adherence and Quality of Life in People Under Glaucoma Treatment George L. Spaeth, MD Introduction to Ocular Pathology Ralph C. Eagle, MD Biopsy Techniques Edward H. Bedrossian, MD Contemporary Management of Retinal Detachment Repair Gaurav K. Shah, MD Herpetic Disease of the Anterior Segment Brad Feldman, MD Visiting Professor Lectures and Cases Joshua R. Ehrlich, MD; Timothy V. Johnson, MD; Jared D. Peterson, MD Chiefs' Rounds Anthony W. Farah, MD; Nina Ni, MD; Michael S. Ehrlich, MD; Kristin M. DiDomenico, MD; Blair K. Armstrong, MD

CANCER CELL:: Proteasome inhibitor mechanism in MM.

Cancer Cell, Volume 24, Issue 3, 289-304, 9 September 2013 Copyright © 2013 Elsevier Inc. All rights reserved. 10.1016/j.ccr.2013.08.009 Authors Chungyee Leung-Hagesteijn, Natalie Erdmann, Grace Cheung, Jonathan J. Keats, A. Keith Stewart, Donna E. Reece, Kim Chan Chung, Rodger E. Tiedemann Highlights MM tumors contain Xbp1s− progenitors that survive proteasome inhibition Xbp1s absence arrests secretory maturation and ER loading, reducing ERAD dependence PI resistance mechanisms in patients differ from in vitro models These data help explain the failure to cure MM with current therapy Summary Proteasome inhibitor (PI) resistance mechanisms in multiple myeloma (MM) remain controversial. We report the existence of a progenitor organization in primary MM that recapitulates maturation stages between B cells and plasma cells and that contributes to clinical PI resistance. Xbp1s− tumor B cells and pre-plasmablasts survive therapeutic PI, preventing cure, while maturation arrest of MM before the plasmablast stage enables progressive disease on PI treatment. Mechanistically, suppression of Xbp1s in MM is shown to induce bortezomib resistance via de-commitment to plasma cell maturation and immunoglobulin production, diminishing endoplasmic reticulum (ER) front-loading and cytotoxic susceptibility to PI-induced inhibition of ER-associated degradation. These results reveal the tumor progenitor structure in MM and highlight its role in therapeutic failure.

UK: Max HOTOPF "HEALTHCARE EUROPA"

Too little, too late as the health supertankers start to turn What is to be gleaned from the latest OECD Health at a Glance 2013? The healthcare service supertankers are starting to alter course but progress remains slow and icebergs of diabetes, dementia and longer life expectancies dwarf expenditure. News French state plans activity ceilings for hospitals The French private hospital sector is enraged by the government’s latest ploy. Behind the scenes, however, we suspect that there is a deal to be done. Asklepios issues loan note - so what happens next? Asklepios has raised €350m with a promissory note. We talk to President of the company Bernard Broermann, and look at how the Helios-Rhoen deal has reshaped the German hospital sector. Hungary - healthcare reform paying off Hungarian sources say that the healthcare reforms pushed through by minister of state for health, Dr. Miklós Szócska, under the Fidesz government, has succeeded in cutting costs substantially. Meanwhile, the government has upped healthcare expenditure ahead of 2014 elections. Medical Properties plans more deals in Europe Medical Properties Trust (MPT), the US healthcare REIT specialising in hospital property, is scouring Northern and Western Europe for deals, following its purchase of the property portfolio of RHM Kliniken. We take a look at its strategy. MC bids for Slotervaart as Dutch hospital sector opens up The Netherlands is on track to pass legislation which would enable private investors to buy shares in the not-for-profit general hospital sector which provides almost all inpatient acute care in the country. Meanwhile, it looks as though Slotervaart, a privatised hospital whose shareholders have been fighting each other looks likely to be taken over by MC Groep, which is one of the first privatisation players in the country. We talk to Chris Van Den Haak, partner at BDO Netherlands, who has just written a report on the financial health of the Dutch general hospital sector. Are we about to see a tsunami of privatisation? Interview/Feature Interview: Dag Andersson, CEO, Diaverum With close to 300 dialysis centres in 19 countries, Dag Andersson claims to run “the most global healthcare service in the world”. We look at how Diaverum is starting to offer a much wider range of services. The company is majority owned by private equity house Bridgepoint, which hired JP Morgan in January 2013 to review its strategic options.

