Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial.

BACKGROUND: Aim of the study was assessment of efficacy and safety of transcutaneous stimulation of the auricular branch of the vagal nerve (t-VNS) in the treatment of chronic migraine. METHODS: A monocentric, randomized, controlled, double-blind study was conducted. After one month of baseline, chronic migraine patients were randomized to receive 25 Hz or 1 Hz stimulation of the sensory vagal area at the left ear by a handhold battery driven stimulator for 4 h/day during 3 months. Headache days per 28 days were compared between baseline and the last month of treatment and the number of days with acute medication was recorded The Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires were used to assess headache-related disability. RESULTS: Of 46 randomized patients, 40 finished the study (per protocol). In the per protocol analysis, patients in the 1 Hz group had a significantly larger reduction in headache days per 28 days than patients in the 25 Hz group (-7.0 ± 4.6 vs. -3.3 ± 5.4 days, p = 0.035). 29.4 % of the patients in the 1 Hz group had a ≥50 % reduction in headache days vs. 13.3 % in the 25 Hz group. HIT-6 and MIDAS scores were significantly improved in both groups, without group differences. There were no serious treatment-related adverse events. CONCLUSION: Treatment of chronic migraine by t-VNS at 1 Hz was safe and effective. The mean reduction of headache days after 12 weeks of treatment exceeded that reported for other nerve stimulating procedures.

[Consistency and Reliability of MDK Expertise Examining the Encoding in the German DRG System]. / Einheitlichkeit der richtlinienkonformen Begutachtung durch den Medizinischen Dienst der Krankenversicherung bei der Prüfung der Kodierung im G-DRG-System.

INTRODUCTION: Hospital inpatient stays are reimbursed on the basis of German diagnosis-related groups (G-DRG). The G-DRG classification system is based on complex coding guidelines. The Medical Review Board of the Statutory Health Insurance Funds (MDK) examines the encoding by hospitals and delivers individual expertises on behalf of the German statutory health insurance companies in cases in which irregularities are suspected. A study was conducted on the inter-rater reliability of the MDK expertises regarding the scope of the assessment. METHODS: A representative sample of 212 MDK expertises was taken from a selected pool of 1 392 MDK expertises in May 2013. This representative sample underwent a double-examination by 2 independent MDK experts using a special software based on the 3MTM G-DRG Grouper 2013 of 3M Medica, Germany. The following items encoded by the hospitals were examined: DRG, principal diagnosis, secondary diagnoses, procedures and additional payments. It was analysed whether the results of MDK expertises were consistent, reliable and correct. RESULTS: 202 expertises were eligible for evaluation, containing a total of 254 questions regarding one or more of the 5 items encoded by hospitals. The double-examination by 2 independent MDK experts showed matching results in 187 questions (73.6%) meaning they had been examined consistently and correctly. 59 questions (23.2%) did not show matching results, nevertheless they had been examined correctly regarding the scope of the assessment. None of the principal diagnoses was significantly affected by inconsistent or wrong judgment. CONCLUSION: A representative sample of MDK expertises examining the DRG encoding by hospitals showed a very high percentage of correct examination by the MDK experts. Identical MDK expertises cannot be achieved in all cases due to the scope of the assessment. Further improvement and simplification of codes and coding guidelines are required to reduce the scope of assessment with regard to correct DRG encoding and its examination.

Headache cessation by an educational intervention in grammar schools: a cluster randomized trial.

BACKGROUND AND PURPOSE: Headache is a common health problem in adolescents. There are a number of risk factors for headache in adolescents that are amenable to intervention. The aim of the study was to assess the effectiveness of a low-level headache prevention programme in the classroom setting to prevent these risk factors. METHODS: In all, 1674 students in 8th-10th grade at 12 grammar schools in greater Munich, Germany, were cluster randomized into intervention and control groups. A standardized 60-min prevention lesson focusing on preventable risk factors for headache (physical inactivity, coffee consumption, alcohol consumption and smoking) and providing instructions on stress management and neck and shoulder muscle relaxation exercises was given in a classroom setting. Seven months later, students were reassessed. The main outcome parameter was headache cessation. Logistic regression models with random effects for cluster and adjustment for baseline risk factors were calculated. RESULTS: Nine hundred students (intervention group N = 450, control group N = 450) with headache at baseline and complete data for headache and confounders were included in the analysis. Headache cessation was observed in 9.78% of the control group compared with 16.22% in the intervention group (number needed to treat = 16). Accounting for cluster effects and confounders, the probability of headache cessation in the intervention group was 1.77 (95% confidence interval = [1.08; 2.90]) higher than in the control group. The effect was most pronounced in adolescents with tension-type headache: odds ratio = 2.11 (95% confidence interval = [1.15; 3.80]). CONCLUSION: Our study demonstrates the effectiveness of a one-time, classroom-based headache prevention programme.

