Reemergence of pertussis in the highly vaccinated population of the Netherlands: observations on surveillance data

We analyzed pertussis reporting, death, hospitalization, and serodiagnostic data from 1976 to 1998 to help explain the cause of the 1996 pertussis outbreak in the Netherlands. The unexpected outbreak was detected by an increase in pertussis reporting and by other surveillance methods. In 1996, according to reporting and serologic data, the increase in pertussis incidence among (mostly unvaccinated) children less than 1 year of age was similar to the increase in hospital admissions. Among older (mostly vaccinated) persons, the increase in hospital admissions was relatively small. The increase in pertussis incidence was higher among vaccinated than among unvaccinated persons of all ages. This resulted in lower estimates of vaccine effectiveness. The proportion of pertussis infections resulting in recognizable symptoms may have increased among vaccinated persons because of a mismatch of the vaccine strain and circulating Bordetella pertussis strains. The small immunogenicity profile of the Dutch vaccine may have resulted in greater vulnerability to antigenic changes in B. pertussis.     

Film coated tablets (ColoPulse technology) for targeted delivery in the lower intestinal tract: influence of the core composition on release characteristics

The design of a film coating technology which allows a tablet to deliver the drug in the ileocolonic segment would offer new treatment possibilities. The objective is to develop a platform technology that is suitable for a broad range of drug compounds. We developed a coated tablet with a delayed, pulsatile release profile based on a pH-sensitive coating technology (ColoPulse). The production process was validated, and the effect of core composition on the in vitro release and water uptake investigated. The release profile of the standard tablet core composition, based on the use of cellulose as a filler, was independent of the coat thickness in a range of 9.0-13.2?mg/cm(2). The release profile of a coated tablet was strongly influenced when cellulose was partly replaced by the model substance glucose (loss of sigmoidal release), citric acid (stabilization), sodium bicarbonate (destabilization) or sodium benzoate (destabilization). The film coating takes up water when below the pH-threshold. However, this did not cause early disintegration of the coating. The ColoPulse technology is successfully applied on tablets. The in vitro release characteristics of the coated tablets are influenced by the composition of the core.     

The risk-based approach to ATMP development – Generally accepted by regulators but infrequently used by companies

Advanced therapy medicinal products (ATMPs) are the cutting edge of drug innovation. ATMPs have different challenges than other drug classes. To accommodate these challenges and facilitate science-driven development, flexibility in the requirements to demonstrate the safety and efficacy of this rapidly evolving drug class is necessary. To create flexibility, the European Union introduced the risk-based approach. This approach provides the possibility of omitting guideline-based studies based on risk analyses. To gain insight into the effect of the risk-based approach on the non-clinical development of ATMPs, two questions are addressed in this paper. Firstly, “Do companies use a risk-based approach for the non-clinical development of ATMPs?” and, secondly, “Does the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) accept non-clinical development programs based on the risk-based approach?” Scientific advice letters formulated by the CHMP were analyzed. The risk-based approach was used to justify deviations from the guidelines in the majority (75%) of the cases. The CHMP accepted 40% of the proposals to omit studies and stated that additional data was necessary to make an informed decision for 35% of the proposals. This indicates that the risk-based approach facilitates the science-driven development of ATMPs.     

The sponsored pandemic of the Mexican flu?

The first reports of the New Influenza A (H1N1) spoke of a markedly increased morbidity and mortality. Later it turned out that this flu was a very mild flu. Gradually the role of the WHO was questioned. The definition of a pandemic flu had been changed and there rose doubts about the independency of the experts advising the WHO. It showed that some of these experts had a conflict of interest with the pharmaceutical industry, especially with those producing vaccines and neuraminidase inhibitors. As of june 2010 the WHO declared the outbreak to be a pandemic. This provided the momentum to produce vaccines. At the outbreak of the pandemic in the northern hemisphere, there was sufficient evidence that the pandemic would not be so serious, that a single vaccination was sufficient, that there were strong doubts about the efficacy of oseltamivir and that the drug, although rarely, could have serious side effects. With the stockpiling of neuraminidase inhibitors and with the recommendation of the vaccination political decisions were involved. These decisions should be driven and supported by independent scientific advisory bodies with no room for even the semblance of conflicts of interest. Stronger measures to limit the impact of experts with conflicts of interest on the development of, among others, guidelines are necessary.     