SWISS MEDICINE: BLOOD-BRAIN BARRIER

Breaking and building the wall: The biology of the blood-brain barrier in health and disease 21/11/2013 Blood-brain-barrier The blood-brain barrier (BBB) is a complex feature of brain endothelial cells that restricts the passage of blood-borne molecules into the brain parenchyma, while ensuring the delivery of essential nutrients and selected biomolecules. Brain vasculature is anatomically distinct from that of other organs and comprises endothelial cells, pericytes and astrocytes, which collectively form the neurovascular unit (NVU). This review provides a brief overview of the cellular components of the NVU and BBB characteristics. In addition, the regulation of brain vasculature by peripheral factors such as diet and systemic disease is discussed. Abstract Proper functioning of the brain vasculature is critical for the maintenance of optimal brain function. Brain ­parenchyma is separated from blood within the cerebral vasculature by the blood-brain barrier (BBB). The BBB is a collective term for brain-specific, endothelial cell characteristics that restrict the passage into the brain of blood-borne molecules that ensure delivery of essential nutrients and selected biomolecules. The principal ­features of the vertebrate BBB are closed cell-cell junctions, a low rate of transcytosis, the expression of various solute carriers and ATP-binding cassette transporters. In addition, blood vessels in the brain are anatomically distinct. The capillary bed of brain vasculature has full longitudinal coverage by pericyte processes. Furthermore, brain vasculature is covered by glial processes, the so-called astrocyte end-feet. The term neuro­vascular unit (NVU) is often used to describe brain blood vessels in order to underline the intimate physical and functional connection between the brain tissue and blood vessels. Another special feature of brain vessels is that they are immunologically quiescent. Specifically, the expression of leucocyte-adhesion molecules is low and few peripheral leucocytes enter into the brain parenchyma. The development and maturation of the BBB and NVU is directed by signals from the surrounding neural tissue and cells forming the NVU. The formation of BBB ­specific cell-cell junctions and expression of trans­porters for glucose and biomolecules on endothelial cells is induced by the neuroepithelium, whereas pericytes regulate the low transcytosis rate of brain ­endothelium. Astrocytes have merged as regulators of BBB immune quiescence and brain water transport. Endothelial cell-cell junctions, the most intensively studied component of the BBB, are composed of adherens and tight junctions, which are established by transmembrane proteins mediating homophilic extracellular interaction. The brain endothelium is equipped with a transport system that provides a selective route for nutrients, ions and bioactive macromolecules, and ensures elimination of toxic molecules. These transporters are expressed in a polarised manner that allows the effective exchange of molecules and ions between blood and the brain parenchyma. The list of CNS pathologies (e.g. leucoencephalopathies, arteriopathies, brain calcifications) caused by the ­dysfunction of cellular and acellular components of the NVU is long. In addition, BBB breakdown is associated with common neurodegenerative diseases such as ­Alzheimer’s and Parkinson’s diseases). Pathological changes in the BBB also occur in the setting of peripheral ­diseases, e.g., acute liver failure and hypoxic conditions such as cardiac arrest. A detailed mechanistic understanding of BBB alterations in these conditions is lacking. Even less well understood is how the BBB is maintained and regulated in the healthy organism. The molecular development and regulation of the BBB is currently under intense investigation. Clearly, a collective effort from research groups working in different fields (vascular biologists, physiologists, neurobiologists etc.) is needed to better understand the development and homeostasis of complex structures such as the BBB and NVU. Although the brain vascular development and deregulation during pathological conditions is better understood at the molecular and cellular level, the majority of specific questions remain unanswered. This is a summary of an open access article on www.smw.ch. Must be cited as: Keller A. Breaking and building the wall: the biology of the blood-brain barrier in health and disease. Swiss Med Wkly. 2013,143:w13892. - See more at: http://blog.smw.ch/breaking-and-building-the-wall-the-biology-of-the-blood-brain-barrier-in-health-and-disease/#sthash.Y8ejfNBj.dpuf

