Mutation in Nav 1.7 causes high olfactory sensitivity.

Mutations in the sodium-channel Nav 1.7, encoded by the gene SCN9A, are known to cause pain disorders. In particular, gain-of-function missense mutations in Nav 1.7 have been shown to be causal in primary erythromelalgia. We present a patient with erythromelalgia, pain attacks and hyperosmia with a mutation within the sodium-channel gene SCN9A. A 50-year-old woman presented with burning pain in both feet and abdominal pain attacks developed over the course of 10 years. Furthermore, this patient experienced a hypersensitivity for odours. Clinical investigation as well as serum/cerebrospinal fluid laboratory findings and electrophysiological testing were unremarkable. Olfactory testing showed high olfactory acuity for all screened modalities and good intranasal sensitivity. Furthermore, quantitative sensory testing within the trigeminal area revealed very low thresholds for thermal, tactile and pain detection. In addition, quantitative sensory testing at the lower legs showed hyperalgesia and, as the disease progresses, thermal sensory function loss. Skin biopsies of the proximal and distal lower limbs revealed reduced epidermal nerve fibre density indicating small fibre neuropathy. Genetic analysis of the SCN9A gene demonstrated a heterozygous mutation in Exon 20 - c.3734A>G (p.N1245S). Treatment with clinically available sodium-channel inhibitors did not result in significant pain relief. Local application of the sodium-channel blocker ambroxol however, reduced pain intensity. Continuous odour exposure stabilised mood and induced a short-term pain relief. This clinical note illustrates the course of middle-age onset erythromelalgia and points to clinical findings related to a likely pathogenic missense mutation affecting the sodium-channel Nav 1.7. SIGNIFICANCE: This case report illustrates the course of middle-age onset erythromelalgia with presumed gain-of-function in olfactory and pain sensation associated with a Nav1.7 channel mutation.

Reprogramming of mPFC transcriptome and function in alcohol dependence.

Despite its limited immediate reinforcement value, alcohol has a potent ability to induce neuroadaptations that promote its incentive salience, escalation of voluntary alcohol intake and aversion-resistant alcohol seeking. A constellation of these traits, collectively called 'post-dependent', emerges following brain exposure to repeated cycles of intoxication and withdrawal. The medial prefrontal cortex (mPFC) and its subdivisions exert top-down regulation of approach and avoidance behaviors, including those that lead to alcohol intake. Here, we review an emerging literature which indicates that a reprogramming of mPFC function occurs with prolonged exposure of the brain to cycles of alcohol intoxication and withdrawal. This reprogramming results in molecular dysregulations that contribute to the post-dependent syndrome. Convergent evidence has identified neuroadaptations resulting in altered glutamatergic and BDNF-mediated signaling, and for these pathways, direct evidence for a mechanistic role has been obtained. Additional evidence points to a dysregulation of pathways involving calcium homeostasis and neurotransmitter release. Recent findings indicate that global DNA hypermethylation is a key factor in reprogramming the mPFC genome after a history of dependence. As one of the results of this epigenetic remodeling, several histone modifying epigenetic enzymes are repressed. Among these, PR-domain zinc-finger protein 2, a methyltransferase that selectively mono-methylates histone H3 at lysine 9 has been functionally validated to drive several of the molecular and behavioral long-term consequences of alcohol dependence. Information processing within the mPFC involves formation of dynamic neuronal networks, or functional ensembles that are shaped by transcriptional responses. The epigenetic dysregulations identified by our molecular studies are likely to alter this dynamic processing in multiple ways. In summary, epigenetic molecular switches in the mPFC appear to be turned on as alcoholism develops. Strategies to reverse these processes may offer targets for disease-modifying treatments.

Mitochondrial abnormalities in the myofibrillar myopathies.

