Search

Describe the 5-year outcomes of the first successful pediatric bilateral hand transplantation.The child underwent quadrimembral amputation at age two and received bilateral hand allografts at age eight. Rehabilitation included biomechanical, neurorehabilitation, and occupational approaches in acute and outpatient settings. Therapist observed outcomes, patient-reported measures, and parent-reported measures were repeated over a 5-year period.Observation assessments revealed functional dexterity skills and modified independence to full independence with self-care activities. The parent reported the child had moderate difficulty with upper extremity functioning 25-, 41-, and 48-months post-transplantation, and mild difficulty at 60-months; the child reported no difficulties in this domain at 41 months. Five years post-transplantation the child reported enjoying many age-appropriate activities, and high-quality peer relations were endorsed by both parent and child.The child developed hand movements for daily activities and was completing daily activities with improved efficiency. Health-related quality of life outcomes were favorable.

Children with hemiplegia often demonstrate gait deviations including increased variability and asymmetry. Step-to-step gait variability decreases over childhood and increases in the presence of neurologic dysfunction. Gait variability in children with hemiplegia should therefore be interpreted in reference to age-related norms RESEARCH QUESTION: Does conversion of the enhanced gait variability index (eGVI) to age-normalized z-scores improve interpretation of gait variability in children with hemiplegia?Ten children (11.2 +/- 4.1 years) with hemiparetic gait due to stroke were recruited for a small prospective pilot intervention study. Participants walked at self-selected speed over an instrumented walkway while barefeet and while wearing shoes. eGVI values from baseline sessions were calculated and converted to age-normalized z-scores (eGVIThere were no differences in raw eGVI or eGVIWe suggest that eGVI values in children be converted to z-scores or otherwise age-normalized so as not to inflate the degree of variability reported in clinical pediatric populations. Future work with larger samples will offer greater insight into gait variability in various clinical pediatric populations.

In the past two decades, three coronaviruses with ancestral origins in bats have emerged and caused widespread outbreaks in humans, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first SARS epidemic in 2002–2003, the appreciation of bats as key hosts of zoonotic coronaviruses has advanced rapidly. More than 4,000 coronavirus sequences from 14 bat families have been identified, yet the true diversity of bat coronaviruses is probably much greater. Given that bats are the likely evolutionary source for several human coronaviruses, including strains that cause mild upper respiratory tract disease, their role in historic and future pandemics requires ongoing investigation. We review and integrate information on bat–coronavirus interactions at the molecular, tissue, host and population levels. We identify critical gaps in knowledge of bat coronaviruses, which relate to spillover and pandemic risk, including the pathways to zoonotic spillover, the infection dynamics within bat reservoir hosts, the role of prior adaptation in intermediate hosts for zoonotic transmission and the viral genotypes or traits that predict zoonotic capacity and pandemic potential. Filling these knowledge gaps may help prevent the next pandemic., Bats harbour a multitude of coronaviruses and owing to their diversity and wide distribution are prime reservoir hosts of emerging viruses. Ruiz-Aravena, McKee and colleagues analyse the currently available information on bat coronaviruses and discuss their role in recent and potential future spillovers.

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents(1,2) and they are dysregulated in multiple human neurological disorders(3–5). Little is known about molecular characteristics of adult human hippocampal imGCs and even their existence is under debate(1,6–8). Here we performed single-nucleus RNA-sequencing (snRNA-seq) aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus during infant, child, adolescent, adult, and aging stages. We identified common molecular hallmarks of human imGCs across the lifespan and discovered age-dependent transcriptional dynamics unique to human imGCs that suggest changes in cellular functionality, niche interactions, and disease relevance, in contrast to those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer’s disease (AD). Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a significant number of imGCs in the adult human hippocampus via low frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in AD.

The measurement of gait is likely influenced by walking speed in children with hemiplegia, but this relationship is not well characterized.What is the influence of walking speed on spatiotemporal and symmetry measures of gait in children with hemiplegia, with consideration of side and footwear condition?Children with hemiparetic gait due to stroke were recruited for a small pilot intervention study. Participants walked at self-selected and fast speeds while barefoot and while wearing shoes. Data from baseline sessions were included in this analysis. The influence of walking speed on five spatiotemporal gait measures was determined using a generalized estimating equation to calculate the proportion of variability in the gait measures that was explained by walking speed. Differences between sides and footwear conditions, and the relationships between walking speed and two symmetry measures, are also reported.A total of 820 steps were analyzed from ten children (11.2 ± 4.1 years). Walking velocity significantly influenced all spatiotemporal measures of gait. As speed increased, step length increased and all temporal measures decreased, on both paretic and nonparetic sides. Wearing shoes increased step length and stance time for both paretic and nonparetic sides, and slowed step time on the nonparetic side. Regardless of footwear, the paretic side demonstrated slower step and swing times, and faster stance and single support times. We did not observe significant relationships between walking speed and gait symmetry.Our observations suggest that walking speed alone influences the spatiotemporal measurement of gait in children with hemiplegia and should be considered in the interpretation of walking function. Yet, controlling for walking speed is often not feasible or not preferred in this population. We offer suggestions for clinicians and researchers who seek to measure gait during overground walking at freely-selected speeds.