Mineral Status of Myocardial Sarcocystosis

Background

The role of minerals on parasite persistency and the interaction between minerals and animal responses to the parasite infestation is not clear. For these reasons, the present research was aimed to compare copper, zinc and iron status in sheep with parasitic myocarditis and healthy ones in 2009.

Methods

Blood and heart tissue samples were collected from 145 slaughtered sheep and histopathological findings were confirmed as myocardial sarcocystosis in 27 cases. Serum and tissue mineral level were determined by atomic absorption spectroscopy. Data were analyzed by Sigmastat program, using One Way Analysis of Variance (ANOVA) at the level of P<0.05.

Results

Myocardial sarcocystosis significantly increase myocardial concentration of Cu, Zn and Fe (P<0.05).

Conclusion

These findings may explain the role of copper, zinc and iron in parasite persistency and may discuss the pathogenesis of sarcocystosis, which relates to evocate mentioned micronutrient to cardiac muscle.     

应用非每日锥形束CT校位减少摆位误差对鼻咽癌调强放疗剂量影响

目的 探讨应用非每日千伏级锥形束CT(KVCBCT)校位能否改善摆位误差对鼻咽癌调强放疗(IMRT)剂量分布影响。方法 对14例行根治性IMRT的鼻咽癌患者治疗开始后连续5次用KVCBCT检测摆位误差,并将其均值作为系统误差预测值,若其＞1.5 mm则在第6次离线校位。假设通过移床能完全校正系统误差,那么从第6次起实际各方向摆位误差值加上离线校位值可得到未行校位时的摆位误差值,在治疗计划系统中通过等中心移位重新计算剂量来模拟应用非每日校位策略前后摆位误差所致的剂量变化。结果 对10例系统误差预测值＞1.5 mm者摆位误差明显降低了靶区剂量:98％大体肿瘤体积(GTV)所接受剂量(GTV-D98)平均减少3.8Gy(Z=-2.81,P=0.005),原发灶临床靶体积(CTVns) D95( CTVns-D95)平均减少4.8Gy(Z=-1.96,P=0.050),高危CTV1 -D95平均减少1.0Gy(Z=-2.82,P=0.005),低危CTV2-D95减少不明显(Z=-0.13,P=0.900)。应用非每日校位后明显减少了摆位误差的三维方向位移总量,均值从3.6 mm减少为2.6mm(t=2.00,P=0.000),GTV-D98平均增加3.8 Gy(Z=-2.70,P=0.007),CTVns-D95平均增加5.0Gy(Z=-2.15,P=0.030),CTV1 -D95平均增加0.9Gy(Z=-2.80,P=0.005),减少了危及器官剂量增加＞3％、5％患者比例。结论 应用非每日KVCBCT校位能有效减少摆位误差对鼻咽癌IMRT剂量分布的不利影响。     

Effects of chronic injection of sphingomyelin-containing liposomes on lymphoid and non-lymphoid cells in the spleen. Transient suppression of marginal zone macrophages.