Renal Denervation: A New Approach to an Old Problem.

Renal sympathetic hyperactivity is associated with hypertension. Renal denervation is an interventional approach to selectively denervate the renal sympathetic fibers. The reduction of systolic and diastolic blood pressure in patients with resistant hypertension has been demonstrated in the Symplicity HTN-1 and HTN-2 trials. Before the patient undergoes an interventional procedure, causes of secondary hypertension or pseudoresistance must be excluded.

An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice.

AIMS/HYPOTHESIS: Loss of circadian clocks from all tissues causes defective glucose homeostasis as well as loss of feeding and activity rhythms. Little is known about peripheral tissue clocks, so we tested the hypothesis that an intrinsic circadian clock of the pancreas is important for glucose homeostasis. METHODS: We monitored real-time bioluminescence of pancreas explants from circadian reporter mice and examined clock gene expression in beta cells by immunohistochemistry and in situ hybridisation. We generated mice selectively lacking the essential clock gene Bmal1 (also known as Arntl) in the pancreas and tested mutant mice and littermate controls for glucose and insulin tolerance, insulin production and behaviour. We examined islets isolated from mutants and littermate controls for glucose-stimulated insulin secretion and total insulin content. RESULTS: Pancreas explants exhibited robust circadian rhythms. Clock genes Bmal1 and Per1 were expressed in beta cells. Despite normal activity and feeding behaviour, mutant mice lacking clock function in the pancreas had severe glucose intolerance and defective insulin production; their isolated pancreatic islets had defective glucose-stimulated insulin secretion, but normal total insulin content. CONCLUSIONS/INTERPRETATION: The mouse pancreas has an autonomous clock function and beta cells are very likely to be one of the pancreatic cell types possessing an intrinsic clock. The Bmal1 circadian clock gene is required in the pancreas, probably in beta cells, for normal insulin secretion and glucose homeostasis. Our results provide evidence for a previously unrecognised molecular regulator of pancreatic glucose-sensing and/or insulin secretion.

Efficient haemodialysis despite complete central venous thrombosis.

Two cases with a fully functional haemodialysis access, in spite of complete thrombotic occlusion of the ipsilateral subclavian and/or brachiocephalic vein are reported. The coincidentally detected complete venous occlusions may indicate that occult venous stenosis or thrombosis is more frequent than generally assumed. In order to avoid deterioration of the haemodynamic situation interventions may be withheld unless clinical problems related to a diminished outflow occur.

Unusual cause of intermittent claudication.

Spontaneous dissection of a peripheral artery is a rare event. We report a case of a spontaneous, non-atherosclerotic and non-aneurysmal dissection limited to the external iliac artery in a 60-year-old woman who was admitted with a left calf claudication. Non-invasive examination documented signs of leg ischemia due to a floating wall dissection of the external iliac artery. After medical treatment over eight weeks the dissection membrane had been adapted to the vessel wall. A similar case of a spontaneous dissection limited to the external iliac artery, followed by a spontaneous healing has not been reported in the literature.

Anemia in chronic kidney disease and congestive heart failure.

Anemia is seen in chronic kidney insufficiency (CKI), dialysis patients, congestive heart failure (CHF), and renal transplantation. Anemia can lead to progressive cardiac damage as well as progressive renal damage. It is not generally appreciated that CHF itself may be a very common contributor to both the production of anemia as well as to the progression of the renal failure. Correction of the anemia with erythropoietin and, as necessary, intravenous iron, may prevent the deterioration of both the heart and the kidneys. We suggest that there is a triangular relationship, a vicious circle, between CHF, CKI and anemia where each of these three can both cause and be caused by the other. We call this syndrome the cardio-renal anemia (CRA) syndrome. All physicians, especially cardiologists and internists who treat CKI and CHF, should be made aware of the dangers of anemia in CKI and CHF and should work with nephrologists to correct it.

Antimycin A resistance in a mutant Leishmania tarentolae strain is correlated to a point mutation in the mitochondrial apocytochrome b gene.

