Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant - a case report.

BACKGROUND: Severely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The use of Anabolic androgenic steroid (AAS) is under-reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels. CASE REPORT: We present a case of a man in his 40s with a large left middle cerebral artery (MCA) territory ischaemic stroke and combined multifocal, extracranial venous, and arterial thrombosis. His past medical history was significant for Crohn's disease and covert use of AAS. A young stroke screen was negative except for a severely elevated total homocysteine concentration, folate and B12 deficiencies. Further tests revealed he was homozygous for the methylenetetrahydrofolate reductase enzyme thermolabile variant (MTHFR c.667 C > T). The etiology of this stroke was a hypercoagulable state induced by raised plasma homocysteine. Raised homocysteine in this case was likely multifactorial and related to chronic AAS use in combination with the homozygous MTHFR c.677 C > T thermolabile variant, folate deficiency and, vitamin B12 deficiency. CONCLUSION: In summary, hyperhomocysteinemia is an important potential cause of ischaemic stroke and may result from genetic, dietary, and social factors. Anabolic androgenic steroid use is an important risk factor for clinicians to consider, particularly in cases of young stroke with elevated serum homocysteine. Testing for MFTHR variants in stroke patients with raised homocysteine may be useful to guide secondary stroke prevention through adequate vitamin supplementation. Further studies looking into primary and secondary stroke prevention in the high-risk MTHFR variant cohort are necessary.

What is the clinical effectiveness and cost-effectiveness of using drugs in treating obese patients in primary care? A systematic review.

BACKGROUND: Obesity [defined as a body mass index (BMI) ≥ 30 kg/m(2)] represents a considerable public health problem and is associated with a significant range of comorbidities and an increased mortality risk. The primary aim of the management of obesity is to achieve weight reduction in the interests of health. For obese patients who cannot achieve or maintain a healthy weight by non-pharmacological means, drug therapy is recommended in combination with non-pharmacological interventions such as dietary modifications and exercise. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of three pharmacological interventions in obese patients. DATA SOURCES: Clinical effectiveness data used in the meta-analysis were sourced from articles identified in a systematic review of the literature. Data used to inform transitions to obesity-related comorbidities were derived from the General Practice Research Database (GPRD). The results of the meta-analysis and GPRD analyses informed the economic model supplemented by data from the Health Survey for England and other UK-specific data sourced from the literature. REVIEW METHODS: A systematic literature review was conducted of the clinical effectiveness and cost-effectiveness of orlistat, sibutramine and rimonabant within their licensed indications for the treatment of obese patients. Electronic bibliographic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched in January 2009, and the reference lists of relevant articles were checked. Studies were included if they compared orlistat, sibutramine or rimonabant with lifestyle and/or exercise advice (standard care), placebo or metformin. RESULTS: Overall, 94 studies involving 24,808 individuals were included in the clinical meta-analysis. Eighty-three trials included data on weight change, 41 included data on BMI change and 45 and 36 studies reported on 5% and 10% body weight loss, respectively. Overall, the results show that the active drug interventions are all effective at reducing weight and BMI compared with placebo. In the case of sibutramine, the higher dose (15 mg) resulted in a greater reduction than the lower dose (10 mg). Generally, the data quality of the trials included was low with poor reporting of standard errors and standard deviations. Results from the BMI risk models derived from the GPRD showed consistent increases in risk with increasing BMI. Adjustments for key confounders, such as age, sex and smoking status, were found to be statistically significant at the 5% level, in all risk models. Applying linear models to estimate BMI trajectories, for the diabetic cohort, an average increase in BMI of 0.040 per year for both men and women was observed. The non-diabetic cohort model showed an increase in BMI of 0.175 per year for women and 0.145 per year for men. The results of the cost-effectiveness analyses suggest that sibutramine 15 mg dominates the other three active interventions and the net benefit analyses show that sibutramine 15 mg is the most cost-effective alternative for thresholds > £2000 per quality-adjusted life-year (QALY). However, both sibutramine and rimonabant have been withdrawn because of safety concerns relating to potential treatment-induced fatal adverse events. If the proportion of patients who experienced a fatal adverse event was > 1.8% (1.5%, 1.0%) for sibutramine 15 mg (sibutramine 10 mg, rimonabant) the treatment would not be considered cost-effective when using a threshold of £20,000 per QALY. LIMITATIONS: The clinical review did not include all possible lifestyle comparators, with the inclusion limited to only those trials included one of the active drug interventions. We also excluded all studies not reported in English. Although the clinical review included data from 94 studies, the quality of data was generally low, particularly in terms of the reporting of standard deviation. There was also inconsistency between the results of the mixed-treatment comparison (MTC) and the pair-wise analyses. CONCLUSION: The MTC of anti-obesity treatments shows that all the active treatments are effective at reducing weight and BMI. The economic results show that, compared with placebo, the treatments are all cost-effective when using a threshold of £20,000 per QALY, and, within the limitations of the data available, sibutramine 15 mg dominates the other three interventions. This work has highlighted many areas of methodological research that could be explored, including assessing inconsistencies within a network to determine differences between the results of pair-wise and MTC analyses; the use of meta-regression methods to look for effect modifiers; exploring the effect of local publication bias; and the use of joint models to analyse the repeated measures of BMI and the time-to-event processes simultaneously. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Prescribing high-dose lipid-lowering therapy early to avoid subsequent cardiovascular events: is this a cost-effective strategy?