The prevalence and intensity of parasites in wild hosts varies across space and is a key determinant of infection risk in humans, domestic animals, and threatened wildlife. Because the immune system serves as the primary barrier to infection, replication, and transmission following exposure, we here consider the environmental drivers of immunity. Spatial variation in parasite pressure, abiotic and biotic conditions, and anthropogenic factors can all shape immunity across spatial scales. Identifying the most important spatial drivers of immunity could help preempt infectious disease risks, especially in the context of how large-scale factors such as urbanization affect defense by changing environmental conditions. We provide a synthesis of how to apply macroecological approaches to the study of ecoimmunology (i.e., macroimmunology). We first review spatial factors that could generate spatial variation in defense, highlighting the need for large-scale studies that can differentiate competing environmental predictors of immunity and detailing contexts where this approach might be favored over small-scale experimental studies. We next conduct a systematic review of the literature to assess the frequency of spatial studies and to classify them according to taxa, immune measures, spatial replication and extent, and statistical methods. We review 210 ecoimmunology studies sampling multiple host populations. We show that whereas spatial approaches are relatively common, spatial replication is generally low and unlikely to provide sufficient environmental variation or power to differentiate competing spatial hypotheses. We also highlight statistical biases in macroimmunology, in that few studies characterize and account for spatial dependence statistically, potentially affecting inferences for the relationships between environmental conditions and immune defense. We use these findings to describe tools from geostatistics and spatial modeling that can improve inference about the associations between environmental and immunological variation. In particular, we emphasize exploratory tools that can guide spatial sampling and highlight the need for greater use of mixed-effects models that account for spatial variability while also allowing researchers to account for both individual- and habitat-level covariates. We lastly discuss future research priorities for macroimmunology, including focusing on latitudinal gradients, range expansions, and urbanization as being especially amenable to large-scale spatial approaches. Methodologically, we highlight critical opportunities posed by assessing spatial variation in host tolerance, using metagenomics to quantify spatial variation in parasite pressure, coupling large-scale field studies with small-scale field experiments and longitudinal approaches, and applying statistical tools from macroecology and meta-analysis to identify generalizable spatial patterns. Such work will facilitate scaling ecoimmunology from individual- to habitat-level insights about the drivers of immune defense and help predict where environmental change may most alter infectious disease risk.

The molecular diversity of glia in the human hippocampus and their temporal dynamics over the lifespan remain largely unknown. Here, we performed single-nucleus RNA sequencing to generate a transcriptome atlas of the human hippocampus across the postnatal lifespan. Detailed analyses of astrocytes, oligodendrocyte lineages, and microglia identified subpopulations with distinct molecular signatures and revealed their association with specific physiological functions, age-dependent changes in abundance, and disease relevance. We further characterized spatiotemporal heterogeneity of GFAP-enriched astrocyte subpopulations in the hippocampal formation using immunohistology. Leveraging glial subpopulation classifications as a reference map, we revealed the diversity of glia differentiated from human pluripotent stem cells and identified dysregulated genes and pathological processes in specific glial subpopulations in Alzheimer's disease (AD). Together, our study significantly extends our understanding of human glial diversity, population dynamics across the postnatal lifespan, and dysregulation in AD and provides a reference atlas for stem-cell-based glial differentiation.

Background A diet in which fat is mainly eaten in the morning and carbohydrates mainly in the evening (compared with the reverse order) was recently shown to worsen glycemic control in people with prediabetes. Objective We investigated the effects of these dietary patterns on energy metabolism, and on the daily profiles of circulating lipids, adipokines, and inflammatory markers. Design In a randomized controlled crossover trial, 29 nonobese men (with normal glucose tolerance, n = 18; or impaired fasting glucose/glucose tolerance, n = 11) underwent 2 isocaloric 4-wk diets: 1) carbohydrate-rich meals until 1330 and fat-rich meals between 1630 and 2200 (HC/HF); or 2) the inverse sequence of meals (HF/HC). During a 12-h clinical investigation day after each intervention period, 2 meal tolerance tests were performed, at 0900 and 1540, respectively. Substrate oxidation and concentrations of circulating lipids, adipokines, and cytokines were assessed pre- and postprandially. The postprandial inflammatory response in leukocytes was analyzed ex vivo. Results Fasting carbohydrate oxidation decreased (P = 0.004) and lipid oxidation increased (P = 0.012) after the HC/HF diet. Fasting concentrations of blood markers did not differ between diets. The diets modulated the daily profiles of carbohydrate oxidation, lipid oxidation, and β-hydroxybutyrate, although the average daily values of these parameters showed no difference between the diets, and no interaction between diet and glucose tolerance status. Diurnal patterns of triglycerides, low-density lipoprotein cholesterol, leptin, visfatin, and of LPS-induced cytokine secretion in blood leukocytes were also modulated by the diets. Average daily concentrations of leptin (P = 0.017) and visfatin (P = 0.041) were lower on the HF/HC diet than on the HC/HF diet. Conclusions Diurnal distribution of carbohydrates and fat affects the daily profiles of substrate oxidation, circulating lipids, and cytokine secretion, and alters the average daily concentrations of adipokine secretion in nonobese nondiabetic humans. The study was registered at clinicaltrials.gov as NCT02487576.

Cognitive functioning, particularly executive functioning, is a strong predictor of functional outcomes in people with schizophrenia. Cognitive remediation has been shown to improve specific cognitive processes, but adjunctive interventions are required for meaningful gains in adaptive functioning, particularly in people with chronic illness. This study examined whether (and how) environmental adaptations, used without training, may circumvent cognitive difficulties and facilitate everyday task performance in individuals with chronic schizophrenia. Forty-two individuals with chronic schizophrenia/schizoaffective disorder were administered cognitive measures and two versions of the Naturalistic Action Test (NAT)—a standard version (ST-NAT), and a user-centered version (UC-NAT) that incorporated environmental adaptations designed to facilitate task performance. The NAT conditions were counterbalanced across participants. Analyses compared performance between the NAT versions and examined the cognitive correlates of each NAT condition. Individuals with schizophrenia made fewer errors on the UC-NAT as compared to the ST-NAT; this between-group difference was significant for all error types. Compared to the ST-NAT, the UC-NAT performance was not significantly associated with an executive function measure of planning. Environmental adaptations may be implemented without extensive training to improve everyday action in individuals with chronic schizophrenia. Environmental adaptations that reduce planning demands may be most effective in this population. (JINS, 2015, 21, 319–329)

Planning of everyday tasks was examined in 48 inpatients with schizophrenia and 26 healthy controls. Participants were administered the Naturalistic Action Test, which requires completion of three everyday tasks (e.g., make toast and coffee). Planning variables, including planning behaviours (e.g., gathering items before engaging in a subtask) and planning time (e.g., period between task instructions and first action) were coded to evaluate forward thinking in these tasks. Results showed that planning variables were reliably coded. Controls demonstrated more planning behaviours than participants with schizophrenia; however, this difference was accounted for by education. People with schizophrenia spent significantly less time planning when planning time was analysed as a proportion of the total time on tasks. Planning variables were related to the ability to accomplish everyday task steps and to perform everyday task steps accurately. Together these findings suggest that rehabilitation strategies that emphasise both planning time and planning behaviours may facilitate everyday functioning in people with schizophrenia.