Myofibrillar myopathies are a genetically diverse group of skeletal muscle disorders, with distinctive muscle histopathology. Causative mutations have been identified in the genes MYOT, LDB3, DES, CRYAB, FLNC, BAG3, DNAJB6, FHL1, PLEC and TTN, which encode proteins which either reside in the Z-disc or associate with the Z-disc. Mitochondrial abnormalities have been described in muscle from patients with a myofibrillar myopathy. We reviewed the literature to determine the extent of mitochondrial dysfunction in each of the myofibrillar myopathy subtypes. Abnormal mitochondrial distribution is a frequent finding in each of the subtypes, but a high frequency of COX-negative or ragged red fibres, a characteristic finding in some of the conventional mitochondrial myopathies, is a rare finding. Few in vitro studies of mitochondrial function have been performed in affected patients.

Resource utilization and productivity loss in persons with spina bifida­an observational study of patients in a tertiary urology clinic in Germany.

BACKGROUND AND PURPOSE: To investigate resource use and burden associated with spina bifida (SB) in Germany. METHODS: A questionnaire was used to obtain information on SB-related healthcare resource use and assistive technologies used for the last 1 and 10 years. Individuals with SB were recruited at a tertiary specialist clinic. To participate, persons with SB required the cognitive ability to respond or a caregiver to answer questions on their behalf. They could use personal medical charts or other records to answer. The analyses included assessment of frequency and extent of resource use for both time frames. RESULTS: Data on 88 persons with a diagnosis of SB were collected (44% female). During the last year, 88.6% (N = 78) reported at least one visit to a general practitioner's (GP's) office, 77.3% (N = 68) to a urologist and 69.3% (N = 61) to a physiotherapist. The annual average number of visits was 7.6 GP, 3.6 urologist and 65.3 physiotherapist visits. Amongst those hospitalized, a single hospitalization lasted 7.3 days on average, whereas the average annual number of hospital days was 14.8 days. During the previous 10 years, 67.0% (N = 59) of responders used a wheelchair, 64.7% (N = 57) used glasses and 59.1% (N = 52) used orthopaedic shoes, with an average of 2.5, 2.8 and 6.1 new items used, respectively. CONCLUSIONS: The results indicate that persons with SB require a substantial amount of interaction with healthcare providers, as well as other healthcare-related resource use, both in the shorter and longer terms.

Coordinated dysregulation of mRNAs and microRNAs in the rat medial prefrontal cortex following a history of alcohol dependence.

Long-term changes in brain gene expression have been identified in alcohol dependence, but underlying mechanisms remain unknown. Here, we examined the potential role of microRNAs (miRNAs) for persistent gene expression changes in the rat medial prefrontal cortex (mPFC) after a history of alcohol dependence. Two-bottle free-choice alcohol consumption increased following 7-week exposure to intermittent alcohol intoxication. A bioinformatic approach using microarray analysis, quantitative PCR (qPCR), bioinformatic analysis and microRNA-messenger RNA (mRNA) integrative analysis identified expression patterns indicative of a disruption in synaptic processes and neuroplasticity. About 41 rat miRNAs and 165 mRNAs in the mPFC were significantly altered after chronic alcohol exposure. A subset of the miRNAs and mRNAs was confirmed by qPCR. Gene ontology categories of differential expression pointed to functional processes commonly associated with neurotransmission, neuroadaptation and synaptic plasticity. microRNA-mRNA expression pairing identified 33 miRNAs putatively targeting 89 mRNAs suggesting transcriptional networks involved in axonal guidance and neurotransmitter signaling. Our results demonstrate a significant shift in microRNA expression patterns in the mPFC following a history of dependence. Owing to their global regulation of multiple downstream target transcripts, miRNAs may have a pivotal role in the reorganization of synaptic connections and long-term neuroadaptations in alcohol dependence. MicroRNA-mediated alterations of transcriptional networks may be involved in disrupted prefrontal control over alcohol drinking observed in alcoholic patients.

[Participation of representatives for patients in the Federal Joint Committee. Results of qualitative interviews]. / Beteiligung von Patientenvertretern im Gemeinsamen Bundesausschuss. Ergebnisse einer qualitativen Befragung.