BACKGROUND: While evidence shows high-dose statins reduce cardiovascular events compared with moderate doses in individuals with acute coronary syndrome (ACS), many primary care trusts (PCT) advocate the use of generic simvastatin 40 mg/day for these patients. METHODS AND RESULTS: Data from 28 RCTs were synthesized using a mixed treatment comparison model. A Markov model was used to evaluate the cost-effectiveness of treatments taking into account adherence and the likely reduction in cost for atorvastatin when the patent expires. There is a clear dose-response: rosuvastatin 40 mg/day produces the greatest reduction in low-density lipoprotein cholesterol (56%) followed by atorvastatin 80 mg/day (52%), and simvastatin 40 mg/day (37%). Using a threshold of £20,000 per QALY, if adherence levels in general practice are similar to those observed in RCTs, all three higher dose statins would be considered cost-effective compared to simvastatin 40 mg/day. Using the net benefits of the treatments, rosuvastatin 40 mg/day is estimated to be the most cost-effective alternative. If the cost of atorvastatin reduces in line with that observed for simvastatin, atorvastatin 80 mg/day is estimated to be the most cost-effective alternative. CONCLUSION: Our analyses show that current PCT policies intended to minimize primary care drug acquisition costs result in suboptimal care.

Diagnostic management strategies for adults and children with minor head injury: a systematic review and an economic evaluation.