EUROPEAN MULTIPLE MYELOMA ACADEMY: FREE CONFERENCE VIDEOS 2013

http://emma.medroom.at/#WSLIST

LANCET: INFECTIOUS DISEASES COMMISSION on ANTIBIOTIC RESISTANCE

http://www.reactgroup.org/uploads/news/Comments-on-The-Lancet-Infectious-Diseases-Commission-on-Antibiotic-Resistance-Nov2013.pdf

ProMED: FREE ebook by GIDEON on Infectious Diseasesof the Philippines.

A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Sat 16 Nov 2013 From: Uri Blackman [edited] A massive effort is underway to supply medical assistance to the Philippines. ProMED has arranged to supply a free copy of Infectious Diseases of the Philippines, 2013, to all subscribers. This e-book (411 pages, 88 graphs, 1869 references) is the only comprehensive source for background information on the status of every individual infectious disease in the Philippines. To obtain Infectious Diseases of the Philippines, 2013: 1. click on the following link: 2. click on "add to cart" 3. click on "add a coupon" and enter ProMED 4. click on "update" 5. fill in identification and mailing information where indicated You will receive a link for the e-book by e-mail, which you can open on your computer or mobile device. Infectious Diseases of the Philippines, 2013, is one in a series of 419 e-books (105 000 pages), with one title dedicated to every disease and every country in the world. All books are updated yearly. The publisher has agreed to offer a 50 percent discount on all titles to ProMED subscribers. To obtain any of these books at a discount: 1. click on the desired title(s) listed at and 2. follow instructions as for Infectious Diseases of the Philippines, 2013 3. at the stage of "add a coupon" enter 50promed13 -- Uri Blackman [We expect that the conditions in the typhoon-affected areas of the Philippines may well result in emerging disease outbreaks and increases in endemic diseases. ProMED appreciates this offer from our friends at GIDEON. - Mod.LM]