In this paper we report the first case of antimycin A resistance in a protozoan parasite that is attributable to a mutation in the mitochondrial apocytochrome b (CYb) gene. We selected for, and isolated, a mutant Leishmania tarentolae strain that is resistant to antimycin A. This resistance was evident at the levels of the in vitro growth and enzymatic activity of the cytochrome bc1 complex. Molecular characterisation of the mutant revealed a Ser35Ile mutation in the expected region of the CYb gene. In kinetoplastids, CYb and other structural genes of the mitochondrial genome are located on the maxicircle component of the mitochondrial DNA, which is present in 20-50 copies. Primer-extension analysis confirmed the presence of the mutation at the mRNA level. The phenotypic manifestation of the mutation implies that the CYb mRNA is edited and translated within the mitochondrion. Thus, this finding provides direct evidence that edited RNAs are translated in kinetoplastid mitochondria. Furthermore, a defined mutation conferring drug resistance to a mitochondrial gene product can be exploited for the development of mitochondrial transfection systems for trypanosomatids.

The use of transgenic Trypanosoma brucei to identify compounds inducing the differentiation of bloodstream forms to procyclic forms.

The expression of procyclins is the earliest known marker of differentiation of bloodstream forms of Trypanosoma brucei to procyclic forms. We have generated transgenic bloodstream and procyclic forms in which the coding region of one procyclin gene was replaced by E. coli beta-glucuronidase (GUS). GUS activity can be monitored in a simple one-step colour reaction in microtitre plates; this assay is potentially suitable for large-scale screening for compounds that influence differentiation. GUS was stage-specifically expressed in procyclic forms and its synthesis occurred in parallel with that of procyclin when bloodstream forms were triggered to differentiate by the addition of cis-aconitate. GUS could also be induced by brief treatment with the proteases trypsin, pronase or thermolysin, but not with pepsin or thrombin. Interestingly, a combination of one of the active proteases with cis-aconitate resulted in increased GUS activity relative to either trigger alone. In contrast to cis-aconitate, protease treatment resulted in considerable cell death. Experiments with the pleomorphic strain AnTat 1.1 showed that long slender bloodstream forms were rapidly killed by proteases, whereas stumpy forms were largely resistant. Stumpy forms treated with trypsin differentiated synchronously and expressed procyclin with faster kinetics than when they were triggered by cis-aconitate. As predicted by the GUS assay, differentiation was even more rapid when both inducers were used simultaneously, with all cells expressing maximal levels of procyclin within 3 h.

Evaluation of laser doppler flowmetry for the study of benign and malignant gastric blood flow in vivo.

BACKGROUND: Tumour vascularisation is a determinant of the development of metastases. AIMS: To measure blood flow in normal stomach and gastric adenocarcinomas by laser Doppler flowmetry and correlate blood flow with vascularisation after immunohistochemical staining of resected specimens for CD31 and von Willebrand factor. PATIENTS: Twenty two undergoing resection for gastric adenocarcinoma and 10 undergoing cholecystectomy. RESULTS: Mean (SD) gastric blood flow was 208 (35) perfusion units (PU) in patients undergoing cholecystectomy and 190 (75) PU in the undiseased part of the stomach in patients with gastric adenocarcinoma. Gastric blood flow was higher in the border of gastric adenocarcinomas (322 (120) PU, p<0.01 v normal stomach) but lower in the centre (74 (27) PU, p<0.01 v normal stomach and tumour border). Blood flow was higher in tumours staged T>/=3 than in those staged T<3. Blood vessel density in normal stomach was 41 (8) stained cells/field viewed and was 1. 9-3.4 times higher in gastric adenocarcinomas. CONCLUSION: Laser Doppler flowmetry is a valuable tool for studying the pathophysiological alterations of malignant blood flow in the human stomach in vivo.

Suicide by cop.

STUDY OBJECTIVE: "Suicide by cop" is a term used by law enforcement officers to describe an incident in which a suicidal individual intentionally engages in life-threatening and criminal behavior with a lethal weapon or what appears to be a lethal weapon toward law enforcement officers or civilians to specifically provoke officers to shoot the suicidal individual in self-defense or to protect civilians. The objective of this study was to investigate the phenomenon that some individuals attempt or commit suicide by intentionally provoking law enforcement officers to shoot them. METHODS: We reviewed all files of officer-involved shootings investigated by the Los Angeles County Sheriff's Department from 1987 to 1997. Cases met the following criteria: (1) evidence of the individual's suicidal intent, (2) evidence they specifically wanted officers to shoot them, (3) evidence they possessed a lethal weapon or what appeared to be a lethal weapon, and (4) evidence they intentionally escalated the encounter and provoked officers to shoot them. RESULTS: Suicide by cop accounted for 11% (n=46) of all officer-involved shootings and 13% of all officer-involved justifiable homicides. Ages of suicidal individuals ranged from 18 to 54 years; 98% were male. Forty-eight percent of weapons possessed by suicidal individuals were firearms, 17% replica firearms. The median time from arrival of officers at the scene to the time of the shooting was 15 minutes with 70% of shootings occurring within 30 minutes of arrival of officers. Thirty-nine percent of cases involved domestic violence. Fifty-four percent of suicidal individuals sustained fatal gunshot wounds. All deaths were classified by the coroner as homicides, as opposed to suicides. CONCLUSION: Suicide by cop is an actual form of suicide. The most appropriate term for this phenomenon is law enforcement-forced-assisted suicide. Law enforcement agencies may be able to develop strategies for early recognition and handling of law enforcement-forced-assisted suicide (suicide by cop). Health care providers involved in the evaluation of potentially suicidal individuals and in the resuscitation of officer-involved shootings should be aware of law enforcement-forced-assisted suicide as a form of suicide.