UGT enzymes catalyze the formation of glucuronic acid conjugates. Specifically selected representative stable isotope (C(13), N(15)) labeled peptide internal standards of each enzyme were employed to quantify UGTs 1A1 and 1A6 by LC-MS/MS using isotope dilution techniques. Inter day variability (n=5) for human liver microsomes wasor= 8.0 % for UGT1A1 andor= 19 % for UGT1A6. Comparison within a human liver microsomal library showed a strong correlation with Western blot for UGT1A1 concentrations (r=0.988). The data presented indicates that an accurate and reproducible method for UGT absolute quantification can be established using LC-MS/MS analysis of characteristic peptides within the protein.

Relative to our understanding of the memory and language deficits associated with Alzheimer's disease (AD), little is known about problems with everyday action performance (i.e., meal preparation, grooming). The resource theory proposes that everyday action problems are best explained by a unitary deficit in general cognitive resources. However, recent research suggests that omission and commission errors may reflect dissociable aspects of action impairment, with only omissions associated with resource limitations. This study examined everyday action performance in 70 participants with AD who also underwent a neuropsychological evaluation. First, correlation and principal component analyses were performed to examine the construct(s) that might explain everyday action impairment. Second, relations between everyday task component(s) and neuropsychological tests were examined by using correlation and regression analyses. Third, differences in everyday action error patterns were examined among participants of comparable overall impairment levels. Results showed omission and commission errors were uncorrelated and distinct components of everyday action performance, predicted by different neuropsychological tests, and differentially distributed even among participants with comparable overall impairment.

The purpose was to identify the prevalence of naked amoebae in tap water in south Florida to ascertain the risk of amoebal infections of the cornea in contact lens wearers. Over the course of a 2-year period, water samples were collected from sites throughout Broward, Palm Beach, and Dade counties, Florida. The presence of amoebae in samples was based on an enrichment cultivation method appropriate for Acanthamoeba. Amoebae were identified using diagnostic features discernable by light microscopy. A total of 283 water samples were processed and amoebae were noted in 80 of these. Acanthamoeba were found on 8 occasions (2.8%). The genera Hartmannella and Vahlkampfia, rarely involved in keratitis cases, were found in 3.5% and 2.8% of samples, respectively. A total of 19 different naked amoebae were recorded and amoebae (regardless of genus) were present in 19.4% of all samples. Previous surveys in England and Korea have shown that acanthamoebae are found in 15 to 30% of tap water samples in the home and have been associated with corneal infection in contact lens wearers. The incidence of acanthamoebae infection in the USA (2.8%) has been found to be lower than that in the UK and it has been postulated that this is related to the lack of a storage water tank in the roof loft space. However, the level of treatment of municipal water is clearly not effective at killing amoebal cysts (or trophozoites) as evidenced by the high occurrence of amoebae (19.4%) in this study.

Neuropsychologists often recommend that patients with dementia and their caregivers use environmental adaptations to improve everyday functioning. Although these recommendations are intuitive (e.g., reduce clutter), most have never been experimentally tested. This study examined whether and how environmental adaptations improved everyday action in Alzheimer's disease (AD). Forty-six outpatients completed the Naturalistic Action Test (NAT; M. F. Schwartz, L. J. Buxbaum, M. Ferraro, T. Veramonti, & M. Segal, 2003), which requires completion of 3 everyday tasks. The NAT was administered under 2 conditions: standard and user centered. The standard NAT followed the procedures of the manual; object placement was standardized, but objects were not meaningfully arranged on the tabletop. In the user-centered NAT, objects were arranged in the order needed in the task, and a visual cue to monitor performance was placed on the table. These conditions were counterbalanced across participants. The user-centered condition improved performance on all NAT items and reduced commission and omission error rates. However, post hoc examination of commission error types showed improvement of substitution and off-task errors but no difference in anticipation and perseveration errors. Thus, environmental adaptations improved everyday performance in AD by facilitating task accomplishment, object selection, and task-congruent actions.

CONTEXT: The circadian clock coordinates numerous metabolic processes with light-dark and feeding regimens. However, in humans it is unknown whether dietary patterns influence circadian rhythms. OBJECTIVE: We examined the effects of switching from a high-carbohydrate, low-fat diet to a low-carbohydrate, high fat (LC/HFD) isocaloric diet on the central and peripheral circadian clocks in humans. DESIGN: Diurnal patterns of salivary cortisol and gene expression were analyzed in blood monocytes of 29 nonobese healthy subjects before and 1 and 6 weeks after the dietary switch. For this, we established a method of rhythm prediction by 3-time point data. RESULTS: The centrally driven cortisol rhythm showed a phase delay 1 and 6 weeks after the dietary switch to a LC/HFD as well as an amplitude increase. The dietary switch altered diurnal oscillations of core clock genes (PER1, PER2, PER3, and TEF) and inflammatory genes (CD14, CD180, NFKBIA, and IL1B). The LC/HFD also affected the expression of nonoscillating genes contributing to energy metabolism (SIRT1) and fat metabolism (ACOX3 and IDH3A). Expression of clock genes but not of salivary cortisol in monocytes tightly correlated with levels of blood lipids and with expression of metabolic and inflammatory genes. CONCLUSIONS: Our results suggest that the modulation of the dietary fat and carbohydrate content alters the function of the central and peripheral circadian clocks in humans.

Mycophenolic acid (MPA; 1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzylfuranyl)-4-methyl-4-hexenoate), the active metabolite of the immunosuppressant prodrug, mycophenolate mofetil, undergoes glucuronidation to its 7-O-glucuronide as a primary route of metabolism. Because differences in glucuronidation may influence the efficacy and/or toxicity of MPA, we investigated the MPA UDP-glucuronosyltransferase (UGT) activities of human liver microsomes (HLMs) and rat liver microsomes with the goal of identifying UGTs responsible for MPA catalysis. HLMs (n = 23) exhibited higher average MPA glucuronidation rates (14.7 versus 6.0 nmol/mg/min, respectively, p0.001) and higher apparent affinity for MPA (K(m) = 0.082 mM versus 0.20 mM, p0.001) compared with rat liver microsomes. MPA UGT activities were reduced80% in liver microsomes from Gunn rats. To identify the active enzymes, human and rat UGT1A enzymes were screened for MPA-glucuronidating activity. UGT1A9 was the only human liver-expressed UGT1A enzyme with significant activity and exhibited both high affinity (K(m) = 0.077 mM) and high activity (V(max) = 28 nmol x min(-1) x mg(-1)). Spearman correlation analyses revealed a stronger relationship between HLM MPA UGT activities and 1A9-like content (r(2) = 0.79) relative to 1A1 (r(2) = 0.20), 1A4-like (r(2) = 0.22), and 1A6 (r(2) = 0.41) protein. A different profile was observed for rat with three active liver-expressed UGT1A enzymes: 1A1 (medium affinity/capacity), 1A6 (low affinity/medium capacity), and 1A7 (high affinity/capacity). Our data suggest that UGT1A enzymes are the major contributors to hepatic MPA metabolism in both species, but 1A9 is dominant in human, whereas 1A1 and 1A7 are likely the principal mediators in control rat liver. This information should be useful for interpretation of MPA pharmacokinetic and toxicity data in clinical and animal studies.