ARTEMISININ RESISTANT MALARIA

MALARIA, ARTEMISININ RESISTANCE - SOUTHEAST ASIA ************************************************ A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Tue 12 Nov 2013 Source: Firstpost [edited] Rise of drug-resistant malaria in Southeast Asia ------------------------------------------------ US experts are raising the alarm over the spread of drug-resistant malaria in several Southeast Asian countries, endangering major global gains in fighting the mosquito-borne disease that kills more than 600 000 people annually. While the communicable disease wreaks its heaviest toll in Africa, it's in nations along the Mekong River where the most serious threat to treating it has emerged. The availability of therapies using the drug artemisinin has helped cut global malaria deaths by a quarter in the past decade. But resistance to it emerged on the Thai-Cambodia border in 2003, and has since been confirmed in Viet Nam and Myanmar too. It has also been detected in southwest China and suspected as far away as Guyana and Suriname, according to a new report by the Center for Strategic and International Studies think tank. The report warns that could be a health catastrophe in the making, as no alternative anti-malarial drug is on the horizon. The UN World Health Organization, or WHO, is warning that what seems to be a localized threat could easily get out of control and have serious implications for global health. "Absent elimination of the malaria parasite in the Mekong, it is only a matter of time before artemisinin resistance becomes the global norm, reversing the recent gains," writes Dr Christopher Daniel, former commander of the US Naval Medical Research Center, in the report for a conference at the Washington think tank Tuesday [12 Nov 2013]. Mosquitoes have developed resistance [it is the malaria parasite which develops resistance, not the mosquito. - Mod.EP] to antimalarial drugs before. The same happened with the drug chloroquine, which helped eliminate malaria from Europe, North America, the Caribbean, and parts of Asia and South-Central America during the 1950s. Resistance first began appearing on the Thai-Cambodia border, and by the early 1990s it was virtually useless as an antimalarial in much of the world. Nowhere are the challenges in countering the threat to drug-resistance greater than in Myanmar, also known as Burma. Some 70 percent of its 55 million people live in malaria-endemic areas, and as a nation, it accounts for about three-quarters of malaria infections and deaths in the Mekong region, the report says. Myanmar's public health system is ill-equipped to cope, as government spending on health dwindled to the equivalent of just 60 US cents per person under military rule, although it has been increased significantly under the quasi-civilian administration that took power in 2011. In a third of townships, there been virtually no public health presence for years. It's an issue of regional concern as Myanmar has large transient populations in its border regions, including ethnic minorities displaced by fighting and migrant workers who cross borders. "It is clear that this country with its chronically under-resourced health system needs urgent additional attention," Daniel said. Resistance to artemisinin can be driven by various factors: delays in giving treatment, use of counterfeit or substandard drugs, and prescribing artemisinin on its own rather than in combination with another longer-acting drug to ensure that all malaria-carrying parasites in a patient's bloodstream are killed off. Cambodia and Laos have banned the use of such monotherapies, and Myanmar's military, which manufactures pharmaceuticals, announced in June [2013] it would cease production of them by early 2014. That comports with the global push by the UN for proper testing, treating, and tracking of malaria cases to prevent the disease spreading. The Center for Strategic and International Studies is advocating greater US involvement and aid for health and fighting malaria in the Mekong region, particularly in Myanmar, where Washington has been in the vanguard of ramping up international aid, as sanctions have been eased to reward it for democratic reforms. The centrist think tank argues that it can increase America's profile in Southeast Asia in a way that will benefit needy people and not be viewed as threatening to strategic rival, China. But securing more funds won't be easy at a time when Washington is cutting back on programs for its own poor. The US is already a major contributor to international anti-malaria efforts, and in Myanmar, is promising USD 20 million per year in health assistance under its recently resumed bilateral aid program. -- Communicated by: ProMED-mail from HealthMap Alerts [The emergence of artemisinin resistance in Myanmar (Burma) and Cambodia and indeed in the rest of Southeast Asia is a matter of grave concern. This is also where resistance to chloroquine (as pointed out in the message), sulfadoxine/pyrimethamine [Fansidar(R)], and mefloquine [Lariam(R)] first developed. The main driver is probably substandard dosing where purchase of single tablets is possible and counterfeit drugs containing substandard doses are common. We have previously argued that the development of resistance is best contained by providing the population with free malaria drugs ensuring a full course of treatment with drugs which contain the active compounds in the required doses (Schlagenhauf P, Petersen E: Antimalaria drug resistance: the mono-combi-counterfeit triangle. Expert Rev Anti Infect Ther. 2009; 7(9): 1039-42). Free drugs are provided to patients with HIV and tuberculosis and should be provided to malaria patients as well to remove the market for counterfeit and substandard drugs. - Mod.EP

Hep. C transmission by tears.

