Impact of age on viral kinetics of peginterferon alfa-2a/ribavirin in chronic hepatitis C: final analysis from the PROPHESYS cohort.

The population of patients with chronic hepatitis C viral infection is ageing; however, elderly, hepatitis C-infected patients are understudied and less frequently treated. This subanalysis of data from the multinational PROPHESYS study examined associations between age (≤65 vs >65 years), on-treatment virological response and sustained virological response (SVR) in patients treated with peginterferon alfa-2a (40KD)/ribavirin in accordance with local licences. PROPHESYS comprised three cohorts studied in 19 countries according to country-specific legal and regulatory requirements. This subanalysis includes treatment-naive HCV mono-infected patients assigned to receive peginterferon alfa-2a (40KD)/ribavirin, with 6276 individuals aged ≤65 years and 349 aged >65 years. Rapid virological response (RVR) rates by Week 4 were consistently lower in older genotype (G) 1 (21.6% vs 27.2% in younger patients), G2 (80.7% vs 85.1%) and G3 (60.0% vs 74.2%) patients. SVR rates were significantly lower (29.8% vs 43.0%) and relapse rates significantly higher (43.1% vs 26.7%) in older G1 patients (P = 0.0002 vs ≤65 years). In contrast, SVR and relapse rates were similar in G2 and G3 patients regardless of age. The positive predictive value of RVR for SVR was comparable in older and younger G1 patients (66.7% vs 68.6%, respectively) and higher in older G2 (80.7% vs 75.6%) and G3 (77.8% vs 66.8%) patients. Virological response rates are generally lower in elderly CHC patients, and RVR is a reliable positive predictor of SVR in patients >65 years.

Hepatitis C virus therapy is associated with lower health care costs not only in noncirrhotic patients but also in patients with end-stage liver disease.

BACKGROUND: The effect of anti-viral treatment on downstream costs for hepatitis C virus (HCV)-infected patients is unknown. AIM: To evaluate follow-up costs in patients with chronic HCV, stratified by liver disease severity. METHODS: Using a US private insurance database, mean all-cause per-patient-per-month (PPPM) US (2010) medical costs were calculated for HCV-infected persons who did and did not receive anti-HCV treatment between January 2002 and August 2010. Analysis was stratified by liver disease severity [noncirrhotic disease (NCD), compensated cirrhosis (CC) or end-stage liver disease (ESLD)] defined by ICD-9 and CPT codes. RESULTS: A total of 33 309 patients were included (78% NCD, 7% CC and 15% ESLD); 4111 individuals (12%) received anti-HCV treatment during the 2-year baseline period. Mean PPPM follow-up health care costs were significantly lower among treated patients with NCD ($900 vs. $1378 in untreated patients, P < 0.001) and ESLD ($3634 vs. $5071, P < 0.001) groups but not in the CC group ($1404 vs. $1795, P < 0.071; t-test). In a multivariable model adjusted for demographic characteristics, comorbidities, index date and geographical region, incremental cost ratios for total health care costs differed significantly (P < 0.001) between treated and untreated patients in the NCD and ESLD groups but not in the CC group. From this model, mean PPPM total health care costs between treated and untreated patients were $885 and $1370 in the NCD, $1369 and $1802 in the CC, and $3547 and $5137 in the ESLD groups, respectively. CONCLUSIONS: Anti-HCV therapy was associated with lower follow-up US health care costs, and these savings were independent of baseline patient comorbidities and stage of disease.

Absolute and relative contraindications to pegylated-interferon or ribavirin in the US general patient population with chronic hepatitis C: results from a US database of over 45 000 HCV-infected, evaluated patients.

