T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer's disease-like cerebral amyloidosis.

Cerebral beta-amyloidosis, one of the pathological hallmarks of Alzheimer's disease (AD), elicits a well-characterised, microglia-mediated local innate immune response. In contrast, it is not clear whether cells of the adaptive immune system, in particular T-cells, react to cerebral amyloidosis in AD. Even though parenchymal T-cells have been described in post-mortem brains of AD patients, it is not known whether infiltrating T-cells are specifically recruited to the extracellular deposits of beta-amyloid, and whether they are locally activated into proliferating, effector cells upon interaction with antigen-presenting cells (APCs). To address these issues we have analysed by confocal microscopy and flow-cytometry the localisation and activation status of both T-cells and APCs in transgenic (tg) mice models of AD-like cerebral amyloidosis. Increased numbers of infiltrating T-cells were found in amyloid-burdened brain regions of tg mice, with concomitant up-regulation of endothelial adhesion molecules ICAM-1 and VCAM-1, compared to non-tg littermates. The infiltrating T-cells in tg brains did not co-localise with amyloid plaques, produced less interferon-gamma than those in controls and did not proliferate locally. Bona-fide dendritic cells were virtually absent from the brain parenchyma of both non-tg and tg mice, and APCs from tg brains showed an immature phenotype, with accumulation of MHC-II in intracellular compartments. These results indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local antigen presentation and T-cell activation. The inability of the brain immune surveillance to orchestrate a protective immune response to amyloid-beta peptide might contribute to the accumulation of amyloid in the progression of the disease.

Is there a need for postoperative follow-up after routine urogynaecological procedures? Patients will self-present if they have problems.

INTRODUCTION AND HYPOTHESIS: The value of outpatient appointments for postoperative review has been questioned for many years, and the surgeon practice around this issue is varied. The aim of this study, as part of a larger study assessing postoperative follow-up, was to assess how many patients self-present to their general practitioner (GP) or the emergency department after surgery for urogynaecology procedures. METHODS: A retrospective observational study of postoperative urogynaecology patients between 2007 and 2012 was performed using the British Society of Urogynaecology (BSUG) database to identify patients. These records were correlated with hospital and GP records to assess whether any patient was seen postoperatively for a procedure-related problem. RESULTS: There were 244 patients with complete data on the BSUG database, of whom 25 (10 %) presented to hospital/secondary care in the year following their surgery; only three of these were admitted for problems related to their surgery. There was a response rate of 70 % from GPs for access to their records. This represented 171 patients, 90 of whom (52.3 %) presented to their GP within a year of surgery mostly for a minor procedure-related event: 11 of these were re-referred to secondary care, and the remainder were treated in the community. CONCLUSIONS: The most important aspect of patient care is safety, and this should not be compromised if, for example, postoperative review were to be moved to primary care. As expected, this study shows that patients will self-present if they have problems postoperatively.

Inflammatory Myeloradiculitis Secondary to Pembrolizumab: A Case Report and Literature Review.

Immune checkpoint inhibitors are the most important new medications in oncology and include inhibitors of programmed cell death protein-1 (PD-1) such as Pembrolizumab, Nivolumab, and Cemiplimab. These anticancer agents prevent tumour immune evasion and have been associated with a range of immune-related adverse events (irAEs) including those involving the nervous system. In this case report and literature review, we present the first case of inflammatory myeloradiculitis secondary to Pembrolizumab. We also summarise the characteristics, treatment, and outcomes of other cases reported in the literature which include a component of myelitis. Finally, we make general recommendations on management.

Ethical issues in funding research and development of drugs for neglected tropical diseases.