Hepatitis C and ocular surface disease. AU Jacobi C, Wenkel H, Jacobi A, Korn K, Cursiefen C, Kruse FE SO Am J Ophthalmol. 2007;144(5):705. PURPOSE: To assess the frequency of changes in the ocular surface and the presence of hepatitis C virus (HCV) in tear samples of patients with chronic HCV infection. DESIGN: Prospective, nonrandomized, clinical, interdisciplinary, single-center study. METHODS: Seventy-one patients with previously untreated chronic HCV infection and a control group consisting of 66 patients without systemic HCV infection were enrolled in the trial. The patients with HCV infection were screened for ocular symptoms, visual acuity, and ocular changes. Tear production was measured by the Jones test. Conjunctival impression cytologic analysis was performed. The presence of HCV ribonucleic acid (RNA) in tear and blood samples was determined by quantitative polymerase chain reaction. RESULTS: On examination, systemic HCV infection was present for a median of 30 months. Fifty percent of all HCV patients showed a decrease in tear production measured by the Jones test. Apart from epithelial changes related to dry eye syndrome in 12 patients,two patients presented mild peripheral corneal thinning. Polymerase chain reaction analysis detected HCV RNA in five (10%) of 52 tear samples. HCV RNA levels in tear samples (mean, 1.0 x 10(4) copies/ml) were considerably lower than in blood samples (mean, 5.3 x 10(5) copies/ml). CONCLUSIONS: Dry eye syndrome is the most frequently observed ocular feature in HCV infection. Patients with HCV infection (age range, 21 to 60 years) compared with the controls had a significant lower tear production (P = .05). The presence of HCV RNA in 10% of tear samples emphasizes the potential risk of viral transmission through tears. AD Department of Ophthalmology, University of Erlangen, Erlangen, Germany. christina.jacobi@augen.imed.uni-erlangen.de PMID 17870047

UTRECHT Univ. Hospital: Prof HENK LOKHORST on DARATUMUMAB for Multiple Myeloma

http://myeloma.org/ArticlePage.action?tabId=0&menuId=0&articleId=4118&aTab=-4 VIDEO of Prof LOKHORST on DARATUMUMAB trials.

ProMED:OBITUARY Dr. J.H.STEELE DVM(Mich.) MPH(Harvard)