BACKGROUND: Patients with minor head injury [Glasgow Coma Scale (GCS) score 13-15] have a small but important risk of intracranial injury (ICI) that requires early identification and neurosurgical treatment. Diagnostic assessment can use either a clinical decision rule or unstructured assessment of individual clinical features to identify those who are at risk of ICI and in need of computerised tomography (CT) scanning and/or hospital admission. Selective use of CT investigations helps minimise unnecessary radiation exposure and resource use, but can lead to missed opportunities to provide early treatment for ICI. OBJECTIVES: To determine the diagnostic accuracy of decision rules, individual clinical characteristics, skull radiography and biomarkers, and the clinical effectiveness and cost-effectiveness of diagnostic management strategies for minor head injury (MHI). DATA SOURCES: Several electronic databases [including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE and The Cochrane Library] were searched from inception to April 2009 (updated searches to March 2010 were conducted on the MEDLINE databases only). Searches were supplemented by hand-searching relevant articles (including citation searching) and contacting experts in the field. For each of the systematic reviews the following studies were included (1) cohort studies of patients with MHI in which a clinical decision rule or individual clinical characteristics (including biomarkers and skull radiography) were compared with a reference standard test for ICI or need for neurosurgical intervention and (2) controlled trials comparing alternative management strategies for MHI. REVIEW METHODS: Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool (for the assessment of diagnostic accuracy) or criteria recommended by the Effective Practice and Organisation of Care Review Group (for the assessment of management practices). Where sufficient data existed, a meta-analysis was undertaken to generate pooled estimates of diagnostic parameters. A decision-analysis model was developed using Simul8 2008 Professional software (Simul8 Corporation, Boston, MA, USA) to estimate the costs and quality-adjusted life-years (QALYs) accrued by management strategies for MHI. The model took a lifetime horizon and NHS perspective. Estimates of the benefits of early treatment, harm of radiation exposure and long-term costs were obtained through literature reviews. Initial analysis was deterministic, but probabilistic sensitivity analysis was also performed. Secondary analyses were undertaken to explore the trade-off between sensitivity and specificity in diagnostic strategies and to determine the cost-effectiveness of scenarios involving hospital admission. RESULTS: The literature searches identified 8003 citations. Of these, 93 full-text papers were included for the assessment of diagnostic accuracy and one for the assessment of management practices. The quality of studies and reporting was generally poor. The Canadian CT Head Rule (CCHR) was the most widely validated adult rule, with sensitivity of 99-100% and 80-100% for neurosurgical and any ICI, respectively (high- or medium-risk criteria), and specificity of 39-51%. Rules for children had high sensitivity and acceptable specificity in derivation cohorts, but limited validation. Depressed, basal or radiological skull fracture and post-traumatic seizure (PTS) [positive likelihood ratio (PLR) > 10]; focal neurological deficit, persistent vomiting, decrease in GCS and previous neurosurgery (PLR 5-10); and fall from a height, coagulopathy, chronic alcohol use, age > 60 years, pedestrian motor vehicle accident (MVA), any seizure, undefined vomiting, amnesia, GCS < 14 and GCS < 15 (PLR 2-5) increased the likelihood of ICI in adults. Depressed or basal skull fracture and focal neurological deficit (PLR > 10), coagulopathy, PTS and previous neurosurgery (PLR 5-10), visual symptoms, bicycle and pedestrian MVA, any seizure, loss of consciousness, vomiting, severe or persistent headache, amnesia, GCS < 14, GCS < 15, intoxication and radiological skull fracture (PLR 2-5) increased the likelihood of ICI in children. S100 calcium-binding protein B had pooled sensitivity of 96.8% [95% highest-density region (HDR) 93.8% to 98.6%] and specificity of 42.5% (95% HDR 31.0% to 54.2%). The only controlled trial showed that early CT and discharge is cheaper and at least as effective as hospital admission. Economic analysis showed that selective CT use dominated 'CT all' and 'discharge all' strategies. The optimal strategies were the CCHR (adults) and the CHALICE (Children's Head injury Algorithm for the prediction of Important Clinical Events) or NEXUS II (National Emergency X-Radiography Utilization Study II) rule (children). The sensitivity and specificity of the CCHR (99% and 47%, respectively) represented an appropriate trade-off of these parameters. Hospital admission dominated discharge home for patients with non-neurosurgical injury, but cost £39 M per QALY for clinically normal patients with a normal CT. CONCLUSIONS: The CCHR is widely validated and cost-effective for adults. Decision rules for children appear cost-effective, but need further validation. Hospital admission is cost-effective for patients with abnormal, but not normal, CT. The main research priorities are to (1) validate decision rules for children; (2) determine the prognosis and treatment benefit for non-neurosurgical injuries; (3) evaluate the use of S100B alongside a validated decision rule; (4) evaluate the diagnosis and outcomes of anticoagulated patients with MHI; and (5) evaluate the implementation of guidelines, clinical decision rules and diagnostic strategies. Formal expected value of sample information analysis would be recommended to appraise the cost-effectiveness of future studies. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Rivaroxaban for the prevention of venous thromboembolism: a single technology appraisal.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rivaroxaban for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's evidence came from four randomised controlled trials (RCTs) comparing rivaroxaban with enoxaparin [RECORD (Regulation of Coagulation in Orthopedic surgery to pRevent Deep venous thrombosis and pulmonary embolism) 1-4] and three comparing dabigatran with enoxaparin [RE-NOVATE (the prevention of venous thromboembolism after total hip replacement trial), RE-MODEL (the prevention of venous thromboembolism after total knee replacement trial) and RE-MOBILIZE (the prevention of venous thromboembolism after total knee arthroplasty trial)]. The evidence from the four RECORD trials indicates that rivaroxaban had superior efficacy over enoxaparin after total hip replacement (THR) and total knee replacement (TKR). For the composite primary outcome of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and death from all causes the relative risk reductions were 70-79% in THR and 31-49% in TKR. Rivaroxaban also had superior efficacy over enoxaparin for the secondary outcome major VTE. Rivaroxaban was not inferior to enoxaparin on the safety outcome of major bleeding. After the correction of some errors found by the ERG, the manufacturer's economic model represented a reasonable model of patients receiving prophylaxis for THR or TKR. In the base-case analyses rivaroxaban dominated both enoxaparin and dabigatran. The incremental costs saved and quality-adjusted life-years (QALYs) gained were small (below 200 pounds and 0.005, respectively, per person). Analyses were conducted sampling from the distributions observed from the RCTs. When all parameters were sampled rivaroxaban dominated enoxaparin in all scenarios except for two, in which enoxaparin produced more QALYs than rivaroxaban and had an incremental cost per QALY gained of 5000 pounds and 8000 pounds respectively. Rivaroxaban dominated dabigatran when RECORD 1 and RECORD 2, individually or pooled, were compared with RE-NOVATE and when all four rivaroxaban RCTs pooled were compared with all three dabigatran RCTs. Dabigatran dominated rivaroxaban comparing RECORD 4 with RE-MODEL and RE-MOBILIZE, and was more cost-effective than rivaroxaban comparing RECORD 3 (incremental cost per QALY gained of rivaroxaban compared with dabigatran of 123,000 pounds) or RECORD 3 and RECORD 4 pooled (incremental cost per QALY gained of dabigatran compared with rivaroxaban of 400 pounds) with RE-MODEL and RE-MOBILIZE. In conclusion, the evidence indicates that rivaroxaban is not inferior to enoxaparin in terms of the primary and secondary outcomes. The submission presents a reasonable estimation of the cost-effectiveness of rivaroxaban compared with enoxaparin and dabigatran, although the uncertainty in the decision has been underestimated. The results are particularly sensitive to any assumed difference in the number of fatal PEs, but the ERG does not believe there is sufficient evidence to support a difference between interventions. The NICE guidance issued as a result of the STA states that: riveroxaban, within its marketing authorisation, is recommended as an option for the prevention of venous thromboembolism in adults having elective THR or elective TKB.