The GMG (Law Modernizing the German Health Care System) was introduced in 2004. It resulted in considerable changes concerning the possibility for patients to participate in decisions in the German health care system. For the first time representatives of patients in the restructured Federal Joint Committee (G-BA), elected by patients and patient-organizations, were institutionalized by law. In later legislation, this route was further pursued: GKV-WSG and the VAndG of 2007. A previous quantitative study performed by the Institute for Health Economics and Clinical Epidemiology of the University of Cologne in 2006 provided some information on the degree of the involvement of patient representatives in the decision-making process of the G-BA. The present study is an attempt to extend this information by further in-depth interviews. The qualitative interviews of patient representatives in the G-BA unravelled a basic need for improvement of their financial and structural resources. This would lead to consequences in nearly all areas of patient participation--beginning with the quality of the patient representatives' contributions, the role within the G-BA and subsequently their role in public relations. It can be concluded that health politicians can be influenced only gradually in a process of permanent discussions on these issues.

[Participation of patient advocates in decision-making on the regulation of medical services in Germany. The perspective of patient advocates in the Federal Joint Committee and in the Federal Office of Quality Assurance]. / Patientenvertreterbeteiligung an Entscheidungen über Versorgungsleistungen in Deutschland. Die Perspektive der Patientenvertreter im Gemeinsamen Bundesausschuss und der Bundesgeschäftsstelle für Qualitätssicherung.

Since 2004 patient advocates have taken part in counseling on the service catalogue in the Federal Joint Committee and since 2005 on quality assurance of hospital care in the Federal Office of Quality Assurance. The current study provides a first overview on the assessment of patient advocates with their contributions and influence on decisions and the satisfaction of their participation in the committees and boards of the self-governing bodies. There is evidence for necessary improvement both in the preparation for the function as a patient advocate as well as in the transparency of the decision-making in the Federal Joint Committee. The influence of patient advocates on decision-making is regarded as minor. The majority of the patient advocates registered for the Federal Office of Quality Assurance regard their participation as having little influence on the results in the expert committees despite the good possibilities of participation, the high acceptance and great satisfaction with the contribution. There is a vast interest for further on-the-job training. One can assume that further political reforms will result in changing the participation of patient advocates in the self-governing bodies. Therefore far reaching and continuous research to follow the further development of processes and results of participation is recommended.

[1-(11)C]acetate uptake is not increased in renal cell carcinoma.

PURPOSE: The purpose of this study was to investigate the potential of [1-(11)C]acetate (AC) as a metabolic tracer for renal cell cancer in human subjects. METHODS: Twenty-one patients with suspected kidney tumours were investigated with AC and dynamic PET. AC uptake was scored on a five-step scale. Tumour localisation was known from CT/MRI. Histology was available in 18/21 patients. The results in these 18 patients are reported. RESULTS: AC uptake by the tumour was less than (n=11), equal to (n=5) or higher than (n=2) uptake in the surrounding renal parenchyma. Histological tumour types showed a typical distribution, with a predominance of clear cell carcinomas (n=14) and only a small number of papillary cell carcinomas (n=2) and oncocytomas (n=2). Only the benign oncocytomas were highly positive with AC. CONCLUSION: In most kidney tumours the AC accumulation was not higher than in normal kidney parenchyma. Therefore, AC PET cannot be recommend for the characterisation of a renal mass.

Extramedullary blast crisis of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation mimicking aggressive, translocation t(14;18)-positive B-cell lymphoma.