OBITUARY: JAMES HARLAN STEELE ***************************** A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: 11 Nov 2013 From: Peter Cowan, ProMED-mail Animal Disease Assistant Moderator Yesterday [10 Nov 2013], we all witnessed the exit of a lion. Over his 100-year-plus lifespan, James Harlan Steele was a true pioneer in Public Health and the rebirth of One Health. He was tenacious in his quest to enlarge the role of veterinary medicine in public health, emboldened by the conviction that any avenue that can benefit the health and well-being of people leads to a more progressive, rational and fair state of affairs for his community, country, and the world. Steele set the direction, found the resources, selected and cultivated enough talented people to achieve his dream of One Health, which was manifested as the establishment of vital veterinary public health infrastructure at the state, national, and international levels. He literally built the 1st of many veterinary public health programs in the United States and the world beginning at CDC in 1946. Dr. Steele was a systems thinker, a strategic analyst, and a magnet for bright, young talented veterinarians, physicians, and other health professionals. He took the idea of One Health and implemented it, building a framework for programs such as rabies control, which could showcase what One Health, 1st named by Steele as Veterinary Public Health, could do. Dr. Steele received a doctorate of veterinary medicine from Michigan State University in 1941 and an MPH from Harvard University in 1942. Until yesterday [10 Nov 2013], he was the oldest living graduate of the Harvard School of Public Health. He founded and named the 1st Veterinary Public Health program at CDC and within the United States Public Health Service where he served for many years. Early on, Jim worked closely with Alex Langmuir and was so critical to the implementation and growth of CDC's EIS training program through the 1950s and 1960s that he was inducted as an honorary EIS member in 1976. He served as Assistant Surgeon General for Veterinary Affairs and the 1st Chief Veterinary Officer of the USPHS. He played a critical part at the 1st meeting of the Veterinary Public Health Expert Committee on Zoonosis at WHO. He played an inspirational role in the development of several European Veterinary Public Health Services, particularly in West Germany. Professor Steele was the Editor in Chief of the CRC Handbook of Zoonoses series and a consultant to the Control of Communicable Disease Manual for decades. These accomplishments are only a brief mention of his activities and barely scratch the surface of his impact both nationally and internationally. Jim's honors and awards are almost too numerous to count. In 1971, he joined the University of Texas School of Public Health's Infectious Disease Center, where he served as Professor until his 80th birthday. He then went into "retirement," which consisted of a whirlwind of writing, editing, consulting, and mentoring that would dwarf the output of many younger people. He was incredibly sharp and active right up to the end, engaging at over 100 years of age in an update of his work on tuberculosis, a short history of One Health, and planning for a special symposium entitled the James H. Steele Challenge: A better world through One Health. His video speech last July [2013] to the American Veterinary Medical Association's 150th anniversary was an inspiration, not solely because he had lived through 2/3rds of the existence of that professional organization dating back to the U.S. Civil War, but because of the forwardness of the thoughts in his speech. To have a vision to hand over to others at age 100 is truly remarkable. Jim loved to tell stories related to the history and purpose of Veterinary Public Health. He recalled this experience many times to many of us: "In 1945, at the end of WW II, Joseph Mountin, a physician and chief of the USPHS's Bureau of State Services, met with him to discuss the global origin and importance of zoonotic diseases. He challenged Steele by saying: "What are you veterinarians going to do for public health now that the war is over?" Jim Steele's response was vital to the future of veterinary public health and the rest of his career. Eventually, he suggested the creation of a program within USPHS that would work on zoonotic diseases. He looked down the hall and saw Dental Public Health and Public Health Nursing and decided Veterinary Public Health would do just fine. He further recommended the establishment of a corps of veterinary officers within the USPHS so that veterinarians who became Commissioned Corps members would have a place in the structure. Craig Carter, at the University of Kentucky, has written a very nice biography entitled One Man, One Medicine, One Health: The James H. Steele story. Over his career, Jim had big megaphones at CDC, WHO, USDA, PAHO, APHA and AVMA, which he used to advocate for acceptance of the idea of One Health. He developed programs which served as models the world over and that proved that good animal health meant good human health, which, in turn, translates to good economic health. Steele played a seminal role in the rebirth of the idea of One Health. His efforts finally flowered in full bloom in the 1st decade of the 21st century, embodied by the wide acceptance of One Health and activities worldwide in response to HPAI H5N1 and other emerging disease threats. Notwithstanding his gargantuan accomplishments and his photographic memory, Jim's singular quality was mentoring. He loved people, especially young people, and for the last 2 decades of his life, everyone was young to Jim. He loved to work with people, and so very many of them became friends. He was an optimist with a sense of humor, and the jokes he made on the occasion of his 100th birthday were too rich to repeat here. He had charisma to the maximum extent, but he was also a hard driving realist who knew how to fund and build programs the world over. He was never too busy, and he truly knew how to listen. Whether the problem was epidemiological or personal, Jim would provide sound advice, oftentimes guiding his mentees towards their own solutions. Jim loved to think and do; he loved to listen and comfort. The list of Jim's "students" included not only those for whom he had acted as a professor at the University of Texas School of Public Health but also so many individuals at CDC and the United States Public Health Service as well as veterinary colleges and the United States Department of Agriculture. The width of the swath cut by Jim's mentees was truly impressive. Bill Foege, the former director of CDC, said at Jim's 90th annual birthday lecture that Jim's seminal contribution was that the health of humans and the health of animals are inseparable. This premise was Jim's greatest gift and allowed us to develop a more rational public health future, because you cannot consider the health of people without considering the health of animals. Dr. Foege finished Jim's 90th birthday address with the following paragraph, which bears repeating now: "And so our tribute to a long life well lived as a generalist, specialist, globalist, futurist, moralist, optimist, and gift giver is mixed with gratitude, gratefulness, and the anticipation of the next decade being the best ever. On behalf of countless generations, yet unborn, we say: Thank you Jim, for this greatest gift." Yes, a lion has roared, and we are all the better for it. -- Peter Cowen ProMED-mail Animal Disease Assistant Moderator