UDP-glucuronosyltransferase 1A6 (UGT1A6) is a major UGT contributing to the glucuronidation of small phenolic compounds. The gene for rat 1A6 is expressed using two promoters, a distal promoter P1 and a proximal promoter P2. Transcripts from P2 are high in liver, gastrointestinal tract, and kidney, whereas P1 transcripts predominate in other tissues. Here we report evidence for primary control of the P2 promoter by hepatic nuclear factor 1 (HNF1). Transient transfection of a P2 reporter plasmid, p(−1354/+65) 1A6P2-luc, resulted in enhanced luciferase activity in HepG2 but not Hepa1 cells compared to cells transfected with pGL3-Basic control vector. A truncated reporter under the control of −224 to +65 exhibited comparable activity. Footprint analysis of the −224/+65 fragment revealed specific binding by rat liver nuclear protein to a region between bases −60 and −37. The binding activity was also observed with HepG2 cell but not Hepa1 cell extract. Electrophoretic mobility shift assays were consistent with the presence of HNF1 in the binding complexes. The functionality of an HNF1-binding site at −51/−37 is also supported by (1) marked decreases in the activity of P2 reporter plasmids containing a three-base substitution in the proposed HNF1 binding site and (2) the enhancement of P2 reporter activity following cotransfection of an HNF1α expression plasmid. The UGT1A6 P1 promoter lacks an HNF1 binding site in the analogous position and showed little response to HNF1 overexpression. Although these data do not strictly rule out an interaction between the P1 promoter and HNF1 bound to −51/−37 of P2, the results suggest a mechanism for the more abundant expression of P2-derived UGT1A6 transcripts in liver and other HNF1-enriched tissues.

The utility of oltipraz as a cancer chemopreventive agent is thought to depend on the induction of enzymes involved in phase 2 xenobiotic detoxification. Although studies of some enzymes induced by oltipraz implicate a novel transcriptional activating pathway involving Nrf2 and antioxidant-response elements (AREs), the mechanism of phenol UGT induction has remained unclear. Previous work showed that UGT1A6 is transcribed from two promoters, P1 and P2, that are both induced by oltipraz in rat liver. The effect also occurs in rat hepatocytes treated with oltipraz (concentrations >3 microM). To investigate the mechanism, luciferase reporter plasmids under the control of P1 [p(-1078/+27)1A6P1-luc] or P2 [p(-1354/+65)1A6P2-luc] were transfected into rat hepatocytes and tested for inducibility. P1, but not P2, showed responsiveness to oltipraz (2- to 5-fold increase) and 3-methylcholanthrene (10- to 30-fold increase). Because P1 contained no visible AREs, the role of a xenobiotic response element (XRE) centered between bases -134 and -129 was evaluated. Mutation of the XRE core reduced the effects of both oltipraz and 3-methylcholanthrene on the P1 reporter. The 1A6 XRE conferred oltipraz responsiveness on the simian virus 40 promoter of pGL3-Promoter. Comparative effects of oltipraz and 3-methylcholanthrene on transfected cytochrome P4501A1 reporters support the general but relatively weak XRE-stimulating activity of oltipraz. The involvement of the aryl hydrocarbon receptor (AHR) and aryl hydrocarbon nuclear translocator (ARNT) in mediating the effects of oltipraz on the XRE is supported by electrophoretic mobility supershift data and AHR/ARNT overexpression studies. These data raise questions about the contribution of AHR and other secondary induction pathways in the mechanism of oltipraz.

Gunn rats glucuronidate acetaminophen (APAP) at reduced rates and show increased susceptibility to APAP-induced hepatotoxicity. This defect is presumed to involve UDP-glucuronosyltransferase (UGT) 1A6, which is nonfunctional in Gunn rats, but it is currently unclear whether other 1A family members are also involved. In humans, two 1A isoforms are known to be active (1A6 and 1A9) but 1A6 form has a 25-fold lower apparent K(m) (2 mM). Rat liver microsomal APAP UGT activity is induced by in vivo treatment with beta-naphthoflavone or oltipraz, an effect correlating with induction of 1A6 and 1A7. To address a possible role of 1A7 in APAP glucuronidation relative to other 1A forms, cDNAs encoding UGTs 1A1, 1A5, 1A6, 1A7, and 1A8 were expressed in human embryonic kidney cells and the contents of expressed enzyme in prepared membrane fractions determined by quantitative immunoblotting. At 2.5 mM APAP, 1A7 showed the highest specific activity (2.8 nmol/min/nmol 1A7 protein), followed by 1A6 (1.1 nmol/min/nmol), and 1A8 (0.27 nmol/min/nmol). 1A1 and 1A5 were essentially inactive. Kinetic comparisons indicated 1A7 had a similar apparent K(m) as 1A6 (4.7 versus 3.9 mM, respectively) but a 2.4-fold higher catalytic activity. These data suggest that in rats, 1A7 plays a major role in APAP glucuronidation and contributes to protection against APAP-induced hepatotoxicity. The involvement of other UGTs besides 1A6 is further underscored by the presence of significant residual APAP-glucuronidating activity by Gunn rat hepatocytes, indicating the activity of an unknown UGT2 family member.

