Modulation of neuronal excitability by serotonin-NMDA interactions in prefrontal cortex

Both serotonin and NMDA signaling in prefrontal cortex (PFC) are implicated in mental disorders, including depression and anxiety. To understand their potential contributions to PFC neuronal excitability, we examined the effect of co-activation of 5-HT and NMDA receptors on action potential firing elicited by depolarizing current injection in PFC pyramidal neurons. In the presence of NMDA, a low concentration of the 5-HT(1A) agonist 8-OH-DPAT substantially reduced the number of spikes, and a low concentration of the 5-HT(2A/C) agonist alpha-Me-5HT significantly enhanced it, while both agonists were ineffective when applied alone. The 8-OH-DPAT effect on firing was mediated by inhibition of protein kinase A (PKA), whereas the alpha-Me-5HT effect was mediated by activation of protein kinase C (PKC). Moreover, the extracellular signal-regulated kinase (ERK), a signaling molecule downstream of PKA and PKC, was involved in both 5-HT(1A) and 5-HT(2A/C) modulation of neuronal excitability. Biochemical evidence showed that 5-HT(1A) decreased, whereas 5-HT(2A/C) increased the activation of ERK in an NMDA-dependent manner. In animals exposed to acute stress, the enhancing effect of 5-HT(2A/C) on firing was lost, while the decreasing effect of 5-HT(1A) on firing was intact. Concomitantly, the effect of 5-HT(2A/C), but not 5-HT(1A), on ERK activation was abolished in stressed animals. Taken together, our results demonstrate that distinct 5-HT receptor subtypes, by interacting with NMDA receptors, differentially regulate PFC neuronal firing, and the complex effects of 5-HT receptors on excitability are selectively altered under stressful conditions, which are often associated with mental disorders.     

American Association of Neuromuscular & Electrodiagnostic Medicine evidenced-based review: use of surface electromyography in the diagnosis and study of neuromuscular disorders

Surface electromyography (sEMG) measures myoelectrical signals recorded from sensors placed on the skin surface. The non-invasive nature of sEMG makes it a potentially useful technology for studying diseases of muscle and nerve. Reviews published by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) and the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN), covering 1964-1994 and 1952-1998, respectively, concluded that sEMG adds no clinical utility over conventional needle EMG (nEMG) for the diagnosis of neuromuscular disease. The AANEM sEMG task force reevaluated the diagnostic utility and added value of this technology for the study of neuromuscular disease based on a contemporary review of relevant literature published between January 1994 and February 2006. The present review concludes that sEMG may be useful to detect the presence of neuromuscular disease (level C rating, class III data), but there are insufficient data to support its utility for distinguishing between neuropathic and myopathic conditions or for the diagnosis of specific neuromuscular diseases. sEMG may be useful for additional study of fatigue associated with post-poliomyelitis syndrome and electromechanical function in myotonic dystrophy (level C rating, class III data).     

Erythrocyte and plasma fatty acid profiles in patients with epilepsy: Does carbamazepine affect omega-3 fatty acid concentrations?

Fatty acids (FAs) determine membrane properties and may affect cardiac and neuronal function. In this study, FA profiles were determined in 56 patients with epilepsy who participated in a 12-week double-blind randomized trial of omega-3 FA supplementation (1 g eicosapentaenoic acid and 0.7 g docosahexaenoic acid daily). At baseline, subjects on carbamazepine (CBZ) had lower docosahexaenoic acid levels, lower levels of long-chain omega-3 FAs, and a lower Omega-3 Index (a risk factor for coronary heart disease mortality), whereas those on oxcarbazepine had higher total polyunsaturated FAs and a higher Omega-3 Index. Following omega-3 FA supplementation, the Omega-3 Index, eicosapentaenoic acid, and docosahexaenoic acid concentrations significantly increased. Patients on CBZ exhibited a less favorable FA profile, associated with a greater risk of coronary heart disease mortality. As arrhythmias are thought to be an important mechanism in coronary heart disease mortality and sudden unexplained death in epilepsy (SUDEP), the effect of CBZ effect in reducing omega-3 FAs might potentially explain some cases of SUDEP among patients prescribed CBZ.     