BACKGROUND: Chronic hepatitis C (HCV) treatment with pegylated-interferon (PEG-IFN)/ribavirin (RBV) is often limited by preexisting medical, psychiatric and psychosocial contraindications. However, limited data exist in general patient populations. AIM: To evaluate the percentage of HCV-infected patients in the general US population who may have contraindications to PEG-IFN/RBV. METHODS: The General Electric (GE) Centricity dataset was used to screen the US population between 2004 and 2009 for HCV infection and contraindications to PEG-IFN/RBV. HCV diagnosis and contraindications were identified using ICD-9-CM codes or laboratory values. Only patients with an encounter 180 days prior to HCV diagnosis were included. Demographic differences were calculated using Pearson's chi-squared test. Frequencies and percentages for absolute and relative contraindications to PEG-IFN and/or RBV were determined and proportions and rates/1000 person-months were calculated. RESULTS: A total of 15 561 021 patients were screened, and 45 690 (0.3%) were HCV-positive and were evaluated. Those with contraindications were significantly younger, female, White, not currently married and receiving Medicare or Medicaid coverage (all P < 0.0001). 17.3% had at least one contraindication to PEG-IFN/RBV (5.5 events/1000 person-months); bipolar disorder (6.5%), anaemia (Hgb < 10 g/dL; 5.9%), pregnancy (1.9%) and neutropenia (neutrophils <750 cells/mm(3) ; 1.2%) were most frequently cited. CONCLUSIONS: Approximately, 17% of HCV-infected patients in the general US population had at least one contraindication to PEG-IFN/RBV. Most contraindications were relative and potentially modifiable. Clinical assessment of contraindications as relative and/or modifiable should be considered and used to determine if patients could benefit from current PEG-IFN-containing triple therapy or future PEG-IFN- or RBV-free regimens.

Fine-tuning of substrate architecture and surface chemistry promotes muscle tissue development.

Tissue engineering has been increasingly brought to the scientific spotlight in response to the tremendous demand for regeneration, restoration or substitution of skeletal or cardiac muscle after traumatic injury, tumour ablation or myocardial infarction. In vitro generation of a highly organized and contractile muscle tissue, however, crucially depends on an appropriate design of the cell culture substrate. The present work evaluated the impact of substrate properties, in particular morphology, chemical surface composition and mechanical properties, on muscle cell fate. To this end, aligned and randomly oriented micron (3.3±0.8 µm) or nano (237±98 nm) scaled fibrous poly(ε-caprolactone) non-wovens were processed by electrospinning. A nanometer-thick oxygen functional hydrocarbon coating was deposited by a radio frequency plasma process. C2C12 muscle cells were grown on pure and as-functionalized substrates and analysed for viability, proliferation, spatial orientation, differentiation and contractility. Cell orientation has been shown to depend strongly on substrate architecture, being most pronounced on micron-scaled parallel-oriented fibres. Oxygen functional hydrocarbons, representing stable, non-immunogenic surface groups, were identified as strong triggers for myotube differentiation. Accordingly, the highest myotube density (28±15% of total substrate area), sarcomeric striation and contractility were found on plasma-coated substrates. The current study highlights the manifold material characteristics to be addressed during the substrate design process and provides insight into processes to improve bio-interfaces.

Ictal dystonic posturing in mesial versus neocortical temporal lobe seizures.

PURPOSE: Ictal contralateral dystonic posturing is a frequently observed clinical feature in temporal lobe seizures. It is generally interpreted as the result of spread of the ictal discharge into basal ganglia structure. In previous reports, analysing ictal behavior, a precise definition and description of the upper limb ictal dystonia is often lacking or contradictory. In our study we aimed to determine whether different subtypes of dystonia and their latency from the clinical onset of seizure might be of value for the differentiation between mesial temporal lobe epilepsy (MTLE) and neocortical temporal lobe epilepsy (NTLE). METHODS: Eighty seizures (51 MTLE and 29 NTLE) and 30 patients (20 MTLE and 10 NTLE) were analyzed with regard to dystonic posturing of the upper limb. Ictal dystonia was subdivided into different subtypes according to distinct clinical features. Their frequency and latency from the clinical onset of seizure were assessed. RESULTS: Frequencies of all subtypes were similar in MTLE and NTLE. Concerning the latencies contralateral dystonic posturing characterized by sustained muscle contractions with flexion of the wrist and fist closure, a frequently appearing feature, occurred significantly earlier in NTLE than in MTLE seizures. CONCLUSIONS: This difference between the two groups may provide a differentiation between an epileptic focus of mesial from neocortical temporal lobe origin.