Prior research using performance-based assessment of functional impairment has informed a novel neuropsychological model of everyday action impairment in dementia in which omission errors (i.e., failure to complete task steps) dissociate from commission errors (i.e., inaccurate performance of task steps) and have unique neuropsychological correlates. However, this model has not been tested in other populations. The present study examined whether this model extends to schizophrenia. Fifty-four individuals with schizophrenia or schizoaffective disorder were administered a neuropsychological protocol and the Naturalistic Action Test (NAT), a performance-based measure of everyday action. A principal component analysis (PCA) was performed to examine the construct(s) comprising everyday action impairment, and correlations between the resultant component(s) and neuropsychological tests were examined. Results showed that omissions and a subset of commissions were distinct components of everyday action. However, results did not support unique associations between these components and specific neuropsychological measures. These findings extend the omission-commission model to schizophrenia and may have important implications for efficient assessment and effective rehabilitation of functional impairment, such as the potential efficacy of targeted interventions for the rehabilitation of omission and commission deficits in everyday functioning. Larger studies with prospective designs are needed to replicate the present preliminary findings. (JINS, 2014, 20, 1–10)

On behavioural as well as physiological levels our daily life is regulated by the circadian clock - endogenous oscillators present in the hypothalamus and in peripheral tissues - which is believed to have evolved as an adaptation to Earth rotation around the Sun and its consequent 24 h dark-light cycle. Accumulative evidence suggests that the circadian clock plays a pivotal role for energy metabolism and energy homeostasis: many hormones, enzymes and transport systems involved in the regulation of energy metabolism have been shown to display circadian rhythms in their expression, secretion and/or activity patterns. The energy metabolism, in turn, can impact on the circadian clock - a process that is called entrainment. Thus, the circadian clock and energy metabolism are intimately intertwined. So far this interplay and its implications for health have not been understood very well. For health maintenance, however, it seems to be crucial to avoid any desynchronisation between the circadian clock and energy metabolism. Form a clinical point of view this might be important for the treatment of obesity and associated disorders and may lead to new life-style approaches.

UDP-glucuronosyltransferase 1A7 (UGT1A7) is a polyaromatic hydrocarbon (PAH)-inducible UGT with activity toward various benzo[a]pyrene (B[a]P) metabolites. To investigate the influence of rat UGT1A7 on B[a]P-induced cytotoxicity, human lymphoblastoid L3 cells were transfected with pMF6 (control expression vector), p167Dtk2 (microsomal epoxide hydrolase expression vector), or p167Dtk2-1A7 (epoxide hydrolase/UGT1A7 coexpression vector), and the cell populations were compared for sensitivity to B[a]P-induced effects. B[a]P inhibited cell proliferation and decreased relative cell survival of p167Dtk2 and p167Dtk2-1A7 cells to a similar extent. Metabolism studies using [(3)H]B[a]P revealed increased formation of glucuronide conjugates of B[a]P-4,5-diol, 3-OH-, or 9-OH-B[a]P and an unidentified metabolite by p167Dtk2-1A7 cells, but the presence of unconjugated metabolites suggested that glucuronidation capacity may be limited. No differences between p167Dtk2 and p167Dtk2-1A7 L3 cells were observed in the growth inhibitory effects of 3-OH-B[a]P or B[a]P-7,8-diol, but p167Dtk2-1A7-expressing cells were found to be less sensitive to B[a]P-3,6-quinone-induced effects on cell proliferation and relative cell survival. The effect was also observed in AHH-1 lymphoblastoid cells expressing UGT1A7 without epoxide hydrolase. The UGT1A7-expressing AHH-1 cells were also less sensitive to growth inhibition by B[a]P-1,6-quinone and B[a]P-6,12-quinone. Flow cytometric analysis of vehicle and B[a]P-3, 6-quinone-exposed cell populations showed an association between UGT1A7 expression and resistance to B[a]P-3,6-quinone-induced apoptosis and loss of cell viability. These data suggest that UGT1A7 may be preferentially active toward B[a]P-quinones and that UGT1A7 may represent the PAH-inducible UGT activity previously implicated in protection against toxic redox cycling by B[a]P-3,6-quinone.

In Crigler-Najjar type II patients and, recently, in Crigler-Najjar type I patients treated with human hepatocyte cell therapy, phenobarbital has been used for reducing the serum bilirubin load. Its effect is attributed to induction of the enzyme required for hepatic bilirubin elimination, UDP-glucuronosyltransferase, UGT1A1. This study investigated the expression and inducibility of UGT1A1 in human donor livers and their corresponding primary hepatocyte cultures. Immunoblot analysis using a specific antibody directed against the amino terminal of the human UGT1A1 isoform showed that 5 hepatocyte donors exhibited a >50-fold difference in UGT1A1 level. UGT1A1 protein level correlated strongly with both liver microsomal bilirubin UGT activity and liver UGT1A1 mRNA level (r(2) =.82 and.72, respectively). Of the 4 patients with the lowest UGT1A1 levels, 3 were homozygotes for the UGT1A1 promoter variant sequence associated with Gilbert's syndrome, and the fourth was a heterozygote. The 3 donors with the highest levels had a history of phenytoin exposure. Hepatocytes isolated from the phenytoin-exposed donors exhibited marked declines in UGT1A1 mRNA levels during culturing. Induction studies using hepatocytes treated for 48 hours with phenobarbital (2 mmol/L), oltipraz (50 micromol/L), or 3-methylcholanthrene (2.5 micromol/L) revealed UGT1A1-inducing effects of phenobarbital, oltipraz, and, in particular, 3-methylcholanthrene. Our data suggest that both genetic and environmental factors play an important role in the marked interindividual variability in UGT1A1 expression. An understanding of these mechanisms could lead to advances in the pharmacological therapy of life-threatening unconjugated hyperbilirubinemia.

Executive function (EF) deficits in schizophrenia (SZ) are well documented, although much less is known about patterns of EF deficits and their association to differential impairments in everyday functioning. The present study empirically defined SZ groups based on measures of various EF abilities and then compared these EF groups on everyday action errors. Participants (n = 45) completed various subtests from the Delis-Kaplan Executive Function System (D-KEFS) and the Naturalistic Action Test (NAT), a performance-based measure of everyday action that yields scores reflecting total errors and a range of different error types (e.g., omission, perseveration). Results of a latent class analysis revealed three distinct EF groups, characterized by (a) multiple EF deficits, (b) relatively spared EF, and (c) perseverative responding. Follow-up analyses revealed that the classes differed significantly on NAT total errors, total commission errors, and total perseveration errors; the two classes with EF impairment performed comparably on the NAT but performed worse than the class with relatively spared EF. In sum, people with SZ demonstrate variable patterns of EF deficits, and distinct aspects of these EF deficit patterns (i.e., poor mental control abilities) may be associated with everyday functioning capabilities.