Neglected and tropical diseases, pervasive in developing countries, are important contributors to global health inequalities. They remain largely untreated due to lack of effective and affordable treatments. Resource-poor countries cannot afford to develop the public health interventions needed to control neglected diseases. In addition, neglected diseases do not represent an attractive market for pharmaceutical industry. Although a number of international commitments, stated in the Millennium Development Goals, have been made to avert the risk of communicable diseases, tropical diseases still remain neglected due to delays in international assistance. This delay can be explained by the form international cooperation has generally taken, which is limited to promoting countries' national interests, rather than social justice at a global level. This restricts the international responsibility for global inequalities in health to a humanitarian assistance. We propose an alternative view, arguing that expanding the scope of international cooperation by promoting shared health and economic value at a global level will create new opportunities for innovative, effective and affordable interventions worldwide. It will also promote neglected diseases as a global research priority. We build our argument on a proposal to replace the patenting system that currently regulates pharmaceutical research with a global fund to reward this research based on actual decreases in morbidity and mortality at a global level. We argue that this approach is beneficent because it will decrease global health inequalities and promote social justice worldwide.

Comparison of health care financing in Egypt and Cuba: lessons for health reform in Egypt.

Egypt and Cuba are both lower-middle income countries with a history of socialist rule, which have embarked on economic liberalization since the 1990s. Cuba has achieved exemplary health status whereas health status in Egypt is lower than could be expected for its level of income. In this article, health care financing mechanisms in both countries are analysed on their effectiveness, efficiency, and equity, with the objective of identifying the determinants of success in the Cuban health system from which valuable lessons for current health reforms in Egypt may be derived.

NGF content in the cerebral cortex of non-demented patients with amyloid-plaques and in symptomatic Alzheimer's disease.

There is increasing evidence that in Alzheimer's disease nerve growth factor (NGF) protein and NGF mRNA content in postmortem cortex is not decreased, but may even be elevated although the NGF-sensitive cholinergic basal forebrain neurons are preferentially affected. However, only little is known about the early pathophysiological events leading to Alzheimer's disease. We therefore measured the post-mortem NGF concentrations in temporal and frontal cortex of Alzheimer's disease patients, non-demented controls without Alzheimer's disease-related pathology, as well as non-demented patients with beta A4 plaques who might be classified as 'preclinical' cases. In the Alzheimer's disease group we found up to 43% increase in NGF concentrations in the frontal and temporal cortex as compared to the two other groups. In a subgroup analysis of the non-demented patients with plaques, NGF concentrations were lower in the frontal cortex when beta A4 plaques were present (46% of the control temporal area) than in patients without evidence of frontal plaques (81% of the control temporal area). This NGF decrease was paralleled to a similar decrease of choline acetyltransferase activity, which is regulated by NGF in the cholinergic basal forebrain. These findings support the hypothesis of lower cortical NGF content at the onset of plaque formation and of elevated NGF levels in the clinically manifest and neuropathologically advanced stage of the disease.

Increase of hypoxic tolerance in rat hippocampal slices following 3-nitropropionic acid is not mediated by endogenous nerve growth factor.

Chemical preconditioning with low dose inhibition of succinic dehydrogenase by 3-nitropropionic acid (3-np) increases tolerance against succeeding hypoxia. Supraphysiological doses of nerve growth factor (NGF) repeatedly were shown to protect against ischemic damage. We investigated whether increased tolerance against hypoxia results from increased or accelerated production of endogenous NGF. Average recovery of population spike amplitude after 15 min of hypoxia and 45 min of reoxygenation was 31 +/- 9% (mean +/- SE) in control hippocampal slices. After pretreatment with 3-np (single i.p. injection of 20 mg/kg body weight 1 h to 3 days prior to slice preparation), recovery exceeded 90% (P < 0.01). However, NGF content did not increase upon slice preparation, hypoxia in vitro, and pretreatment with 3-np in vivo 1 h to 1 day prior to slice preparation with and without additional hypoxia in vitro. We conclude that early-onset tolerance to hypoxia induced by 3-np treatment is not caused by induction of endogenous NGF production.

Cu,Zn SOD in German families with ALS.

We studied the gene for Cu,Zn SOD in 15 German patients with familial ALS and did not find any mutation. Activity of the enzyme and its expression at the protein level was also normal in each patient and in 18 patients suffering from the sporadic form of ALS.

Multicenter field trial on possible health effects of toluene. I. Toluene body burdens in workers of the rotogravure industry.

