Effects of cholinergic modulation on responses of neocortical neurons to fluctuating input

Neocortical neurons in vivo are spontaneously active and intracellular recordings have revealed strongly fluctuating membrane potentials arising from the irregular arrival of excitatory and inhibitory synaptic potentials. In addition to these rapid fluctuations, more slowly varying influences from diffuse activation of neuromodulatory systems alter the excitability of cortical neurons by modulating a variety of potassium conductances. In particular, acetylcholine, which effects learning and memory, reduces the slow alterhyperpolarization, which contributes to spike frequency adaptation. We used whole-cell patch-clamp recordings of pyramidal neurons in neocortical slices and computational simulations to show, first, that when fluctuating inputs were added to a constant current pulse, spike frequency adaptation was reduced as the amplitude of the fluctuations was increased. High- frequency, high-amplitude fluctuating inputs that resembled in vivo conditions exhibited only weak spike frequency adaptation. Second, bath application of carbachol, a cholinergic agonist, significantly increased the firing rate in response to a fluctuating input but minimally displaced the spike times by < 3 ms, comparable to the spike jitter observed when a visual stimulus is repeated under in vivo conditions. These results suggest that cholinergic modulation may preserve information encoded in precise spike timing, but not in interspike intervals, and that cholinergic mechanisms other than those involving adaptation may contribute significantly to cholinergic modulation of learning and memory.      

Characterization of xenobiotic-metabolizing enzymes and nitrosamine metabolism in the human esophagus

Esophageal cancer has been associated with tobacco smoking, and nitrosamines are possible causative agents for this cancer. The present study investigated the metabolism of the tobacco carcinogens N'- nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK), and N-nitrosodimethylamine (NDMA), as well as the presence of xenobiotic-metabolizing enzymes in human esophageal tissues from individuals in the United States and Huixian, Henan Province, China (a high-risk area for esophageal cancer). All esophageal microsomal samples activated NNN and the metabolic rate was 2-fold higher in the esophageal samples from China than the USA. All microsomal samples activated NDMA. However, most of the microsomal samples did not activate NNK. Troleandomycin (an inhibitor of cytochrome P450 3A) decreased the formation of NNN-derived keto acid by 20-26% in the esophageal microsomes. The activities for NADPH: cytochrome c reductase, ethoxycoumarin O-deethylase, NAD(P)H: quinone oxidoreductase and glutathione S-transferase were present in the esophageal samples. Coumarin 7-hydroxylase (a representative activity for P450 2A6) activity was not detected in the esophageal microsomal samples. The activities for nitrosamine metabolism and xenobiotic- metabolizing enzymes were decreased (by 30-50%) in the squamous cell carcinomas compared with their corresponding non-cancerous mucosa. The presence of activation and detoxification enzymes in the esophagus may play an important role in determining the susceptibility of the esophagus to the carcinogenic effect of nitrosamines. Our results suggest that P450s 3A4 and 2E1 are involved in the activation of NNN and NDMA, respectively, in the human esophagus.      

Toxic cardiogenic shock in a patient receiving weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin

A 54-year-old man was treated with weekly 24-h infusion of high-dose 5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon cancer. At first, he tolerated the treatment well and no significant toxicity was identified. After a total of eight courses of treatment, a stable disease was observed, but mild shortness of breath was found on occasion. The patient had no previous history of cardiac disease and the heart performance assessed by left ventricular ejection fraction before treatment was normal. Unfortunately, acute pulmonary edema with lethal cardiogenic shock occurred during the ninth course of treatment, in spite of intensive medical treatment. The chest X-ray showed extreme cardiomegaly. Repeated assessment of his heart function by echocardiogram and ventricular ejection fraction revealed a very poor cardiac performance. Toxic cardiogenic shock during weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin is extremely rare. To the best of our knowledge, no case has been reported in the English literature. We report a case and the relevant literature about the incidence, clinical picture and possible pathophysiology on 5-fluorouracil-related cardioxicity is reviewed.      

Objective methods in postlingually and prelingually deafened adults for programming cochlear implants: ESR and NRT

This study compared responses of prelingually and postlingually deafened adult Nucleus 24 cochlear implant users on two objective measures employed to predict programming levels: neural response telemetry (NRT) and electrically evoked stapedial reflexes (eSR). Thirty experienced postlingually and prelingually deafened adult implant users underwent standard behavioural judgements of maximum comfortable loudness levels (C levels) and thresholds (Ts) followed by eSR and NRT measurements. Two different programs were created based on both the subjective judgement and the objective estimates of C levels (eSR thresholds) and these were compared. Relationships between the subjective and the objective measures were statistically analysed. Maximum stimulation levels estimated by both eSR and NRT were highly correlated with C levels. Variability of NRT results was higher than for eSR results. Mean NRT thresholds for postlingually deafened patients were higher than for prelingually deafened patients. A number of prelingually deafened users could distinguish no difference between programs; however, the majority of postlingually deafened users were sensitive to the difference and many reported preference for the program with eSR-estimated C levels. Neural response telemetry thresholds and eSRTs obtained in Nucleus 24 patients are highly correlated with C levels and Ts. Results suggest that estimation of C levels and Ts using NRT or eSR requires different correction factors for prelingually versus postlingually deafened adult subjects.     