It has been shown that transesophageal echocardiography (TEE) is useful in evaluating atheromatous disease of the aortic arch and that such disease is a risk factor for stroke in medical patients. Data obtained by traditional methods of evaluating the aortic arch prior to cardiac surgery, namely, chest x-ray (CXR) and cardiac catheterization (CATH), were compared with that detected by TEE. Images of the descending thoracic aorta and aortic arch seen on intraoperative TEE in 258 cardiac surgical patients were graded as I = normal, II = intimal thickening or plaques

Although often incidentally found, diverticular disease of the small bowel and duodenum may generate complications and impose surgical treatment. Diagnosis of small bowel diverticulosis is difficult because the clinical picture is usually ambiguous. We report a case of diverticulosis of the whole intestine including a giant symptomatic retro-pancreatic duodenal diverticulum in a 74-year-old patient who presented with recurrent episodes of abdominal pain, weight loss and intestinal obstruction. The diagnosis was made by MRI enteroclysis and endoscopy. Open diverticulectomy with choledochostomy and insertion of a T-tube was performed and resulted in a rapid improvement of the symptoms.

Directly measured food intake in 31 overweight female smokers to test whether (a) calorie and carbohydrate intakes increase after smoking cessation and (b) double-blind d-fenfluramine (30 mg), a serotonin-releasing drug, suppresses weight gain, overeating, and dysphoric mood associated with stopping smoking. Placebo-treated patients grew dysphoric after smoking withdrawal and ate 300 kcal/day more from 2 to 28 days after, showing a 3.5-lb weight gain. Fat and protein intakes did not change, but carbohydrate intake increased (30% to 40%). D-fenfluramine prevented postcessation dysphoria. Although drug-treated patients ate more carbohydrate snacks just after quitting, they returned to baseline by 4 weeks, showing a 1.8-lb weight loss. Agents that enhance brain serotonin-mediated neurotransmission may help prevent weight gain, overeating, and dysphoric mood after smoking withdrawal.

Data based on the 1987 National Health Interview Survey are presented depicting factors associated with the knowledge and use of three tests for the early detection of colorectal and prostate cancer: digital rectal examination, fecal occult blood tests, and flexible sigmoidoscopy. The percentage of the at risk adult population who have ever heard of or had these tests is reported. The association of demographic, personal resource, and health system factors with knowledge of these tests is explored using multivariate logistic regression. Health system factors are most consistently associated with use of the tests and with knowledge. Family income, family size, education, knowledge of cancer early warning signs, and measures of encounters with the health care system are associated both with knowledge of and, independent of knowledge, with use of the tests. Residency in the non-South, being white or female, and having an optimistic attitude about cancer prevention are all factors associated with greater knowledge of the tests, but not greater use among those aware of the tests. Membership in a health maintenance organization is more strongly associated with knowledge and use of fecal occult blood tests than the other tests. No association was found between current smoking status and knowledge of or use of any of the tests.

Everyday action is impaired among individuals with schizophrenia, yet few studies have characterized the nature of this deficit using performance-based measures. This study examined the performance of 20 individuals with schizophrenia or schizoaffective disorder on the Naturalistic Action Test (M. F. Schwartz, L. J. Buxbaum, M. Ferraro, T. Veramonti, & M. Segal, 2003). Performance was coded to examine overall impairment, task accomplishment, and error patterns and was compared with that of healthy controls (n = 28) and individuals with mild dementia (n = 23). Additionally, 2 competing accounts of everyday action deficits, the resource theory and an executive account, were evaluated. When compared with controls, the participants with schizophrenia demonstrated impaired performance. Relative to dementia patients, participants with schizophrenia obtained higher accomplishment scores but committed comparable rates of errors. Moreover, distributions of error types for the 2 groups differed, with the participants with schizophrenia demonstrating greater proportions of errors associated with executive dysfunction. This is the 1st study to show different Naturalistic Action Test performance patterns between 2 neurologically impaired populations. The distinct performance pattern demonstrated by individuals with schizophrenia reflects specific deficits in executive function.

This article is an updated report of a symposium held at the June 2000 annual meeting of the American Society for Pharmacology and Experimental Therapeutics in Boston. The symposium was sponsored by the ASPET Divisions for Drug Metabolism and Molecular Pharmacology. The report covers research from the authors' laboratories on the structure and regulation of UDP-glucuronosyltransferase (UGT) genes, glucuronidation of xenobiotics and endobiotics, the toxicological relevance of UGTs, the role of UGT polymorphisms in cancer susceptibility, and gene therapy for UGT deficiencies.

This study was designed to determine whether ambulatory electrocardiography in patients with recent stroke would lead to a change in clinical management or outcome and to express these findings in terms of cost benefit. A prospective, consecutive sample of patients (n = 100) with recent stroke referred from the neurology or medical services for ambulatory electrocardiography was identified. Ambulatory electrocardiograms were reviewed to identify patients with potentially important bradyarrhythmias, tachyarrhythmias, or atrial fibrillation. Patients were then followed up without interference with ongoing care to determine whether these findings led to changes in clinical management that might influence patient outcome. Of the 100 patients, 16 had an index "important" arrhythmia. No significant bradyarrhythmias were noted. Nonsustained ventricular tachycardia (or = 6 complexes) in two patients and supraventricular tachycardia (or = 10 complexes) in seven patients did not lead to management changes. Four patients had a history of atrial fibrillation who were in sinus rhythm; anticoagulation had been addressed in three; the fourth patient died before the issue could be addressed. Of three patients in atrial fibrillation, there was a history of atrial fibrillation and a decision regarding anticoagulation in each before monitoring. The cost of these 100 ambulatory electrocardiograms was about $55,000. In conclusion, these findings do not support the routine use of ambulatory electrocardiography in the evaluation of patients with stroke.