Mice were injected with sphingomyelin/cholesterol or phosphatidylcholine/cholesterol (PC/C) liposomes, from twice up to 10 times, on alternate days. Administration of sphingomyelin/cholesterol (SM/C) liposomes gave rise to hepato and splenomegaly, microgranulomatous infections and changes in macrophage numbers and activity in spleen and liver. Enzyme and immuno-cytochemical methods were used, to demonstrate the effect of liposomes on the lymphoid and non-lymphoid cell populations, on cryostat sections of the spleen. Routine histological staining, of sphingomyelin/cholesterol treated animals, showed no drastic changes in morphology or compartmentalization of the spleen, apart from a small enlargement (with some microgranulomas) of the red pulp. No significant differences were found in the presence or localization of T-helper, T-cytotoxic/suppressor, T-total-lymphocytes, B-total-lymphocytes, red pulp macrophages, marginal metallophils, or non-lymphoid dendritic cells. However, a transient suppression of cells expressing marginal zone macrophage surface marker ERTR-9, was observed between the second and eighth (intravenous) administration of sphingomyelin/cholesterol liposomes. Immunization of these animals with trinitrophenyl (TNP)-ficoll, a thymus-independent type-2 antigen which is specifically processed by marginal zone macrophages (MZM), showed that these cells were not suppressed with regard to their immunological function. We conclude that chronic administration of sphingomyelin liposomes influences macrophages, probably through a general phagocytic-system overload, but not permanent or damaging changes in splenic cell populations or immunological functions occur.     

Enhanced leukocyte binding by intestinal microvascular endothelial cells in inflammatory bowel disease

BACKGROUND & AIMS: Microvascular endothelial cells mediate leukocyte homing, angiogenesis, and inflammation and healing and show tissue- specific adhesion molecules and functions. The activation of human intestinal mucosal microvascular endothelial cells (HIMECs) was studied in vitro to uncover possible abnormalities associated with inflammatory bowel disease. METHODS: HIMECs were isolated from normal and inflammatory bowel disease mucosa and assessed for phenotypic and morphological features, proliferative response, leukocyte binding capacity, and adhesion molecule expression. RESULTS: Basal proliferation by HIMECs was less than that of human umbilical vein endothelial cells (HUVECs) but increased proportionally more in response to vascular endothelial growth factor. Proinflammatory stimuli induced an activated, spindle-shaped morphology in HIMEC monolayers. Compared with HUVECs, unstimulated HIMECs showed less adhesiveness for U937 and MOLT4 cells and neutrophils, but cytokines and lipopolysaccharide substantially increased the binding capacity of HIMECs. HIMECs derived from inflammatory bowel disease mucosa showed a markedly greater leukocyte-binding capacity than normal mucosal HIMECs. Patterns of intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and E-selectin messenger RNA expression were distinct in HIMECs, HUVECs, and mucosal mesenchymal cells. CONCLUSIONS: HIMECs represent differentiated endothelial cells with unique functional properties. Their dramatically enhanced capacity to bind leukocytes in inflammatory bowel disease suggests that HIMECs play an important role in initiating or maintaining inflammation. (Gastroenterology 1997 Jun;112(6):1895-907)     

Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferon-gamma in the serum of patients with septic shock. Swiss-Dutch J5 Immunoglobulin Study Group

Serum concentrations of immunoreactive tumor necrosis factor/cachectin (TNF), interleukin-1 beta (IL-1 beta), interferon-gamma (IFN gamma), and interferon-alpha (IFN alpha) were prospectively measured in 70 patients with septic shock to determine their evolution and prognostic values. In a univariate analysis, levels of TNF (P = .002) and IL-1 beta (P = .05) were associated with the patient's outcome, but not IFN alpha (P = .15) and IFN gamma (P = .26). In contrast, in a stepwise logistic regression analysis, the severity of the underlying disease (P = .01), the age of the patient (P = .02), the documentation of infection (nonbacteremic infections vs. bacteremias, P = .03), the urine output (P = .04), and the arterial pH (P = .05) contributed more significantly to prediction of patient outcome than the serum levels of TNF (P = .07). After 10 days, the median concentration of TNF was undetectable (less than 100 pg/ml) in the survivors, whereas it remained elevated (305 pg/ml, P = .002) in the nonsurvivors. Thus, in patients with septic shock due to various gram-negative bacteria, other parameters than the absolute serum concentration of immunoreactive TNF contributed significantly to the prediction of outcome.