Future aspects of the presurgical evaluation in epilepsy.

Epilepsy surgery is a successful therapeutic approach in patients with medically intractable epilepsy. The presurgical evaluation aims to detect the epileptogenic brain area by use of different diagnostic techniques. In this review article the current diagnostic procedures applied for this purpose are described. The diagnostic armamentarium can be divided conceptually into three different groups: assessment of function/dysfunction, structural/morphologic imaging methods and functional neuroimaging techniques. Properties, diagnostic power and limits of all diagnostic tools used in the diagnostic evaluation are discussed. In addition, future perspectives and the diagnostic value of new technologies are mentioned. Some are increasingly gaining acceptance in the routine preoperative diagnostic procedure like MR volumetry or MR spectroscopy of the hippocampus in patients with temporal lobe epilepsy. Some, on the other hand, like MEG and 11C-flumazenil PET, still remain experimental diagnostic tools as they are technically demanding and cost intensive. Besides the refinement of established techniques, co-registration of different modalities like spike-triggered functional MRI will play an important role in the non-invasive detection of the epileptic seizure focus and may change the regimen of the preoperative diagnostic work up of epilepsy patients in the future.

Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.

We report on a large four-generation Austrian family with autosomal dominant distal hereditary motor neuronopathy type V (distal HMN V). Forty-seven at-risk family members, of whom 21 were definitely affected, underwent detailed clinical, electrophysiological and genetic studies. The age at onset was in the second decade of life in most affected individuals, but clinical presentation was rather variable. While the majority of patients were primarily disabled by progressive asymmetrical wasting of the thenar and the first dorsal interosseus muscles, others had marked foot deformity and gait disturbance with the occasional absence of hand involvement. Sensation sense was normal except for the reduced response to vibration. Many individuals showed brisk tendon reflexes and some elevated muscle tone in the lower limbs, but extensor plantar responses were rarely observed. Electrophysiological evaluation revealed normal or reduced motor nerve conduction velocities, normal or prolonged distal motor latencies, and low compound motor action potentials, depending on the degree of muscle wasting. Sensory nerve studies were usually within the normal range or slightly to moderately abnormal in older or severely affected persons. Electromyography showed high-amplitude motor unit potentials and reduced recruitment compatible with anterior horn cell degeneration. Central motor conduction times were prolonged in two-thirds of the patients. Molecular genetic studies excluded Charcot-Marie-Tooth 1A syndrome and proximal spinal muscular atrophy linked to chromosome 5q as well as the known gene loci for distal HMN II on chromosome 12q, HMN V on chromosome 7p and juvenile amyotrophic lateral sclerosis on chromosome 9q. The findings in this family thus provide detailed clinical and electrophysiological information on HMN V and demonstrate broad phenotypic variability in this disorder. Hallmark features are discussed that appear to be most reliable to differentiate this type of HMN V from other variants of hereditary neuropathies, and a set of diagnostic criteria is proposed. Furthermore, this is the first report of prolonged central motor conduction times in HMN V, which indicates additional involvement of the central motor pathways in this disease. Finally, molecular genetic studies demonstrate genetic heterogeneity, suggesting the existence of at least a second genetic subtype in HMN V.

Gamma knife radiosurgery for hypothalamic hamartomas in patients with medically intractable epilepsy and precocious puberty. Report of two cases.