Short-term benefits have been demonstrated for laparoscopic-assisted colectomy. However, minimally invasive surgery is still in an evolutionary phase. In demonstrating that robotic devices also are useful in laparoscopic colonie surgery, it is fundamental to prove that a single surgeon can perform almost the entire operation on his own. METHODS: A single surgeon performed forty-one, laparoscopic-assisted, colorectal resections with the assistance of a robotic device (Automated Endoscopie System for Optimal Positioning, Computer MotionTM) maneuvering the laparoscope. A surgical assistant was included only for the open part of the operation. Main outcome measures were conversion rate, total operating time, and percentage of assistance by a second surgeon. RESULTS: There were no intraoperative complications, one case of conversion to open surgery, and three postoperative complications. The total operating time ranged from 126 to 252 minutes. A single surgeon with the assistance of a robotic device was able to perform approximately 70 percent of an ileocecal resection, 70 percent of a right hemicolectomy, 80 percent of a sigmoid resection, and 85 percent of a anterior rectal resection without further help of a surgeon. CONCLUSIONS: A single surgeon with the assistance of a computerized robotic system can complete at least two-thirds of a laparoscopic-assisted, colorectal resection on his own. The use of a robotic device in laparoscopic-assisted, colonie surgery is safe, efficient, and feasible, and will proven even more so in future. This also will result in a patient-driven demand for high-standard, minimally invasive surgery.

Background: The magnitude of surgical trauma after laparoscopic and open colonic resection was evaluated by examining postoperative serum values of interleukin-6 (IL-6), IL-10, C-reactive protein (CRP), and granulocyte elastase (GE) for further evidence of the benefit realized with minimally invasive approaches in colonic surgery. Methods: Altogether, 42 patients with Crohn's disease (n = 20) or colon carcinomas/adenomas (n = 22) were matched by age, gender, body mass index (BMI), and Crohn's Disease Activity Index for either a laparoscopic (n = 21) or an open colonic resection (n = 21). In both groups the postoperative serum levels of IL-6, IL-10, C-RP, and granulocyte elastase were determined, as indicators of surgical stress. Results: Laparoscopic and open colonic resection caused a significant increase in serum IL-6, IL-10, CRP, and granulocyle elastase levels. The comparison between laparoscopic and open colonic resections, however, showed significantly lower serum IL-6, IL-10, CRP, and granulocyte elastase levels after laparoscopic colonic resection, which was most evident for IL-6 and granulocyte elastase. Conclusions: Our study demonstrated that IL-6 and granulocyte elastase may be appropriated particularly to monitor surgical stress. By using these parameters, we found a significant reduction in surgical trauma after laparoscopic surgery, was compared with the open procedure. This supports the clinical findings of a clear benefit for patients undergoing laparoscopic colonic surgery.

UDP-glucuronosyltransferase 1A6 (UGT1A6), a key enzyme catalyzing the glucuronidation of small planar phenols and amines, is expressed in a tissue- and inducer-dependent manner. Expression is high in kidney, gastrointestinal tract, and induced liver, with low expression in spleen, lung, and ovary. Exposure to certain chemicals, such as 3-methylcholanthrene, benzo[a]pyrene, β-naphthoflavone, and oltipraz elevates UGT1A6 mRNA in liver and to a lesser extent gastrointestinal tract and kidney, but not in other tissues. The mechanisms underlying this complex pattern of expression have been elusive. We have identified a new type of UGT1A6 mRNA (class 2) that differs in its 5′ untranslated sequence. The class 2 transcript is the more abundant type expressed in liver, gastrointestinal tract, and kidney. Transcription of the class 2 mRNA is initiated 107 bases 5′ of the UGT1A6 coding exon. The promoter region flanking the transcription start site contains an HNF1-like binding site identical to that in the human UGT1A6 gene. Both class 1 and class 2 mRNAs were elevated in liver by 3-methylcholanthrene, benzo[a]pyrene, β-naphthoflavone, and oltipraz, with preferential elevation of class 1 occurring after 3-methylcholanthrene and benzo[a]pyrene treatment. These data suggest that transcription from a second promoter contributes to tissue- and inducer-specific expression of rat UGT1A6.

One of the most important mechanisms involved in host defense against xenobiotic chemicals and endogenous toxins is the glucuronidation catalysed by UDP-glucuronosyltransferase enzymes (UGT). The role of genetic factors in determining variable rates of glucuronidation is not well understood, but phenotypic evidence in support of such variation has been reported. In the present study, six single nucleotide polymorphisms were discovered in the first exon of the UGT1A7 gene, which codes for the putative substrate-binding domain, revealing a high structural heterogeneity at the UGT1 gene locus. The new UGT1A7 proteins differ in their primary structure at amino acid positions 129, 131 and 208, creating four distinct UGT1A7 allelic variants in the human population: UGT1A7*1 (N129 R131 W208), *2 (K129 K131 W208), *3 (K129 K131 R208), and *4 (N129 R131 R208). In functional studies, HEK cells stably transfected to express the four allelic UGT1A7 variants exhibited significant differences in catalytic activity towards 3-, 7-, and 9-hydroxy-benzo(a)pyrene. UGT1A7*3 exhibited a 5.8-fold lower relative Vmax compared to wild-type *1, whereas *2 and *4 had a 2.6- and 2.8-fold lower relative Vmax than *1, respectively, suggesting that these mutations confer slow glucuronidation phenotype. Kinetic characterization suggested that these differences were primarily attributable to altered Vmax. Additionally, it suggested that each amino acid substitutions can independently affect the UGT1A7 catalytic activity, and that their effects are additive. The expression pattern of UGT1A7 studied herein and its catalytic activity profile suggest a possible role of UGT1A7 in the detoxification and elimination of carcinogenic products in lung. A population study demonstrated that a considerable proportion of the population (15.3%) was found homozygous for the low activity allele containing all three missense mutations, UGT1A7*3. These findings suggest that further studies are needed to investigate the impact of the low UGT1A7 conjugator genotype on individual susceptibility to chemical-induced diseases and responses to therapeutic drugs.

The Clarion cochlear implant is the result of many years of research and development, first at the University of California, San Francisco and the Research Triangle Institute of North Carolina, and then at Advanced Bionics Corporation in Sylmar, California. Approved by the US Food and Drug Administration after carefully monitored investigational clinical trials in both the adult and pediatric populations, it has now been implanted in approximately 3,000 patients worldwide. A fully flexible, programmable system, the Clarion offers multiple strategies and options in speech processing. The coupling mode, the stimulating waveform, and the temporal pattern of stimulation can be selected to allow each patient an opportunity to be fitted with the strategy that offers the highest level of performance. This paper describes the current status of the Clarion system. However, Clarion development has been a dynamic process, and from its initial introduction in 1991, the system has been modified and continually improved. The process of improvement and advancement is ongoing. New speech processing strategies and hardware developments are briefly summarized at the conclusion of this paper.

