Melatonin modulates spike coding in the rat suprachiasmatic nucleus

The effects of the application of melatonin in vitro on the electrophysiological activity of suprachiasmatic neurones were characterised using novel measures of coding based on the analysis of interspike intervals. Perfusion of 1 nM melatonin in vitro (n = 53) had no consistent effect on mean spike frequency (Wilcoxon's sign rank, z = -0.01, P = 0.989), but increased the irregularity of firing (Student's paired t-test, t = -3.02, P = 0.004), as measured by the log interval entropy, and spike patterning (z = -3.43, P < 0.001), as measured by the mutual information between adjacent log intervals. Intracellular recordings in vitro in current clamp mode showed that 1 nM melatonin significantly hyperpolarised (n = 11, z = -2.35, P = 0.019) those cells that showed 'rebound' spikes upon termination of a hyperpolarising current pulse. Grouping all cells together (n = 27), melatonin application decreased the duration of the afterhyperpolarisation (z = -2.49, P = 0.013) and increased the amplitude of the depolarising afterpotential (z = -2.71, P = 0.007). The effects of melatonin seen in vitro from extracellular recordings on interspike interval coding were consistent with the changes in spike shape seen from intracellular recordings. A melatonin-induced increase in the size of the depolarising afterpotential of suprachiasmatic cells might underlie the increased irregularity of spike firing seen during the subjective night time. The method of analysis demonstrated a difference in spike firing that is not revealed by frequency alone and is consistent with the presence of a melatonin-induced depolarising current.     

Semantic-phonologic treatment for noun and verb retrieval impairments in aphasia

Nouns and verbs differ in their neural and psycholinguistic attributes. It is not known whether these differences lead to distinct patterns of response to treatment for individuals with word retrieval impairments associated with aphasia. Eight participants with naming disorders induced by left hemisphere strokes were treated with a semantic-phonologic treatment protocol for nouns and verbs using a single participant multiple baseline design. We measured treatment gains in a picture naming measure and other secondary language and communication measures. Treatment led to improved picture naming for trained nouns and verbs in five of eight patients, with no difference evident between nouns and verbs. Improvements for untrained words were minimal. Improvement in verb retrieval was associated with increases on a functional measure of communicative effectiveness. Improvement for nouns and verbs was associated with severity of word retrieval impairment at onset. Although distinct in neural and psycholinguistic attributes, nouns and verbs were affected by treatment in a similar pattern in this group of individuals. Training-specific effects suggest the need for careful selection of training words to have potential for functional benefit in daily communication.     

Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene

Desminopathy represents a subgroup of myofibrillar myopathies caused by mutations in the desmin gene. Three novel disease-associated mutations in the desmin gene were identified in unrelated Spanish families affected by cardioskeletal myopathy. A selective pattern of muscle involvement, which differed from that observed in myofibrillar myopathy resulting from mutations in the myotilin gene, was observed in each of the three families with novel mutations and each of three desminopathy patients with known desmin mutations. Prominent joint retractions at the ankles and characteristic nasal speech were observed early in the course of illness. These findings suggest that muscle imaging in combination with routine clinical and pathological examination may be helpful in distinguishing desminopathy from other forms of myofibrillar myopathy and ordering appropriate molecular investigations.     

Genotoxicity of glyphosate assessed by the comet assay and cytogenetic tests

It was evaluated the genotoxicity of glyphosate which up to now has heterogeneous results. The comet assay was performed in Hep-2 cells. The level of DNA damage in the control group (5.42±1.83 arbitrary units) for tail moment (TM) measurements has shown a significant increase (p<0.01) with glyphosate at a range concentration from 3.00 to 7.50mM. In the chromosome aberrations (CA) test in human lymphocytes the herbicide (0.20-6.00mM) showed no significant effects in comparison with the control group. In vivo, the micronucleus test (MNT) was evaluated in mice at three doses rendering statistical significant increases at 400mg/kg (13.0±3.08 micronucleated erythrocytes/1000 cells, p<0.01). In the present study glyphosate was genotoxic in the comet assay in Hep-2 cells and in the MNT test at 400mg/kg in mice. Thiobarbituric acid reactive substances (TBARs) levels, superoxide dismutase (SOD) and catalase (CAT) activities were quantified in their organs. The results showed an increase in these enzyme activities.     

The way forward

Good public-health decisionmaking is dependent on reliable and timely statistics on births and deaths (including the medical causes of death). All high-income countries, without exception, have national civil registration systems that record these events and generate regular, frequent, and timely vital statistics. By contrast, these statistics are not available in many low-income and lower-middle-income countries, even though it is in such settings that premature mortality is most severe and the need for robust evidence to back decisionmaking most critical. Civil registration also has a range of benefits for individuals in terms of legal status, and the protection of economic, social, and human rights. However, over the past 30 years, the global health and development community has failed to provide the needed technical and financial support to countries to develop civil registration systems. There is no single blueprint for establishing and maintaining such systems and ensuring the availability of sound vital statistics. Each country faces a different set of challenges, and strategies must be tailored accordingly. There are steps that can be taken, however, and we propose an approach that couples the application of methods to generate better vital statistics in the short term with capacity-building for comprehensive civil registration systems in the long run.     

