BAFF, a Novel Ligand of the Tumor Necrosis Factor Family, Stimulates B Cell Growth

Members of the tumor necrosis factor (TNF) family induce pleiotropic biological responses, including cell growth, differentiation, and even death. Here we describe a novel member of the TNF family, designated BAFF (for B cell activating factor belonging to the TNF family), which is expressed by T cells and dendritic cells. Human BAFF was mapped to chromosome 13q32-34. Membrane-bound BAFF was processed and secreted through the action of a protease whose specificity matches that of the furin family of proprotein convertases. The expression of BAFF receptor appeared to be restricted to B cells. Both membrane-bound and soluble BAFF induced proliferation of anti-immunoglobulin M–stimulated peripheral blood B lymphocytes. Moreover, increased amounts of immunoglobulins were found in supernatants of germinal center–like B cells costimulated with BAFF. These results suggest that BAFF plays an important role as costimulator of B cell proliferation and function

Breast Tumor Cells with PI3K Mutation or HER2 Amplification Are Selectively Addicted to Akt Signaling

Dysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy.A selective allosteric inhibitor of Akt kinase was used to interrogate a panel of breast cancer cell lines characterized for genetic lesions that activate PI3K/Akt signaling: HER2 amplification or PI3K or PTEN mutations in order to determine the biochemical and biologic consequences of inhibition of this pathway. A variety of molecular techniques and tissue culture and in vivo xenograft models revealed that tumors with mutational activation of Akt signaling were selectively dependent on the pathway. In sensitive cells, pathway inhibition resulted in D-cyclin loss, G1 arrest and induction of apoptosis, whereas cells without pathway activation were unaffected. Most importantly, the drug effectively inhibited Akt kinase and its downstream effectors in vivo and caused complete suppression of the growth of breast cancer xenografts with PI3K mutation or HER2 amplification, including models of the latter selected for resistance to Herceptin. Furthermore, chronic administration of the drug was well-tolerated, causing only transient hyperglycemia without gross toxicity to the host despite the pleiotropic normal functions of Akt.These data demonstrate that breast cancers with PI3K mutation or HER2 amplification are selectively dependent on Akt signaling, and that effective inhibition of Akt in tumors is feasible and effective in vivo. These findings suggest that direct inhibition of Akt may represent a therapeutic strategy for breast and other cancers that are addicted to the pathway including tumors with resistant to Herceptin

Selective immunisation strategy to protect newborns at risk for transmission of hepatitis B: retrospective audit of vaccine uptake

BACKGROUND: 90% of newborns infected perinatally will develop chronic hepatitis B infection with the risk of liver cirrhosis or hepatocellular carcinoma. In Switzerland, screening of all pregnant women for hepatitis B virus (HBV) has been recommended since 1983. Neonates at risk for perinatally acquired HBV are passively and actively immunised immediately after birth as well as at 1 and 6 months of age. The objective of this study was to evaluate the proportion of newborns immunised in accordance with the proposed vaccination schedule. METHODS: Patient records of 3997 mothers who gave birth to a liveborn infant during a two-year period at Zürich University Hospital were screened by computer. 128 women were identified as HBsAg positive or anti-HBc alone positive. Of 133 infants born to these mothers, complete data were available for 94 (71%). RESULTS: Immunisation was started in 88 infants (94%), but only in 78 (83%) within the first 24 hours of life. 85 (90%) received the 2nd immunisation but only 72 (77%) within the given time limit. 80 (85%) of the infants received the 3rd immunisation but only 69 (73%) within the correct time limit. In summary, only 51 (54%) of the infants at risk for HBV infection were immunised correctly (immunoglobulin within 24 hours and active prophylaxis at 0, 1 and 6 months). CONCLUSIONS: The success of the immunisation strategy following maternal screening and selective immunisation of newborns at risk for HBV infection is limited for various reasons (lack of screening results at birth, problems with correct documentation and communication). To overcome these drawbacks, selective vaccination strategy should be improved and general vaccination strategy, including infants, should be reconsidered

Biologisch abbaubares Nano-Polymer auf Basis eines Heparansulfatanalogons bei therapierefraktärer Varizellen-Keratitis Biodegradable nano-polymer agent, an analogue of heparan sulfate, in therapy-refractory varicella keratitis

Das Varicella-zoster-Virus (VZV) gehört zur Familie der Herpesviren. Die primäre Infektion mit VZV führt zum Krankheitsbild der Varizellen, die spätere endogene Reaktivierung des Virus aus Spinal- und Hirnnervenganglien, in welchen das Virus nach der Erstinfektion lebenslang in einem latenten Zustand persistiert, zum Krankheitsbild des Herpes zoster.Varizellen sind gewöhnlich eine selbstlimitierende Infektionskrankheit mit harakteristischen Hauterscheinungen, die manchmal mit schweren Komplikationen einhergehen kann [1]. Zu den okulären Komplikationen gehören die Konjunktivitis, Skleritis, Keratitis, Uveitis, Retinitis, Neuritis nervi optici, Katarakt, das Glaukom sowie die internukläre Ophthalmoplegie [1], [2], [3], [4], [5]. Wir präsentieren den Fall eines 8-jährigen Knaben mit einer Varizellen-Keratitis, die unter etablierten Therapieformen einen langwierigen, therapierefraktären Verlauf zeigte und erst nach Anwendung eines neuen biologisch abbaubaren Nano-Polymers (Cacicol20®) ausheilte

Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study

OBJECTIVE: To compare the tolerability of malaria chemoprophylaxis regimens in non-immune travellers. DESIGN: Randomised, double blind, study with placebo run-in phase. SETTING: Travel clinics in Switzerland, Germany, and Israel. MAIN OUTCOME MEASURE: Proportion of participants in each treatment arm with subjectively moderate or severe adverse events. PARTICIPANTS: 623 non-immune travellers to sub-Saharan Africa: 153 each received either doxycycline, mefloquine, or the fixed combination chloroquine and proguanil, and 164 received the fixed combination atovaquone and proguanil. RESULTS: A high proportion of patients reported adverse events, even in the initial placebo group. No events were serious. The chloroquine and proguanil arm had the highest proportion of mild to moderate adverse events (69/153; 45%, 95% confidence interval 37% to 53%), followed by mefloquine (64/153; 42%, 34% to 50%), doxycycline (51/153; 33%, 26% to 41%), and atovaquone and proguanil (53/164; 32%, 25% to 40%) (P = 0.048 for all). The mefloquine and combined chloroquine and proguanil arms had the highest proportion of more severe events (n = 19; 12%, 7% to 18% and n = 16; 11%, 6% to 15%, respectively), whereas the combined atovaquone and proguanil and doxycycline arms had the lowest (n = 11; 7%, 2% to 11% and n = 9; 6%, 2% to 10%, respectively: P = 0.137 for all). The mefloquine arm had the highest proportion of moderate to severe neuropsychological adverse events, particularly in women (n = 56; 37%, 29% to 44% versus chloroquine and proguanil, n = 46; 30%, 23% to 37%; doxycycline, n = 36; 24%, 17% to 30%; and atovaquone and proguanil, n = 32; 20%, 13% to 26%: P = 0.003 for all). The highest proportion of moderate or severe skin problems were reported in the chloroquine and proguanil arm (n = 12; 8%, 4% to 13% versus doxycycline, n = 5; 3%, 1% to 6%; atovaquone and proguanil, n = 4; 2%, 0% to 5%; mefloquine, n = 2; 1%, 0% to 3%: P = 0.013). CONCLUSIONS: Combined atovaquone and proguanil and doxycyline are well tolerated antimalarial drugs. Broader experience with both agents is needed to accumulate reports of rare adverse events

Effects of long-term, self-monitored exercise on the serum lipoprotein and apolipoprotein profile in middle-aged men

To study the effects of long-term, self-monitored exercise on the serum lipid profile and body composition of middle-aged non-smoking males, a controlled study was conducted in 61 sedentary, middle-class Swiss men. Thirty-nine men were randomly allocated to jog 2 h/wk for 4 months on an individually prescribed, heart rate-controlled basis, whereas 22 men served as controls. Despite varying adherence to the exercise regimen, the following 4-month net changes (effect in exercise group minus effect in control group) in lipids were seen: HDL cholesterol (C) +0.12 mmol/l (95% CI 0.02, 0.22; P = 0.028), LDL-C +0.08 mmol/l (ns), VLDL-C -0.26 mmol/l (-0.45, -0.07; P = 0.009), total triglycerides (TT) -0.21 mmol/l (ns), HDL-C/total C +0.02 (0.001, 0.05; P = 0.047). The net changes in endurance capacity and resting heart rate in favour of exercisers were significant as well, whereas no significant changes in apolipoprotein levels were seen. Exploratory analyses revealed, for example, associations of the increase in total physical activity with an increase in the HDL-C/total C ratio (r = 0.46; P less than 0.001), and of the change in estimated body fat content with an opposed change in the HDL-C/total C ratio (r = -0.40; P less than 0.001), or an inverse relationship of the change in subcutaneous fat with a change in the HDL2-C level (r = -0.39; P less than 0.001). Multivariable regression analysis suggested that much of the effect of jogging on HDL-C was apparently mediated through a decrease in body fat content. A change in the waist/hip ratio was unrelated to lipoprotein changes but was related to the change of TT level (r = 0.22; P less than 0.05). This study confirms that individually prescribed, unsupervised jogging can increase HDL-C levels and improve the serum lipoprotein profile in self-selected nonsmoking males. Although the effect is modest, it may be relevant to preventive cardiology, given the evidence for a reduction in cardiovascular risk even after apparently small decreases in risk factor levels