This study evaluated the current clinical use and costs of ambulatory electrocardiographic (AECG) monitoring for arrhythmia detection based on a cost per management decision analysis.Consecutive inpatient and outpatient 24-hour AECGs (n = 650) performed during the calendar year 1991 were retrospectively reviewed for clinical indication, arrhythmia detection, diary information, and whether a management decision that might alter patient outcome was derived from the data. The cost per management decision (based on a representative reimbursement of $550 per AECG) and the cost index (CI) (all tests divided by useful tests) were calculated.Although arrhythmias were identified in 91% of the patients, management decisions were indicated in only 18% (cost per decision, $2974; CI = 5.4). Management decisions were most often derived from the data in patients being evaluated for arrhythmia therapy (37 of 37 patients; cost per decision, $550; CI = 1). Symptoms and arrhythmias were correlated in only 11 patients (2%). More often typical clinical symptoms were present (26 patients) in the absence of an arrhythmia. Of 101 AECGs following a cerebrovascular event, four had unsuspected atrial fibrillation (cost per decision, $13,888; CI = 25.0). Dizziness or lightheadedness associated with other cardiac symptoms was more likely to lead to a management decision than the same symptoms in isolation (29% vs 7%; P.05). No patient had central nervous system symptoms correlated with an arrhythmia during the recording period or unsuspected ventricular tachycardia.Ambulatory electrocardiography has a highly variable and indication-dependent effectiveness and cost. The results suggest a strategy for improving the use of AECG based on knowing what testing indications are more likely to lead to useful clinical information.

In conclusion, TTM appears more effective than ambulatory ECG for the detection of arrhythmias associated with intermittent central nervous system or cardiac symptoms. Limiting TTM to patients with primarily cardiac symptoms and to a 1-week time period would have optimized cost-effectiveness in this group of patients.

Speech perception skills were measured in five children who had received a 3M/House single-channel cochlear implant and were subsequently upgraded to a multichannel cochlear implant (Nucleus). A rationale was developed based upon performance with the single-channel device and anticipated performance with the multichannel device. All subjects demonstrated improved acoustic thresholds with the multichannel device. Three of the children demonstrated improvements on identification tasks and two on word recognition tasks.

Under phase I of an FDA-approved Investigational Device Exemption (IDE), six patients at the University of California, San Francisco (UCSF) have been implanted with the Clarion, a new multichannel, multiprogrammable cochlear implant system. Over a period of 5 years, the Clarion has been collaboratively developed by UCSF, the Research Triangle Institute (RTI) of North Carolina, and the device manufacturer and sponsor, MiniMed Technologies of Sylmar, California. For UCSF, it represents the culmination of 21 years of cochlear implant research. The Clarion incorporates the 16-contact electrode array developed at UCSF. This electrode is designed with a gentle curve and an elastic memory that allow it to hug the modiolar wall of the scala tympani. In addition, the electrode has mechanical features that prevent it from rotating upward and injuring the basilar membrane. One of the innovations necessary to allow broad clinical application of this device has been the development of an electrode insertion tool to assist the surgeon in safe placement. In each of the six UCSF cases, the insertion tool was used and electrode placement was achieved with ease. With the availability of a variety of speech processing strategies, the Clarion has also provided the opportunity for all of the patients tested to date to achieve some degree of open-set, auditory-only speech recognition. Surgical considerations and preliminary audiologic data demonstrate that the design rationale and objectives of the Clarion have been met.

Cigarette smoking suppresses body weight, discouraging many smokers from trying to quit. Behavioural therapies have so far proved unsuccessful in preventing post-cessation weight gain, and have in fact tended to undercut abstinence from smoking. The mental demands of implementing behavioural weight management strategies may compete with the concentration needed to maintain abstinence from smoking. Consequently, a pharmacological approach offers potential treatment advantages by minimizing the effort needed to achieve weight control. Of the agents found effective in minimizing weight gain, serotoninergic drugs, particularly dexfenfluramine, show special promise because they prevent an increase in caloric intake but do not decrease energy intake below pre-cessation levels.

A new cochlear implant has become available. This device, called the Clarion Multichannel Cochlear Implant, is the result of collaborative efforts between the University of California, San Francisco (UCSF), the Research Triangle Institute (RTI), Research Triangle Park, North Carolina, and the device manufacturer and sponsor, Mini Med Technologies of Sylmar, California. The Clarion represents a new generation of multi-programmable cochlear implant systems. Options in waveform, the stimulation mode, and the temporal distribution of the signal permit the device to be optimally customized for each individual patient. The speech coding scheme offering the greatest opportunity for speech recognition can be selected. The first Clarion recipient has recently been implanted at UCSF, initiating the Clarion's investigational clinical trials. A description of the device and preliminary patient results are presented.

Performance on speech perception, speech production, and language tests was measured over time in children who used the 3M/House or the Nucleus cochlear implant. The speech perception and production results demonstrated higher performance levels and faster rates of learning for the multichannel than for the single-channel users. The performance of the children with the single-channel implant on the speech perception and production measures reached a plateau by 1.5 years post implant, whereas the children using the multichannel device continued to show improvement after 2 or more years of implant use. Changes in language were limited over time with no obvious difference in performance as a function of type of implant.

A longitudinal study is under way to examine the speech perception and production skills of deaf children who use a single- or multi-channel cochlear implant, or a two-channel tactile aid. The speech perception data showed that the majority of subjects who achieved the highest scores on a range of measures used the multi-channel cochlear implant. The production data showed that all three types of sensory aids were effective in promoting production skills, with the cochlear implant users showing the greatest gains in this area.

A speech perception hierarchy has been developed and applied to assess the influence of cochlear implants and tactile aids on the acquisition of auditory, speech, and language skills in deaf children. Encouraging improvements were noted with both types of sensory aids at the detection level. The House 3M and Nucleus cochlear implant designs appear to offer advantages over the Tactaid II in providing ancillary speech perception cues to deaf children. Preliminary observations suggest that the multichannel cochlear implant design may be superior to the single-channel coding scheme.