Evidence for mutation showers

Mutants in the Big Blue transgenic mouse system show spontaneous clustered multiple mutations with unexpectedly high frequency, consistent with chronocoordinate events. We tested the prediction that the multiple mutations seen within the lacI mutation target sometimes occur in the context of chronocoordinate multiple mutations spanning multiple kilobases (mutation showers). Additional sequencing of mutants was performed in regions immediately flanking the lacI region (total of 10.7 kb). Nineteen additional mutations were found outside the lacI region ("ectomutations") from 10 mutants containing two or more lacI mutations, whereas only one ectomutation was found in 130 mutants with a single mutation (P < 0.0001). The mutation showers had an average of approximately one mutation per 3 kb. Four mutants showed closely spaced double mutations in the new sequence, and analysis of the spacing between these mutations revealed significant clustering (P = 0.0098). To determine the extent of the mutation showers, regions (8.5 kb total) remote from the lacI region (approximately 16-17 kb away) were sequenced. Only two additional ectomutations were found in these remote regions, consistent with mutation showers that generally do not extend more than approximately 30 kb. We conclude that mutation showers exist and that they constitute at least 0.2% and possibly 1% or more of mutational events observed in this system. The existence of mutation showers has implications for oncogenesis and evolution, raising the possibilities of "cancer in an instant" and "introns as sponges to reduce the deleterious impact of mutation showers."     

Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study

OBJECTIVE: To assess the safety and efficacy of memantine, an uncompetitive antagonist of the N-methyl-D-aspartate receptor as treatment of HIV-associated cognitive impairment. METHODS: This was a Phase II randomized, double-blind, placebo-controlled, multicenter trial within the Adult AIDS Clinical Trials Group. One-hundred and forty HIV-infected adults with mild to severe AIDS dementia complex receiving stable antiretroviral therapy were enrolled. Memantine was initiated at 10 mg daily escalated to 40 mg daily, or up to the maximum tolerated dose and continued for 16 weeks (primary evaluation visit) followed by a 4-week washout period and re-evaluation at week 20. Changes in cognitive performance were measured as percent change from baseline to week 16 in the average of eight neuropsychological test scores (NPZ-8). Brain metabolism was measured by magnetic resonance spectroscopy in a subgroup of subjects. RESULTS: Sixty-one percent of subjects in the memantine group and 85% in the placebo group reached the 40 mg dose while the reported adverse experiences between the two groups were similar. There were no significant improvements in neuropsychological performance over 16 weeks; however, memantine was associated with a significant increase at week 16 in the N-acetyl aspartate to creatine ratio, in the frontal white matter (P = 0.040) and parietal cortex (P = 0.023). CONCLUSIONS: Memantine was safe and tolerated by HIV-infected subjects with cognitive impairment. Although we observed no significant differences in cognitive performance, the magnetic resonance spectroscopy data suggest that memantine may ameliorate neuronal metabolism, an important step to stabilizing or preventing neuronal injury. These results underscore the need for longer studies to assess the full potential of neuroprotective agents.     

Impact of therapeutic interventions induced by capsule endoscopy on long term outcome in chronic obscure GI bleeding

BACKGROUND: The diagnostic yield and the clinical impact of capsule endoscopy (CE) in obscure gastrointestinal bleeding (OGIB) are well known. The aim of this study was to determine the impact of therapeutic interventions induced by CE findings on long term outcome. PATIENTS AND METHODS: Patients with chronic OGIB referred to our center from September 2003 to June 2005 for CE were included. Treatment of intestinal lesions was prescribed according to the clinical characteristics of patients and the nature of the lesions. RESULTS: Forty patients were included, 18 females and 22 males. Median age was 54 yrs (range: 5-87) with a median follow-up of 13 months (range: 6-22). The diagnostic yield of CE was 75% (30/40). From 30 patients with positive CE, 16 received treatment (Group I) and 14 did not (Group II). Thus clinical impact was 40%. Ten patients had negative CE (Group III). During follow-up, bleeding recurrence was observed in only 1 patient from Group I (6%), 5 from Group II (36%) and 1 from Group III (10%). There were only significant differences between Group I vs Group II (P=0.002). CONCLUSIONS: CE results had a favorable influence in patient outcome allowing for specific treatment as they showed significantly reduced recurrent bleeding.     

Congenital asplenia (Ivemark syndrome) revealed by mesenteric vein thrombosis in a 77 year old patient

Congenital asplenia (Ivemark syndrome) is usually associated with major cardiac malformations, which determine the clinical presentation and often result in death before 6 months of age. We report the unusual case of a 77 year-old patient with a congenital asplenia that was incidentally detected during a laparotomy for mesenteric vein thrombosis. The other abnormal findings in the abdomen were a para-esophageal hiatal hernia and left kidney hypotrophy. A segmental resection of the mid-jejunum was performed, with uneventful recovery. A thoraco-abdominal CT scan failed to reveal any associated vascular malformations in the retroperitoneum or the thorax. This case suggests that, in some instances, congenital asplenia, when isolated, may remain asymptomatic and be compatible with a long, and functionally normal life.