Benefits of bilateral cochlear implantation: a review

PURPOSE OF REVIEW: Although unilateral cochlear implantation generally provides good speech understanding under quiet conditions, cochlear implantation patients frequently report difficulty understanding speech when exposed to background noise and with sound localization. Since these two listening functions require binaural stimulation for normal individuals and hearing aid recipients, it is not surprising that there is growing interest in binaural implants. This update reviews the basics of binaural listening and the advantages and disadvantages of binaural cochlear implantation. RECENT FINDINGS: Although the psychoacoustic literature has long demonstrated the benefits of binaural hearing, only recently have studies shown improvement in speech intelligibility with bilateral implants compared with unilateral implants. Of the three known binaural mechanisms, the head shadow effect provides greater benefit than binaural squelch or summation. In addition, binaural cochlear implants improve the ability to localize sound. SUMMARY: Bilateral implantation provides multiple benefits to patients with severe to profound hearing loss. Research is currently directed at improving speech intelligibility by utilizing evolving technologies in speech-processing strategies.     

The active components of effective training in obstetric emergencies

Confidential enquiries into poor perinatal outcomes have identified deficiencies in team working as a common factor and have recommended team training in the management of obstetric emergencies. Isolated aviation-based team training programmes have not been associated with improved perinatal outcomes when applied to labour ward settings, whereas obstetric-specific training interventions with integrated teamwork have been associated with clinical improvements. This commentary reviews obstetric emergency training programmes from hospitals that have demonstrated improved outcomes to determine the active components of effective training. The common features identified were: institution-level incentives to train; multi-professional training of all staff in their units; teamwork training integrated with clinical teaching and use of high fidelity simulation models. Local training also appeared to facilitate self-directed infrastructural change.     

Reduction of atherosclerosis in cholesterol-fed rabbits and decrease of expressions of intracellular adhesion molecule-1 and vascular endothelial growth factor in foam cells by a water-soluble fraction of Polygonum multiflorum

Polygonum multiflorum stilbeneglycoside （PMS） is a water-soluble fraction of Polygonum multiflorum Thunb. , one of the most famous tonic traditional Chinese medicines, that has protective effects on the cardiovascular system. The purpose of the present study is to elucidate the effects of PMS on macrophage-derived foam cell functions and the reduction of severity of atherosclerosis in hypercholesterolemic New Zealand White （NZW） rabbits. NZW rabbits were fed for 12 weeks with a normal diet, a high cholesterol diet, or a high cholesterol diet associated with irrigation with different doses of PMS （25, 50, or 100 mg/kg）. Treatment of NZW rabbits fed with high cholesterol diet with 100 mg/kg PMS attenuated the increase in plasma cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and plasma triglyceride. Treatment with 50 and 100 mg/kg PMS caused 43% and 60% decrease in atherosclerotic lesioned area ratio to total surface area, respectively. In U937 foam cells, PMS could decrease the high expression of intercellular adhesion molecule （ICAM）-1 protein and the vascular endothelial growth factor （VEGF） protein levels in the medium induced by oxidized lipoprotein when analyzed by flow cytometry. The results proved that PMS is a powerful agent against atherosclerosis and that PMS action could possibly be through the inhibition of the expression of ICAM-1 and VEGF in foam cells.     

Prevalence of cluster headache in the Republic of Georgia: results of a population-based study and methodological considerations

We present a study of the general-population prevalence of cluster headache in the Republic of Georgia and discuss the advantages and challenges of different methodological approaches. In a community-based survey, specially trained medical residents visited 500 adjacent households in the capital city, Tbilisi, and 300 households in the eastern rural area of Kakheti. They interviewed all ( n  = 1145) biologically unrelated adult occupants using a previously validated questionnaire. The household responses rates were 92% in Tbilisi and 100% in Kakheti. The survey identified 32 persons with possible cluster headache, who were then personally interviewed by one of two headache-experienced neurologists. Cluster headache was confirmed in one subject. The prevalence of cluster headache was therefore estimated to be 87/100 000 (95% confidence interval < 258/100 000). We used a conservative approach, which has an obvious advantage of high-quality data collection, but is very demanding of manpower and time.     

Clinical features and outcome in childhood T-cell leukemia-lymphoma according to stage of thymocyte differentiation: a Pediatric Oncology Group Study

The immunophenotypes of lymphoblasts from children with newly diagnosed T-cell acute lymphoid leukemia (T-ALL, n = 101) or T-cell non-Hodgkin lymphoma (T-NHL, n = 31) were analyzed to correlate stage of thymocyte differentiation with clinical features and outcome. The 67 boys and 34 girls with T-ALL were 1 month to 18 years old (median, 8 years) with leukocyte counts ranging from 2 to 810 x 10(9)/L (median, 55 x 10(9)/L). Eighteen of these patients were black, and 70 had a mediastinal mass. Twenty-six boys and five girls with a median age of 9 years (range, 1 to 20 years) had T-NHL. Seven of these patients were black, and 24 had a mediastinal mass. The distributions of thymocyte developmental stages (early [CD7+], intermediate [CD1+ and/or CD4+ and/or CD8+], and mature [CD3+]) in cases of T-ALL and T-NHL were significantly different: 34%, 43%, and 23% v 6%, 62%, and 32% (P = .02). A comparison of the patients' clinical features according to the maturational stage of thymocytes failed to disclose significant differences in the majority of characteristics studied. However, patients with mature-stage T-NHL, with or without the addition of subjects with mature-stage T-ALL, were less likely to have a mediastinal mass (P = .02 for both comparisons). Those with intermediate-stage T-cell malignancy (T-ALL and T-NHL combined) were the subgroup most likely to have a mediastinal mass (P = .01). Response to remission induction therapy was significantly worse in the T-ALL subgroup with an early-stage phenotype: a failure rate of 21% v 0% and 6% for the two more differentiated phenotypic subgroups (P = .007). Event-free survival was not affected by thymocyte maturational stage in cases of either T-ALL or T-NHL. Despite evidence of clinical heterogeneity among the maturational stages of T-cell malignancies in children, these developmental subdivisions do not appear to be critical determinants of outcome once remission is achieved. We conclude that such phenotypes need not be included in the stratification plans for clinical trials using common induction treatment.