We report the case of a 42-year-old male patient who was diagnosed with a large tumor of the right thoracic aperture 30 months after unrelated hematopoietic stem cell transplantation (HSCT) for accelerated phase of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Biopsy revealed an immature lymphoid neoplasia with blastic tumor cell morphology and immunoreactivity for CD34, CD79a, CD43, and CD30 as well as slight positivity for TdT and CD20. Bcr-Abl rearrangement was found in interphase tumor cell nuclei by fluorescence in situ hybridization (FISH). Furthermore, a translocation t(14;18)(q32;q21) was amplified by polymerase chain reaction (PCR). Bone marrow (BM) examination showed regular hematopoiesis including a negative FISH analysis for Bcr-Abl and complete donor chimerism. Nested PCR from peripheral blood (PB), but not conventional PCR, was positive for the b3a2 Bcr-Abl transcript. Neither radiation nor intensive chemotherapy was capable of achieving a tumor remission, and the patient died from progressive disease 6 months later. Postmortem examinations showed a shift of immunophenotype with appearance of myeloperoxidase-positive tumor cells and loss of lymphoid antigens. In addition, there were characteristic cytogenetic findings of multiple Ph chromosomes and a clonal loss of P53 tumor suppressor gene. The latter was already deleted before HSCT. We conclude that lymphoid neoplasia occurring in our patient should be interpreted as an extramedullary, very immature blast crisis of CML expressing lymphoid differentiation markers rather than a true de novo NHL.

Prognostic significance of advanced neuromonitoring after traumatic brain injury using neural networks.

While the therapeutic impact of tissue oxygenation (PtiO2) supplementing ICP-monitoring is proven by several clinical studies, its prognostic value is not well studied. In the following study artificial neural networks (ANN) were used to analyze the accuracy of outcome prediction after traumatic brain injury (TBI) for different combinations of clinical data and parameters derived from neuromonitoring. The total group included 95 patients suffering from TBI. For all patients clinical data (age, GCS, pupillary response etc.) were recorded and outcome was classified using Glasgow outcome scale after 6 months. In a first step a subgroup of 60 patients was chosen to train a neural network to predict outcome based only on clinical data. In a second step the resting 35 patients all having continuous neuromonitoring with automatic data storage of ICP and PtiO2 were chosen. Different network models were composed using the former clinical model plus up to three additional input units for the following parameters: (a) relative number of ICP > 40 mmHg, (b) relative number of PtiO2 < 5 mmHg and (c) relative number of ICP > 30 mmHg with simultaneous PtiO2 < 10 mmHg. For each model the following time periods were analyzed: day 1-2, day 1-3 and day 1-4 after trauma and additionally day 1-4 after trauma plus last day of neuromonitoring. Pure clinical data allowed to predict outcome with 74.3% accuracy. A combination of clinical data with ICP (a) significantly increased the confidence levels of outcome prediction in all time periods (p < 0.05) with accuracy rates rising up to 82.9% for the longer time periods. The combination of clinical data and ICP & PtiO2 (c) lead to comparable results. In contrast, no significant increases were observed in the early time periods when combining clinical data with PtiO2 (b) while accuracy rates rose up to 80% for extended time periods after trauma. A combination of all parameters lead to results lying between the above results. The results indicate that prediction of outcome can be improved by combining clinical and neuromonitoring data. The prognostic value of ICP might be superior to that of PtiO2.

S100B infusion into the rat hippocampus facilitates memory for the inhibitory avoidance task but not for the open-field habituation.

Adult male Wistar rats were bilaterally implanted with indwelling cannulae in the hippocampus. Forty-eight hours after surgery, animals were habituated to an open-field box during 2 min, being tested 24 h later; next they were trained in a step-down inhibitory avoidance task (3.0 s, 0.4 mA foot-shock), being tested again 24 h later. Immediately after the training session of each task, animals received a 0.5-microl infusion of calcium-phosphate-buffered saline (PBS) and S100B (20, 200, 2000, or 20,000 nM). In the inhibitory avoidance task, animals infused with the two highest concentrations of S100B, 2 and 20 microM, obtained higher scores of retention relative to controls in the test session (p<0.05), and a trend toward an increase was observed in animals infused with 200 nM (p<0. 10). In both sessions of the habituation task, groups were not different regarding crossings, rearings, and time for leaving the first square (p>0.10). These results indicate that, in rats, post-training increased hippocampal levels of S100B right after training facilitate, in a dose-dependent way, long-term memory for an inhibitory avoidance task, but not for an open-field habituation.