In vivo import of unspliced tRNATyr containing synthetic introns of variable length into mitochondria of Leishmania tarentolae.

The mitochondrial genomes of trypanosomatids lack tRNA genes. Instead, mitochondrial tRNAs are encoded and synthesized in the nucleus and are then imported into mitochondria. This also applies for tRNATyr, which in trypanosomatids contains an 11 nt intron. Previous work has defined an exon mutation which leads to accumulation of unspliced precursor tRNATyr. In this study we have used the splicing-deficient tRNATyr as a vehicle to introduce foreign sequences into the mitochondrion of Leishmania tarentolae. The naturally occurring intron was replaced by synthetic sequences of increasing length and the resulting tRNATyr precursors were expressed in transgenic cell lines. Whereas stable expression of precursor tRNAsTyr was obtained for introns up to a length of 76 nt, only precursors having introns up to 38 nt were imported into mitochondria. These results demonstrate that splicing-deficient tRNATyr can be used to introduce short synthetic sequences into mitochondria in vivo. In addition, our results show that one factor which limits the efficiency of import is the length of the molecule.

PET with 18fluorodeoxyglucose and hexamethylpropylene amine oxime SPECT in late whiplash syndrome.

BACKGROUND: Many patients have cognitive abnormalities and psychological problems after whiplash injury to the cervical spine. To our knowledge, neuroradiologic imaging has not depicted brain damage that explains the symptoms. Parietotemporo-occipital perfusion deficits on hexamethylpropylene amine oxime (HMPAO) SPECT studies have been described among patients who have sustained whiplash injury. METHODS: We examined 13 patients with typical late whiplash syndrome (study group) using HMPAO SPECT, 18fluorodeoxyglucose (FDG) PET, and MRI of the brain and compared the findings with those for 16 control subjects who underwent FDG PET. RESULTS: In the study group, statistical parametric mapping revealed significantly decreased FDG uptake in the frontopolar and lateral temporal cortex and in the putamen. The frontopolar hypometabolism correlated significantly with scores of the Beck Depression Inventory. However, in individual cases, reliability in the depiction of hypometabolic areas was relatively low. No alterations were found in the parietotemporo-occipital area. In these areas, decreased uptake of HMPAO and FDG correlated with cortical mass. CONCLUSION: FDG PET did not allow reliable diagnosis of metabolic disturbances for individual patients. Therefore, we do not recommend FDG PET or HMPAO SPECT as a diagnostic tool in routine examinations of patients with late whiplash syndrome.

A brief history of work expectations for welfare mothers.

The best known of the nation's welfare programs, Aid to Families with Dependent Children (AFDC), has from its inception reflected a tension between the desire to support children in poor, lone-parent families and the belief that parents should be held responsible for providing for themselves and their children. Against that backdrop, this article reviews the history of the AFDC program and traces the emergence of policies and programs intended to encourage employment of the parents (almost exclusively mothers) who receive benefits. The article examines in detail the Work Incentive Program (WIN) launched in 1967 and the Family Support Act of 1988, comparing these to each other and to the outlines of welfare reform signed into law in 1996. The article emphasizes the importance of sustained attention to the implementation of policy goals in concrete programs and shows that the merits of those early programs have not been fully tested because they were never funded or implemented at the scale intended. The article also outlines ways in which welfare-to-work programs can be used to assist children as well as parents, and urges that children's well-being remain the core purpose of welfare policy.

The Pseudomonas aeruginosa outer membrane protein I vaccine: immunogenicity and safe administration in man.