Ambient air toluene concentrations as well as corresponding individual blood toluene levels were measured under conditions of a field trial, as basis for a correlation with possible acute effects. While the results of various psycho-physiological and medical evaluations after acute (Neubert et al., 2001) and long-term toluene exposure (Gericke et al., 2001) are published in accompanying papers, this publication deals with the exposure levels and body burdens characteristic of workers in the rotogravure industry in Germany at the time of the investigation (1993-1995). Besides providing some information on the exposure at various work-areas under occupational conditions, the correlation between a time-weighted average of the ambient air concentration with the corresponding blood toluene levels is analyzed. Limitations of such an attempt and possible pitfalls are discussed. In the largest field study so far performed on toluene exposure, 12 companies of the German rotogravure industry (and a total of 1528 volunteers) participated. Altogether, complete data sets, i.e. on both ambient air as well as blood toluene levels, were obtained from 1244 male and 124 female participants of the rotogravure industry with quite different degrees of toluene exposure. Rotogravure printers and their helpers were exposed to the highest toluene concentrations in ambient air. On the day of the evaluation, of 806 male volunteers within this group (of 1261 with verified exposure in air), 35 were exposed to a time-weighted average of 100 ppm (i.e. 375 mg/m(3)) or above, and 155 of the printers to concentrations between 50 and 100 ppm. Of the remaining 455 male participants of the rotogravure factories ('non-printers and helpers'), only three were exposed to toluene concentrations above 50 ppm. Only one of the 124 women working in the rotogravure factories was exposed to an average toluene concentrations above 100 mg/m(3) (i.e. 27 ppm). In 66 of the male volunteers toluene levels in blood of >850 microg/l were measured and 14 showed levels exceeding 1700 microg/l. When attempting to predict the resulting individual blood toluene levels from measurements of ambient air concentrations under field conditions, a considerable uncertainty is to be expected. We found a correlation coefficient of the regression curve of about 0.70, with numerous outliers (and a variation of the 12 factories between 0.52 and 0.88).

Multicenter field trial on possible health effects of toluene. III. Evaluation of effects after long-term exposure.

In rotogravure industry, contributing considerably to mass color printing of catalogues and magazines, toluene is still extensively used as paint solvent, and many printers have been exposed to this chemical for several decades. Information on adverse health effects associated with long-term toluene exposure is still controversial. In a multi-center study, adverse health effects possibly associated with long-term toluene exposure were evaluated. In 12 rotogravure factories, 1226 male volunteers were recruited, and sufficient information on exposure and on medical data was compiled for about 1077 of them. Evaluations included: physical examination, standard tests of psycho-physiological and psycho-motoric performances, self-report of subjective symptoms, and data on a variety of laboratory blood tests. The medical data were correlated with the length (months) of toluene exposure, and a rough estimate of the extent of exposure (i.e. highly exposed printers and their helpers versus employees working at locations with low or negligible toluene exposure). A small reference group (n=109) was selected from companies of the paper industry. When linear regression curves were calculated (test results versus duration of exposure), extremely low overall coefficients of determination (r(2) adj.) of a few percent were estimated within the data clouds, with sometimes statistically significant P-values. Closer analyses revealed a strong influence of the confounding factor age, no clustering of abnormal values of highly toluene-exposed volunteers, and the vast majority or all values of the highly and long-term toluene-exposed participants staying within the reference ranges. Thus, no medical relevance of P-values <0.05 could be recognized in this evaluation, and there may have been some border-line deviations or results largely occurring by chance in the large trial. In a small cluster of the many rotogravure printers toluene-exposed for more than 20 years, the highest systolic blood pressure values of the study were found, but many possible confounding factors were not taken into account. Data on acute exposure and possible effects are presented in accompanying papers (Neubert et al., 2001a, Neubert et al., 2001b). Restricting the conclusions to the end points evaluated as well as the apparent limitations of the evaluation, no evidence was found that long-term occupational toluene exposure extending over several decades in the rotogravure industry in the Western part of Germany was convincingly associated with chronic adverse health effects or convincingly altered surrogate markers in still working male volunteers. Several peculiarities and pitfalls arising when interpreting medical data associated with such a type of environmental exposure must be considered. Reversibility of alterations previously induced at higher levels of toluene-exposure, as well as a healthy workers effect, cannot be excluded for some of the medical end points evaluated.