Enhancing Osteochondral Allograft Viability: Effects of Storage Media Composition

Osteochondral allograft transplantation is a well-accepted treatment for articular cartilage damage. However, chondrocyte viability declines during graft storage, which may compromise graft performance. We first tested the hypothesis that the composition of commonly used storage media affects the viability of articular chondrocytes over time; we then tested the hypothesis that the addition of insulin growth factor-1 or the apoptosis inhibitor ZVAD-fmk could enhance the storage properties of serum-free media. Bovine osteochondral grafts were stored at 4°C in lactated Ringer’s, Dulbecco’s modified eagle’s media (DMEM), DMEM supplemented with either insulin growth factor-1 or ZVAD-fmk, and a commercial storage media. Chondrocyte viability in lactated Ringer’s declined rapidly to 20.4% at 2 weeks. Viability in DMEM declined more slowly to 54.8% at 2 weeks and 31.2% at 3 weeks. Viability in commercial storage media was 83.6% at 3 weeks and 44.8% at 4 weeks. Viability was increased in DMEM + insulin growth factor-1 (56.4%) and DMEM + ZVAD (52.4%) at 3 weeks compared with DMEM alone. These results confirm the hypotheses that media composition greatly influences chondrocyte viability during cold storage and that insulin growth factor-1 and ZVAD improve the storage properties of DMEM. One or more of the authors (HTK) have received funding from the Musculoskeletal Transplant Foundation.     

Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response

The best time and hepatitis B virus (HBV) DNA level during an early lamivudine treatment period for predicting the long-term outcome are unknown. We aimed to determine the optimal time and HBV DNA level during an early treatment period for the prediction of the response after a 5-year lamivudine treatment. The HBV DNA levels at the baseline, at weeks 2, 4, 8, 12, 16, 24, and 32, and at yearly intervals until year 5 were measured in 74 hepatitis B e antigen (HBeAg)-positive chronic HBV patients receiving lamivudine treatment. Seventeen patients achieved an ideal response [HBV DNA level < 2000 copies/mL (400 IU/mL), HBeAg seroconversion, normal alanine aminotransferase levels, and absence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations] at year 5. Receiver operating characteristic curves showed good predictions as early as week 4. The areas under the curve for weeks 4 and 16 were 0.89 and 0.94, respectively. Predictive indices revealed 4 and 3.6 log copies/mL (2000 and 800 IU/mL, respectively) to be the best cutoff HBV DNA levels for these 2 times, respectively. All patients with HBV DNA levels lower than these respective cutoff levels at the 2 times achieved an ideal response at year 5. Patients with HBV DNA levels above these cutoff values had 83.8% and 87.7% chances of not achieving an ideal response at year 5, respectively. Conclusion: The measurement of the HBV DNA levels at week 4 of lamivudine treatment should be performed in all patients to predict the long-term outcome. The treatment can be continued for those with HBV DNA levels of less than 4 log copies/mL (2000 IU/mL). The addition of or switch to alternative antiviral agents should be considered for patients who fail to achieve this early target.     

Profiling of HIV clinic patients to determine the prevalence and characteristics of recent infections