Changes in serum lipids and postprandial glucose and insulin concentrations after consumption of beverages with beta-glucans from oats or barley: a randomised dose-controlled trial.

OBJECTIVES: To investigate side by side the effects on serum lipoproteins and postprandial glucose and insulin concentrations of beverages enriched with 5 or 10 g of beta-glucans from oats or barley. DESIGN AND SETTING: An 8-week single blind, controlled study with five parallel groups carried out at two centres under identical conditions. SUBJECTS: A total of 100 free-living hypercholesterolaemic subjects were recruited locally and 89 completed the study. INTERVENTIONS: During a 3-week run-in period all subjects consumed a control beverage. For the following 5-week period four groups received a beverage with 5 or 10 g beta-glucans from oats or barley and one group continued with the control beverage. Blood samples in weeks 0, 2, 3, 7 and 8 were analysed for serum lipids, lipoproteins, glucose and insulin. Postprandial concentrations of glucose and insulin were compared between control and the beverage with 5 g of beta-glucans from oats or barley. RESULTS: Compared to control, 5 g of beta-glucans from oats significantly lowered total-cholesterol by 7.4% (P<0.01), and postprandial concentrations of glucose (30 min, P=0.005) and insulin (30 min, P=0.025). The beverage with 10 g of beta-glucans from oats did not affect serum lipids significantly in comparison with control. No statistically significant effects compared to control of the beverages with barley beta-glucans were found. CONCLUSIONS: A daily consumption of 5 g of oat beta-glucans in a beverage improved the lipid and glucose metabolism, while barley beta-glucans did not.