After expression in Escherichia coli and purification by Ni++ chelate-affinity chromatography, the outer membrane protein I (OprI) of Pseudomonas aeruginosa was tested in experimental animals for its safety and pyrogenicity. Four groups of 7 adult human volunteers were then vaccinated 3 times at four-weekly intervals with either 500 micrograms, 200 micrograms, 50 micrograms or 20 micrograms of OprI adsorbed onto aluminum hydroxide. The vaccinations were well tolerated and without systemic side effects, but a significant rise of antibody titers against OprI was measured in the serum of those who had received the 500 micrograms, 200 micrograms or 50 micrograms doses. Raised antibody titers against OprI were still present 30 weeks after the final vaccination. It was possible to demonstrate binding of the complement component C1q to the elicited antibodies, and this confirms their ability to promote antibody-mediated complement-dependent opsonization.

Theophylline and warfarin interaction studies with grepafloxacin.

Two phase I trials, each involving 16 healthy adult volunteers, were performed to investigate possible interactions between grepafloxacin and theophylline or warfarin. In the theophylline study, grepafloxacin 600 mg was administered once daily for 10 days to 12 volunteers who were receiving a maintenance dose of theophylline. This dose of theophylline was designed to produce mean serum theophylline concentrations of 7.5 mg/L; 4 volunteers received theophylline plus placebo. Pharmacokinetic parameters of theophylline were determined before grepafloxacin treatment and on day 10 of grepafloxacin or placebo administration. Peak theophylline concentrations and the area under the concentration-time curve increased significantly during grepafloxacin treatment, and apparent total clearance of theophylline was reduced by approximately 50%. No changes were observed in the placebo group and theophylline appeared to have no effect on the pharmacokinetics of grepafloxacin. In the warfarin study, grepafloxacin 600 mg was given once daily for 14 days to volunteers receiving a maintenance dose of warfarin. Warfarin was discontinued during the last 4 days of grepafloxacin administration. The pharmacodynamics of warfarin did not change after administration of grepafloxacin. Similarly, warfarin had no significant effect on the pharmacokinetics of grepafloxacin. We conclude that during treatment with grepafloxacin maintenance, doses of theophylline should be reduced by 50%, and we recommend that serum concentrations of theophylline be monitored during treatment with grepafloxacin. However, no dose adjustment is necessary for grepafloxacin when it is coadministered with theophylline, and dose adjustment does not seem to be required in concomitant treatment with grepafloxacin and warfarin.

Coordinate frame for pattern recognition in unilateral spatial neglect.

The present research examines the effect of spatial (object-centered) attentional constraints on pattern recognition. Four normal subjects and two right-hemisphere-damaged patients with left visual neglect participated in the study. Small, letterlike, prelearned patterns served as stimuli. Short exposure time prevented overt scanpaths during stimulus presentation. Attention was attracted to a central (midsagittal) hation point by precuing this location prior to each stimulus presentation. Minute (up to 1.5° of visual angle) rightward and leftward stimulus shifts caused attention to be allocated each time to a different location on the object space, while remaining in a fixed central position in viewercentered coordinates. The task was to decide which of several prelearned patterns was presented in each trial. In the normal subjects, best performance was achieved when the luminance centroid (LC; derived from the analysis of low-spatial frequencies in the object space) of each pattern coincided with the spatial position of the precue. In contrast, the patients with neglect showed optimal recognition performance when precuing attracted attention to locations within the object space, to the left of the LC. The normal performance suggests that the LC may serve as a center of gravity for attention allocation during pattern recognition. This point seems to be the target location where focal attention is normally directed, following a primary global analysis based on the low spatial frequencies. Thus, the LC of a simple pattern may serve as the origin point for an object-centered-coordiate-frame (OCCF), dividing it into right and left. This, in turn, serves to create a prototype description of the pattern, in its own coordinates, in memory, to be addressed during subsequent recognition tasks. The best match of the percept with the stored description may explain the observed advantage of allocating attention to the LC. The performance of the brain- damaged patients can be explained in terms of neglect operating in the OCCE.

Safety and immunogenicity of a Pseudomonas aeruginosa outer membrane protein I vaccine in human volunteers.

The outer membrane protein I (OprI) of Pseudomonas aeruginosa was expressed in Escherichia coli and purified by Ni2+ chelate-affinity chromatography. After safety and pyrogenicity evaluation in animals, four groups of seven adult human volunteers were vaccinated three times at four week intervals with either 500 micrograms, 200 micrograms, 50 micrograms or 20 micrograms of OprI adsorbed onto Al(OH)3. All vaccinations were well tolerated and no systemic side effects were detected. A significant rise of antibody titers against OprI could be measured in the serum of all volunteers who had received the 500 micrograms, 200 micrograms or 50 micrograms doses. Elevated antibody titers against OprI could still be measured 30 weeks after the final vaccination. Binding of the complement component C1q to the elicited antibodies could be demonstrated, showing the ability of the latter to promote antibody-mediated complement-dependent opsonization.