Patients newly attending the government HIV clinic in Hong Kong were studied for the prevalence and characteristics of recent HIV infection, which was defined as having a negative HIV antibody test and/or seroconversion illness within one year of a first positive antibody result. Fifty-nine (12.0%) of 492 HIV-positive patients first seen from 2001 to 2004 were determined to be recently infected. This likely represented the lower bound of the real situation. Compared with non-recent infections on univariate analysis, recent cases were more likely to be men who have sex with men (OR 2.23; 95%CI, 1.23-4.05), never married (OR 1.96; 95%CI, 1.03-3.89), had tertiary or above education (OR 3.93; 95%CI, 1.65-10.09) and with a baseline CD4>=500 cells/ul (OR 3.65; 95%CI, 1.87-6.93). Upon multivariate analysis, tertiary or above education (adjusted OR 4.23; 95%CI, 1.76-10.16) and CD4>=500 cells/ul at diagnosis (adjusted OR 3.58; 95%CI, 1.88-6.84) remained independent variables. HIV clinics are feasible settings for collecting epidemiological information of on-going infection. Differences in the profile between recent and non-recent cases may shed light on targeting efforts to prevent new HIV infections.     

Etiologies of chronic liver diseases in Hong Kong

BACKGROUND: In Hong Kong, chronic hepatitis B (CHB) is endemic with a prevalence rate of 8.8%. Data, however, on chronic hepatitis C infection and other nonviral causes of chronic liver disease (CLD) are limited. AIM: To investigate the spectrum of CLDs in Hong Kong. METHODS: Records of all patients attending the Hepatology Clinic of Queen Mary Hospital, Hong Kong, in 2004 were reviewed to identify those with CLDs and their underlying causes. RESULTS: A total of 6106 patients were found to have CLD. CHB accounted for 89.4% of the cases, followed by chronic hepatitis C infection (5.1%). Nonviral causes accounted for the remaining 5.5% [alcoholic liver disease (ALD) (1.7%), nonalcoholic fatty liver disease (1.5%), primary biliary cirrhosis (PBC) (1.3%)]. Patients with CHB and Wilson's disease were significantly younger than patients with other causes (P<0.002). More than 90% of patients with autoimmune hepatitis and PBC were women. The prevalence of CHB infection was lower in patients with PBC than the general population. Among patients with ALD, the prevalence rate was higher for chronic hepatitis C but similar for CHB, as compared with the general population. CONCLUSIONS: Despite universal HBV vaccination since 1988, CHB remains the commonest cause of CLD in Hong Kong. PBC and nonalcoholic fatty liver disease were not rare in the Chinese population, being important causes of nonviral liver disease. The prevalence of chronic viral infection among patients with PBC or ALD confirmed the findings of other published literatures.     

Breast carcinomas with strong high-signal intensity on T2-weighted MR images: pathological characteristics and differential diagnosis

PURPOSE: To investigate the histopathological characteristics of breast carcinomas with strong high-signal intensity (SHi) on T2-weighted (T2W) MR images (T2-SHi), and discuss the differential diagnosis between T2-SHi breast carcinomas and T2-SHi fibroadenomas. MATERIALS AND METHODS: Thirty of 480 breast carcinomas examined by MRI were defined as tumors with T2-SHi (defined as homogeneous higher signal intensity (SI) compared to surrounding normal breast tissue on fat-suppressed T2W imaging (T2WI). They included eight mucinous and 22 nonmucinous carcinomas. The histopathological characteristics of T2-SHi breast carcinomas, their signal-to-noise ratios (SNRs) on T2WI, contrast-enhancement patterns, and morphology were compared with those of 22 non-T2-SHi breast carcinomas and 19 T2-SHi fibroadenomas. RESULTS: In nonmucinous carcinomas T2-SHi was attributable to a mixture of background matrix, a higher proportion of cells than stroma, abundant cytoplasm, edematous stroma, and hemorrhage. The significantly high SNR (mean = 75) and enhancing internal septations seen in mucinous carcinomas, and the washout phenomenon, irregular border, absence of internal septation, and rim enhancement seen in nonmucinous carcinomas provide useful information for differentiating these tumors from T2-SHi fibroadenomas. CONCLUSION: A mixture of several histopathological characteristics was associated with T2-SHi breast carcinomas. The combined information from T2WI and contrast-enhanced (CE) imaging may help distinguish T2-SHi breast carcinomas from T2-SHi fibroadenomas.