Multicenter field trial on possible health effects of toluene. II. Cross-sectional evaluation of acute low-level exposure.

Data on possible acute effects of today's relevant low-level exposure to toluene are contradictory, and information on possible effects of exposure under occupational conditions is largely lacking. In a controlled, multi-center, blinded field trial, effects possibly associated with acute toluene exposure were evaluated in workers of 12 German rotogravure factories. Medical examinations (inquiries on subjective symptoms, and standard tests of psycho-physiological and psycho-motor functions) were performed on almost 1500 volunteers, of whom 1290 were toluene-exposed (1178 men and 112 women), and about 200 participants served as references (157 men and 37 women), but the main aim of the trial was to reveal dose-response relationships. All volunteers were of the morning work-shift (6 h exposure). Both individual ambient air concentrations (time-weighted average) during the work-shift, as well as blood toluene concentrations after the work-shift were measured. Therefore, the medical data could for the first time be correlated with the actual individual body burden (blood toluene level) at the time of testing. In order to largely exclude confounding by chronic toluene exposure, kinetic measurements as well as the psycho-physiological and psycho-motoric tests were performed before and after the work-shift. Except for minor statistical deviations, neither convincing dose-dependent acute effects could be demonstrated with regression analyses in male volunteers at the exposure levels evaluated, nor were significant differences found when applying group statistics (highly toluene-exposed group versus volunteers with negligible exposure). Due to the rather large number of participants, the predictive power of the study is high, especially when compared with previous publications. In two psycho-physiological tests, a few more female volunteers with quite low toluene body burdens (<340 microg/l blood) showed relatively low scores when compared with participants of the reference group. Although evidence for a medical relevance is meager, the small numbers of participants, in both the exposure and the reference groups, hamper a reliable interpretation of the results concerning exposure levels above 85 microg toluene/l blood, and it is difficult to take confounding factors adequately into account. For the end points evaluated and under occupational conditions, neither blood toluene levels of 850 to 1700 microg/l (in the highest exposure group [EXPO-IV] with 56 participants), as measured 1/2 (+/-1/2) h after the work-shift, nor ambient air concentrations (time-weighted average over 6 h) between 50 and 100 ppm (188-375 mg/m(3)) were convincingly associated with alterations in psycho-physiological and psycho-motoric performances or increased the frequency of subjective complaints in male volunteers. For higher dose ranges of toluene exposure (i.e. >1700 microg toluene/l blood [or >100 ppm in ambient air]), our data set is too small for far reaching conclusions. Our data are insufficient for conclusions on a possibly higher susceptibility to toluene of some female workers. Results of kinetic studies and possible effects of long-term exposure are discussed in two accompanying publications (Neubert et al., 2001; Gericke et al., 2001).

Efficacy of lamotrigine in idiopathic generalized epilepsy syndromes: a video-EEG-controlled, open study.

PURPOSE: This prospective, open, video-EEG-controlled study examined the efficacy of lamotrigine (LTG) as add-on and monotherapy in idiopathic generalized epilepsy (IGE). METHODS: 47 patients received LTG either because of insufficient seizure control (n = 35) or serious side effects of prior antiepileptic drugs (AED). Long-term video-EEG recordings were performed before and after the introduction of LTG. The mean follow-up time was 25.5 months. RESULTS: Of 12 patients with refractory childhood absence epilepsy, 9 became seizure free; in one child with absences with eyelid myoclonia, absence frequency was reduced > 50%; in 2 children with absences with a mild atonic component, seizure reduction was only transient. Of 12 patients with juvenile absence epilepsy, 10 became seizure-free and, in 2, a > 50% reduction was obtained. In 15 patients with juvenile myoclonic epilepsy, complete seizure control was achieved in 7 patients, in 6 patients myoclonia persisted. In one patient generalized tonic-clonic seizures also persisted and another patient developed a rash, LTG was therefore stopped. Of 5 patients with grand-mal on awakening, 3 became seizure-free, and a reduction of > 50% was obtained in one patient; LTG was stopped in one patient because of poor compliance. Three patients with pure photosensitive epilepsy became seizure-free. At the end of the study, 11 patients were seizure-free on LTG monotherapy, and in most other patients concomitant AED dosage could be substantially reduced. CONCLUSIONS: Lamotrigine was effective and well tolerated in patients with various IGE syndromes, although differences were observed between individual syndromes and seizure types.