Human endothelial cell activation and mediator release in response to the bacterial exotoxins Escherichia coli hemolysin and staphylococcal alpha-toxin.

Escherichia coli hemolysin (HlyA) and Staphylococcus aureus alpha-toxin are membrane-perturbating bacterial exotoxins that have been implicated as significant virulence factors in human diseases. We investigated the capacity of these toxins to cause cell activation and mediator release in human endothelial cells, compared with the efficacies of thrombin and the Ca2+ ionophore A23187. Concentration ranges tested were 1 to 1000 ng/ml (HlyA), 0.01 to 10 micro/ml (alpha-toxin), 0.01 to 10 U/ml (thrombin), and 0.01 to 10 microM (A23187). All stimuli caused dose-dependent generation of platelet-activating factor, nitric oxide, and prostaglandin I2. HlyA and thrombin effected time- and dose-dependent accumulation of large quantities of inositol phosphates, with maximum effects at 100 ng/ml and 1 U/ml, respectively. Corresponding time course and dose dependency were noted for HlyA-elicited diacylglycerol formation. In contrast, only the highest concentrations of alpha-toxin (10 microg/ml) and A23187 (10 microM) effected some moderate inositol phosphate accumulation, and this was suppressed in the presence of the platelet-activating factor antagonist WEB 2086. Metabolic and secretory responses elicited by alpha-toxin were dependent on the presence of extracellular Ca2+. We conclude that both HlyA and alpha-toxin are potent inductors of inflammatory and vasodilatory mediators in human endothelial cells. HlyA-elicited effects may proceed predominantly via activation of the phosphatidylinositol hydrolysis-related signal transduction pathway, whereas transmembrane Ca2+ flux appears to be the major event underlying the release of mediators in response to alpha-toxin. These toxin properties may contribute to vasoregulatory and inflammatory disturbances encountered in states of severe infection and sepsis.

Case-control study on stomach cancer in Germany.

A multicentric hospital-based case-control study was simultaneously performed in a high-risk and a low-risk area for stomach cancer in Germany, 143 patients with incident stomach cancer and 579 controls completing a retrospective interview about life style aspects. Periods of non-centralized water supply or well water as the only source compared to life-long central water supply, and preservation of meat by smoking it with spruce compared to no home smoking of meat, were significantly associated with an increased stomach cancer risk. use of a refrigerator at home for 30 and more years compared to 24 years or less showed an inverse relationship, whereas salt intake estimated by questionnaire showed no relationship to stomach cancer risk. Tobacco smoking was negatively associated with risk for current smokers of cigarettes compared to non-smokers but was presumably not causally related. After adjustment for other food constituents, only increased vitamin C consumption showed an inverse relation to risk. For food groups, increased consumption of fruit, citrus fruit, cheese and whole-meal bread were associated with decreased risk. A similar effect was also seen for increased consumption of raw vegetables. Total vegetable consumption was not particularly associated with risk. Increased consumption of processed meat and of beer showed a positive association with risk whereas increased wine and liquor consumption showed a significant negative association. The association of alcoholic beverages with stomach cancer risk may reflect a particular life style rather than being causally related to risk.

Human intestinal motor activity and transport: effects of a synthetic opiate.

Effects of opiates on intestinal motor activity and transport of water and electrolytes have been studied separately in previous investigations. The aim of these experiments was to evaluate simultaneously the effects of a synthetic opiate, loperamide, on motor activity and transport in the human intestine. Jejunal, ileal, and colonic perfusions were performed in 9 healthy volunteers. After application of loperamide (12 mg), cyclically recurring migrating motor complexes in the small intestine occurred at a significantly higher frequency than after application of placebo. This was primarily due to a decrease in the duration of irregular motor activity (phase II). Loperamide increased the transit time in the jejunum but not in the ileum or in the colon. Transport rates of water and electrolytes and transmural electrical potential differences were not significantly affected by the drug. These results suggest that opiates exert their constipating effect by inhibiting phase II-related irregular motor activity.