Human brain areas involved in the analysis of auditory movement.

This work tests the hypothesis that a network of areas involving bilateral premotor cortex and right parietal cortex subserves the analysis of sound movement. The components of this network have been examined at the level of individual subjects in a study where 720 fMRI scans were acquired per subject. Additionally, the effect of movement direction was investigated by varying this property systematically. Linear sound ramps that are perceived as movement toward one side of the head or the other were used in an experiment in which the principal contrast was between movement, and a stationary control stimulus made up of identical component interaural phase and amplitude cues. In a group analysis, the network of bifrontal and right parietal areas suggested by previous work was confirmed. The frontal activation included both dorsal premotor activity in the region of the frontal eye fields and discrete ventral premotor activation in an area corresponding to primate areas for multimodal spatial analysis and motor planning. The right parietal activation included both superior and inferior parietal cortex. Analysis of the individual data showed a similar pattern of activation in each subject, with the greatest variability within the right parietal area. The pattern of activation did not vary when the direction of movement was varied, suggesting that both directions of movement are represented in the network we have demonstrated.

Can sensitivity to auditory frequency modulation predict children's phonological and reading skills?

Understanding how letter units represent particular speech sounds is a crucial skill for developing competent reading skills. However it is not known whether such phonological ability is constrained by basic auditory capacities such as those necessary for detecting the frequency modulations characteristic of many phonemes. Here we show that nearly 40% of the variability in normal children's phonological and reading skills can be predicted from their sensitivity to 2 Hz frequency modulated (FM) tones. This relationship does not hold for sensitivity to 240 Hz FM. Because lower but not higher rates of FM provide information important for speech comprehension, dynamic auditory sensitivity is likely to play an important role in children's phonological and reading skill development.

Molecular modeling and preclinical evaluation of the humanized NR-LU-13 antibody.

A mouse-human chimeric monoclonal antibody (chNR-LU-13), specific for the EGP40 pancarcinoma antigen, was humanized through three-dimensional molecular modeling. Humanization of the chNR-LU-13 antibody is expected to enhance its use for patients undergoing immunotherapy. On the basis of the observed amino acid sequence identity, chNR-LU-13 complementary determining regions (CDRs) of the V(L) and V(H) regions were grafted onto the human anti-DNA-associated idiotype immunoglobulin clone, R3.5H5G'CL. Ten amino acids residues within the humanized framework were back-mutated to their corresponding chNR-LU-13 sequence, because they were predicted to disrupt the canonical classification of the CDRs or were within 5 A of a CDR. Synthesis of the V(L) and V(H) regions was accomplished by recursive PCR, and the dual-chain expression vector p451.C4 was positioned under control of the CMV(P+E). We observed by competitive ELISA that the recombinant humanized NR-LU-13 (huNR-LU-13) IgG1 antibody exhibited an indistinguishable immunoreactivity profile when compared with the murine monoclonal antibody (muNR-LU-10). The huNR-LU-13 antibody was effective in mediating both antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity when assayed against either the breast carcinoma cell line, MCF-7, or the colon adenocarcinoma cell line, SW1222. Biodistribution studies using i.v. coinjected 131I-muNR-LU-10 and 125I-huNR-LU-13 confirmed that the huNR-LU-13 specifically targets to the tumor in athymic BALB/c mice bearing the SW1222 human tumor xenograft. Humanization of the chNR-LU-13 antibody is expected to eliminate an undesired human antimouse antibody response, allowing for repeated i.v. administration into humans.

Sensitivity to dynamic auditory and visual stimuli predicts nonword reading ability in both dyslexic and normal readers.