[Perception of natural orifice surgery. Results of a survey of female physicians and nursing staff]. / Perzeption der "natural orifice surgery". Ergebnisse einer Umfrage bei weiblichem Ärzte- und Pflegepersonal.

BACKGROUND: Natural orifice surgery (NOS) is now being elaborated with the aim to make abdominal surgery simpler and safer. In order to obtain women's perception of NOS and their willingness to consent to this type of approach a survey was conducted among female employees from surgical disciplines at the University Hospital Charité Berlin. MATERIAL AND METHODS: A written description and information on minimally invasive surgery and the NOS concept were distributed among 500 female physicians and nursing staff along with a 14-item questionnaire. Of the staff members 118 participants completed the questionnaire anonymously. Data analysis was carried out using SPSS 16.0. RESULTS: With regard to ovarectomy 55% of women surveyed indicated that they would prefer a transvaginal approach to standard laparoscopy (44%) or a transgastric approach (1%). When asked about preferred access for cholecystectomy only 31% would prefer the transvaginal method compared to 61% for the laparoscopic technique. Objections against the transvaginal access concerned the impact on a healthy sexual life and effects on fertility. Reasons for choosing NOS were no wound pain and no scar. CONCLUSION: This survey shows that among the surveyed female medical employees the transvaginal approach is associated with concerns and fears but these are not justifiable, as the transvaginal access has been used for more than 100 years for gynecological purposes. There is a strong need for outcome data to enlighten female patients and to help guide physicians when talking to patients regarding NOS and the transvaginal approach.

Drug prescription patterns in schizophrenia outpatients: analysis of data from a German health insurance fund.

INTRODUCTION: The aim of this study was to investigate routine administrative data from a major German health insurance fund, Techniker Krankenkasse, which covers 5.4 million insured individuals. Using a retrospective cohort design, this study analysed data collected from patients with a hospital diagnosis of schizophrenia in 2003 (index hospitalisation) in order to evaluate prescription patterns of antipsychotic drugs. METHODS: Patients with an ICD-10 diagnosis of schizophrenia, at least one year prior membership with the insurance fund and a follow-up period of one year were identified. Results were standardised by age and stratified by the severity of their illness, defined by the number of hospital bed days during the three years preceding the index hospitalisation. RESULTS: A total of 3,121 patients with schizophrenia (male 56.4%, female 43.6%) received 56 692 single prescriptions of antipsychotics. Of these, 35.4% of the prescriptions were for typical and 64.6% for atypical antipsychotics; 55% were for high-potency, 45% for low-potency typical antipsychotics. The most frequently prescribed drugs were olanzapine (26.6%), clozapine (21.3%) and risperidone (19%). There were no relevant gender differences concerning prescription patterns. During a 12-month follow-up period after the first hospitalisation, 1 372 patients (43.9%) were treated exclusively with an atypical antipsychotic, another 499 patients (16%) had a combination of an atypical plus a low-potency typical antipsychotic. Thus, basal therapy with an atypical was observed in 59.9% of our study population. Only 327 patients (10.5%) were treated exclusively with a typical antipsychotic. A total of 645 patients (20.7%) were treated with a combination of atypical plus typical antipsychotic. Changes of medication within one substance group occurred more often with typical antipsychotics (50%) as compared to atypical antipsychotics (25%). DISCUSSION: At 60%, the proportion of patients in this study treated with atypical antipsychotics was surprisingly high. Of significant interest is the frequent prescription of clozapine (14%). The results are discussed in comparison to comparable studies from other countries.

[Comparison of the legal basis for health prevention and promotion in the school laws of the federal states in Germany]. / Vergleich der Schulgesetze der Länder der Bundesrepublik Deutschland im Hinblick auf die Verankerung von Prävention und Gesundheitsförderung im Gesetzestext.