Hamartoma of the hypothalamus represents a well-known but rare cause of central precocious puberty and gelastic epilepsy. Due to the delicate site in which the tumor is located, surgery is often unsuccessful and associated with considerable risks. In the two cases presented, gamma knife radiosurgery was applied as a safe and noninvasive alternative to obtain seizure control. Two patients, a 13-year-old boy and a 6-year-old girl, presented with medically intractable gelastic epilepsy and increasing episodes of secondary generalized seizures. Abnormal behavior and precocious puberty were also evident. Magnetic resonance (MR) imaging revealed hypothalamic hamartomas measuring 13 and 11 mm, respectively. After general anesthesia had been induced in the patients, radiosurgical treatment was performed with margin doses of 12 Gy to 90% and 60% of isodose areas, covering volumes of 700 and 500 mm3, respectively. After follow-up periods of 54 months in the boy and 36 months in the girl, progressive decrease in both seizure frequency and intensity was noted (Engel outcome scores IIa and IIIa, respectively). Both patients are currently able to attend public school. Follow-up MR imaging has not revealed significant changes in the sizes of the lesions. Gamma knife radiosurgery can be an effective and safe treatment modality for achieving good seizure control in patients with hypothalamic hamartomas.

A model of computation in neocortical architecture.

We propose that the specific architecture of the neocortex reflects the organization principles of neocortical computation. In this paper, we place the anatomically defined concept of columns into a functional context. It is provided by a large-scale computational hypothesis on visual recognition, which includes both, rapid parallel forward recognition, independent of any feedback prediction, and a feedback controlled refinement system. Short epochs of periodic clocking define a global reference time and introduce a discrete time for cortical processing which enables the combination of parallel categorization and sequential refinement. The presented model differs significantly from conventional neural network architectures and suggests a novel interpretation of the role of gamma oscillations and cognitive binding.

[Practice-oriented control of BVD virus infection in cattle herds]. / Praxisorientierte Bekämpfung der BVD-Virusinfektion in Rinderbeständen.

The BVD-virus-infection is at present the economically most important disease of bovine animals. A control program requires to take into consideration the given epidemiological facts. Sufficient diagnostic examination procedures are available for estimation of the infection taking place in a herd. An effective preventive measure prior to the infection as well as the quick limitation of an already existing infection taking place consists in a consequent vaccination program. Pre-condition for the vaccination program is the attention to a strict indication of vaccines available, the detailed information of the animal owner as well as taking into consideration the cost-profit-proportion of the envisaged control measurements.

Roussy-Lévy syndrome is a phenotypic variant of Charcot-Marie-Tooth syndrome IA associated with a duplication on chromosome 17p11.2.

The Roussy-Lévy syndrome (MIM #180800) was described in 1926 as a disorder presenting with pes cavus and tendon areflexia, distal limb weakness, tremor in the upper limbs, gait ataxia and distal sensory loss. We report a family with affected members in four generations, showing these clinical signs of Roussy-Lévy syndrome and a partial duplication at chromosome 17p11.2. This genetic defect is commonly found in patients with the hypertrophic form of the Charcot-Marie-Tooth syndrome. Our finding provides evidence against the Roussy-Lévy syndrome as a distinct entity but suggests a close relation with the Charcot-Marie-Tooth syndrome. What causes the additional features of gait ataxia and essential tremor needs further clarification.

[Patients' evaluation of coercion in a psychiatric department. Interview studies in psychiatric departments for adult patients at the Hillerød hospital]. / Patienternes vurdering af tvang på psykiatrisk afdeling. Interviewunders gelse på de voksenpsykiatriske afdelinger ved Hillerød Sygehus.

During an 11 month period, use of coercion was prospectively registered in a psychiatric department. Of all patients who had been subjected to coercion 36% were (n = 86) interviewed subsequently. Eleven percent of the interviewed patients did not know, that they had been submitted to coercion, 22% did not know the reason and 30% did not agree with the motivation for the decision. Forty-seven percent were satisfied with the information they had been given concerning how to complain of their treatment, 50% were satisfied with their adviser and 70% were satisfied with their overall admission. Sixty-five percent accepted that there should be a law allowing the use of coercion in psychiatry.