BACKGROUND: Developmental dyslexia is a specific disorder of reading and spelling that affects 3-9% of school-age children and adults. Contrary to the view that it results solely from deficits in processes specific to linguistic analysis, current research has shown that deficits in more basic auditory or visual skills may contribute to the reading difficulties of dyslexic individuals. These might also have a crucial role in the development of normal reading skills. Evidence for visual deficits in dyslexia is usually found only with dynamic and not static stimuli, implicating the magnocellular pathway or dorsal visual stream as the cellular locus responsible. Studies of such a dissociation between the processing of dynamic and static auditory stimuli have not been reported previously. RESULTS: We show that dyslexic individuals are less sensitive both to particular rates of auditory frequency modulation (2 Hz and 40 Hz but not 240 Hz) and to dynamic visual-motion stimuli. There were high correlations, for both dyslexic and normal readers, between their sensitivity to the dynamic auditory and visual stimuli. Nonword reading, a measure of phonological awareness believed crucial to reading development, was also found to be related to these sensory measures. CONCLUSIONS: These results further implicate neuronal mechanisms that are specialised for detecting stimulus timing and change as being dysfunctional in many dyslexic individuals. The dissociation observed in the performance of dyslexic individuals on different auditory tasks suggests a sub-modality division similar to that already described in the visual system. These dynamic tests may provide a non-linguistic means of identifying children at risk of reading failure.

Right parietal cortex is involved in the perception of sound movement in humans.

Changes in the delay (phase) and amplitude of sound at the ears are cues for the analysis of sound movement. The detection of these cues depends on the convergence of the inputs to each ear, a process that first occurs in the brainstem. The conscious perception of these cues is likely to involve higher centers. Using novel stimuli that produce different perceptions of movement in the presence of identical phase and amplitude modulation components, we have demonstrated human brain areas that are active specifically during the perception of sound movement. Both functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) demonstrated the involvement of the right parietal cortex in sound movement perception with these stimuli.

Spatial and temporal auditory processing deficits following right hemisphere infarction. A psychophysical study.

Higher auditory function in a patient was investigated following a right hemisphere infarction between the middle and posterior cerebral artery territories involving the insula. The patient complained of lack of musical appreciation and a battery of tests confirmed a dissociated receptive musical deficit in the presence of normal appreciation of environmental sounds and speech. The ability to detect continuous changes in sound frequency in the form of sinusoidal frequency modulation was preserved. There was, however, a deficit in the analysis of rapid temporal sequences of notes which could underlie his musical deficit. This case provides further evidence for the existence of amusia as a distinct form of auditory agnosia, but does not support the hypothesis that bilateral lesions are required to produce such a deficit. Unexpectedly, the patient was also found to have a deficit in the perception of apparent sound-source movement. We suggest that this deficit is analogous to the visual phenomenon of akinetopsia, and is in accord with PET work suggesting involvement of areas outside primary auditory cortex in sound movement perception. A possible common deficit in auditory temporal and spatial 'scene analysis' is discussed.

Diagnosis of Hirschsprung's disease.

OBJECTIVE: Our aims were to determine the validity of using low-osmolality water-soluble contrast enemas (WSCE) in neonates and infants with suspected Hirschsprung's disease (HD) and to devise a scoring system that uses a checklist of radiologic signs to determine the probability of HD. MATERIALS AND METHODS: The records of all patients referred by pediatric surgeons from 1988 through 1992 for the radiologic investigation of possible HD were retrospectively reviewed. Thirty-eight patients who were from 2 days to 9 months old were studied; 20 of them were neonates (less than 1 month old). Of all the patients, 24 underwent WSCE and the other 14 underwent barium enema. For all patients, HD had been diagnosed by rectal biopsy or excluded by biopsy, clinical follow-up, or both. Radiographs were read by a gastrointestinal radiologist who used a checklist of diagnostic criteria reported in the literature. The sensitivity had specificity of the findings were compared with those in the literature. RESULTS: Of the 18 patients with HD, 12 were neonates. All reported radiologic diagnostic criteria were seen; the frequency, sensitivity, and specificity of the findings were reported. Twenty percent (n = 2) of HD patients in the WSCE group (n = 10) had negative findings. Two of the 12 neonates developed colonic perforation, one during the enema and the other within 24 hr of the procedure. CONCLUSION: WSCE has a sensitivity and specificity equivalent to those of the barium enema for the detection of HD. For the two patients with perforation, the use of WSCE was of considerable benefit, avoiding the problems associated with barium spillage into the peritoneal cavity. A scoring system for diagnostic enemas is feasible.