BACKGROUND: Health prevention and promotion in schools are key public health tasks in most countries. This study focuses on the importance given to prevention and promotion of health in law texts through comparatively analysing school laws for the sixteen federal states in Germany. MATERIAL AND METHODS: The basis for the analysis are the sixteen federal school laws in Germany. A conceptual framework to analyse the law texts has been developed grouped according to the following categories: aims of literacy and education; development of organization; individual and social health; and security and accident prevention. Examples for second level categories include nutrition, motility, alcohol, violence, and road-traffic accident prevention. Based on a point-system of valuation, a ranking for the federal states was derived in terms of an assessment of the importance of health prevention and promotion in federal states' school laws. RESULTS: Berlin, Brandenburg and Mecklenburg-Vorpommern -- three "new" states (i. e. formerly East-German) are leading the ranking. Bavaria and Baden-Württemberg, two states that had been ruled by conservative governments for a long time, had special difficulties to take over new values in their legislation and occupied rank 14 in our ranking. The last place was taken by a state under social-democratic rule -- Nordrhein-Westfalen. However, this law dated from 1952 and a new law has just been passed in August 2005. CONCLUSION AND DISCUSSION: The comparison of the school laws of the federal states in Germany demonstrates that there has been a substantial amount of change in recent years. In some school laws, the impulses of the Ottawa Charta regarding health prevention can be clearly recognised. In others prevention and promotion of health are only subordinated subjects. As in many other areas of social importance, reorientation is taking place. In particular, federal states who have placed little emphasis on school health will have to renew their corresponding legislation.

Chronic alcohol intoxication in rats leads to a strong but transient increase in NGF levels in distinct brain regions.

Nerve growth factor (NGF), a member of the neurotrophin family, is an essential mediator of neuronal activity and synaptic plasticity of basal forebrain cholinergic neurons. In this study NGF-protein levels were determined in areas of the basal forebrain cholinergic system, its projection areas as well as the striatum and the cerebellum after long-term exposure (6 and 9 months) to ethanol and a phase of withdrawal in male Sprague-Dawley rats. 6-month alcohol treatment led to an increase of NGF to 650-850% of controls in the basal forebrain and the septum and to a 210-485% increase in the cholinergic projection areas (anterior cortex, hippocampus and olfactory bulb). After 9 months exposure to ethanol, a decrease of NGF by 16% in the frontal cortex was observed compared to controls. In the other brain regions no differences in NGF expression were detectable at this time-point. These results support the idea of an endogenous neuroprotective mechanism acting through a transient NGF induction followed by a decrease in NGF-levels during the course of further neuronal degeneration.

Effects of fentin hydroxide on reproduction of the Japanese quail (Coturnix coturnix japonica).

In a one-generation reproductive study, the fungicidal compound triphenyltin hydroxide (fentin) was administered to adult Japanese quail for 6 weeks at dietary levels of 3 and 30 ppm. Reproduction was significantly impaired in the high-dose group. The principal adverse finding was a marked increase in embryonic mortality, resulting in a lower hatch rate. Furthermore, a reduction in egg production was observed with ongoing duration of treatment. Most of the other reproduction-related parameters were not affected. The in ovo losses are assumed to result from a direct toxic effect of the test substance on chick embryos. At the low dietary level, reproduction was not altered. In contrast to the obvious reproductive toxicity, there was only limited evidence of adverse treatment-related findings in the adult birds. However, because such minor effects as an increase in mean liver weight, which was accompanied by macroscopic liver findings and a decrease in T4 serum concentration, were still seen at 3 ppm, a no-observed-effect level could not be established.

Ethical issues in funding orphan drug research and development.

This essay outlines the moral dilemma of funding orphan drug research and development. To date, ethical aspects of priority setting for research funding have not been an issue of discussion in the bioethics debate. Conflicting moral obligations of beneficence and distributive justice appear to demand very different levels of funding for orphan drug research. The two types of orphan disease, rare diseases and tropical diseases, however, present very different ethical challenges to questions about allocation of research funds. The dilemma is analysed considering utilitarian and rights based theories of justice and moral obligations of non-abandonment and a professional obligation to advance medical science. The limitations of standard economic evaluation tools and other priority setting tools used to inform health policy decision makers on research funding decisions are outlined.