[Occurrence of dementia and depression in an elderly Danish population]. / Forekomsten af demens og depression i en dansk aeldrebefolkning.

A community survey of all Danish speaking residents above the age of 64 in a geographically delimited area was performed. The aim of the survey was to establish the prevalence of dementia disorders and depression by the use of international screening tools: the Mini Mental State Examination for dementia and the Beck's Depression Inventory for depression. The screening was performed during the period of one year in the municipality of Karlebo and the interviews took place in the homes of the participants. Six hundred and sixty-four (66%) of the 1,008 eligible persons entered the study. Six percent were residents in nursing homes. Thirteen point seven percent were found to be suffering from dementia. Nine point six percent had symptoms of depression. These prevalences would indicate that more than 6,000 persons in Frederiksborg county suffer from dementia while more than 4,000 might be suffering from depression. The study confirms knowledge obtained in other studies, indicating that one out of seven of the elderly suffers from dementia. We do not conclude, however, that nine point six percent suffer from depression, but rather that they need further examination to make it possible to decide whether they are indeed depressed.

[The use of coercion at psychiatric departments for adults, Hillerød hospital. A descriptive study of the period 10 January 1991-31 August 1992]. / Tvangsudøvelse på de voksenpsykiatriske afdelinger, Hillerød Sygehus. En deskriptiv undersøgelse i perioden 1.10.1991-31.8.1992.

The study describes the type and amount of coercion used during 11 months of 1992. Four hundred and fourty-one cases were included. Young patients i.e. 10 to 29 years old, demented patients and patients suffering from organic psychoses were, overall, more often subjected to coercive measures. When looking at each type of coercion separately, it was found that detainment, compulsive treatment and fixation were especially used on the young and on patients suffering from schizophrenia. However, fixation used as a protective measure was mainly used on the demented and the 60 to 79 year-old patients.

Multiple sclerosis-like syndrome in a woman heterozygous for adrenoleukodystrophy.

A 28-year-old asymptomatic woman was diagnosed to be heterozygous for adrenoleukodystrophy (ALD) by elevated very long-chain fatty acids in serum and fibroblasts after ADL had been diagnosed in her son. A year later she had transient unilateral blurred vision. Evoked potentials and brain magnetic resonance imaging showed further separate cerebral white matter lesions suggesting multiple sclerosis (MS). MS-like syndromes in women heterozygous for ALD may be more frequent than previously recognized.

Ethanol radical-induced protein-DNA crosslinking. A radiolysis study.

Aqueous solutions of double-stranded DNA from calf thymus and bovine serum albumin (BSA) were irradiated at pH 7 under N2O and N2 in the presence of 10(-1) mol dm-3 ethanol, which was partly 14C-labelled. Ethanol protects DNA from strand breakage by scavenging OH radicals, but ethanol radicals induce protein-DNA crosslinks. Ethanol radicals react readily with BSA mainly by addition. They react also with double-stranded DNA, but produce crosslinking only very slowly. Based on these results the following mechanism is proposed: ethanol radicals bind to BSA producing protein radicals which become crosslinked to DNA.

[EEG mapping in schizophrenia and depression--a multivariate approach]. / EEG-Mapping bei Schizophrenie und Depression--ein multivariater Zugang.

EEG Brain Mapping offers a promising approach to study complex pattern of brain function. However, traditional usage of this method was focussed mainly on isolated details of the whole specter. The present study was, therefore, aimed at the simultaneous observation of all available parameters. Discriminant analysis was used to distinguish between 4 groups of patients suffering from either schizophrenia (acute/off drugs; improved/on drugs) or depression (acute/off drugs; improved/on drugs) and healthy volunteers, each group with n = 10. The multivariate pattern of 50 topographical spectral variables brought about correct group classification of 49 out of 50 probands. Results suggest that more complex statistical paradigms that take advantage of all available parameters add to an integrative explanation of psychophysiological mechanisms in mental illness.