Binaural masking and sensitivity to interaural delay in the inferior colliculus.

The binaural masking level difference (BMLD) is a psychophysical effect whereby signals masked by a noise at one ear become unmasked by sounds reaching the other. BMLD effects are largest at low frequencies where they depend on signal phase, suggesting that part of the physiological mechanism responsible for the BMLD resides in cells that are sensitive to interaural time disparities. We have investigated a physiological basis for unmasking in the responses of delay-sensitive cells in the central nucleus of the inferior colliculus in anaesthetized guinea pigs. The masking effects of a binaurally presented noise, as a function of the masker delay, were quantified by measuring the number of discharges synchronized to the signal, and by measuring the masked threshold. The noise level for masking was lowest at the best delay for the noise. The mean magnitude of the unmasking across our neural population was similar to the human psychophysical BMLD under the same signal and masker conditions.

Neuronal responses to amplitude-modulated and pure-tone stimuli in the guinea pig inferior colliculus, and their modification by broadband noise.

Neuronal responses were recorded to pure and to sinusoidally amplitude-modulated (AM) tones at the characteristic frequency (CF) in the central nucleus of the inferior colliculus of anesthetized guinea pigs. Temporal (synchronized) and mean-rate measures were derived from period histograms locked to the stimulus modulation waveform to characterize the modulation response. For stimuli presented in quiet, the modulation gain at low frequencies of modulation (approx less than 50 Hz) was inversely proportional to the neuron's mean firing rate in response to both the modulated stimulus and to a pure tone at an equivalent level. In 43% of units the mean discharge rates in response to the AM stimuli were greatest for those modulation frequencies that generated the largest temporal responses. These discharge-rate maxima occurred at signal intensities corresponding to the steeply sloping part of the neuron's pure-tone rate-intensity function (RIF). The change in mean-rate response to modulated stimuli, as a function of intensity, was qualitatively similar to the pure-tone RIF. Adding broadband noise to the modulated stimulus increased the neuron's temporal response to low modulation frequencies. This increase in modulation gain was correlated with mean firing rate in response to the modulation but did not bear a simple relationship to the noise-induced shift in the RIF measured for a pure tone.

Dynamic properties of the responses of single neurons in the inferior colliculus of the rat.

The responses of single cells in the central nucleus of the inferior colliculus of the rat were studied with characteristic frequency tones amplitude modulated by pseudorandom noise or sinusoidal waveforms, in order to investigate the degree to which these responses can be described by a linear model. When pseudorandom noise was used as the modulating waveform, period histograms of the response locked to the periodicity of the noise were cross-correlated with a single period of the noise. The response of a model, having this cross-correlogram as its impulse response and the pseudorandom noise sequence as the input waveform, differed in appearance from the corresponding period histogram of the neural discharges, indicating that the latter contained a non-negligible, nonlinear component. Further manipulation of the data showed that the most significant nonlinearities were of even order, which indicates that the changes in neural discharge rate to increments and decrements in stimulus intensity are asymmetrical. In some units, particularly at low mean stimulus intensities, this was clearly evident as a halfwave rectification of the period histogram. The magnitude of the modulation of the period histograms increased as a function of the sound intensity for some units, while in others it decreased; in still other units the magnitude of the modulation of the neural discharges was relatively constant over a large range of stimulus intensities. When the modulation transfer functions were estimated from the responses to noise-modulated sounds they were found to be very similar to those obtained using sinusoidally modulated sound, despite large degrees of nonlinearity being present in the responses to both types of sound.

Experimental drug intoxication: treatment with charcoal haemoperfusion.

Dogs were given large doses of barbiturates, glutethimide, ethanol, methaqualone, ethchlorvynol, meprobamate, chloral hydrate, paracetamol and aspirin. These were treated by haemoperfusion using a column packed with charcoal coated with an acrylic hydrogel. Clearances for most drugs were significantly higher than those reported for haemodialysis. Minimal clearances of common biochemical entities were observed and although leucocyte and platelet counts were diminished, no deleterious effects attributable to this were encountered. Careful histological examination of tissues derived from perfused dogs revealed no evidence of charcoal emboli.