Effect of Age on GABA+ and Glutathione in a Pediatric Sample.

BACKGROUND AND PURPOSE: Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the human brain and is implicated in several neuropathologies. Glutathione is a major antioxidant in the brain and is considered a marker of oxidative stress. Several studies have reported age-related declines in GABA levels in adulthood, but the trajectory of both GABA and glutathione during childhood has not been well explored. The aim of this study is to establish how GABA and glutathione vary with age during early development. MATERIALS AND METHODS: Twenty-three healthy children (5.6-13.9 years of age) were recruited for this study. MR imaging/MR spectroscopy experiments were conducted on a 3T MR scanner. A 27-mL MR spectroscopy voxel was positioned in the frontal lobe. J-difference edited MR spectroscopy was used to spectrally edit GABA and glutathione. Data were analyzed using the Gannet software, and GABA+ (GABA + macromolecules/homocarnosine) and glutathione were quantified using water (GABA+H2O and GlutathioneH2O) and Cr (GABA+/Cr and glutathione/Cr) as concentration references. Also, the relative gray matter contribution to the voxel volume (GMratio) was estimated from structural images. Pearson correlation coefficients were used to examine the association between age and GABA+H2O (and glutathioneH2O), between age and GABA+/Cr (and glutathione/Cr), and between age and GMratio. RESULTS: Both GABA+H2O (r = 0.63, P = .002) and GABA+/Cr (r = 0.48, P = .026) significantly correlated with age, whereas glutathione measurements and GMratio did not. CONCLUSIONS: We demonstrate increases in GABA and no differences in glutathione with age in a healthy pediatric sample. This study provides insight into neuronal maturation in children and may facilitate better understanding of normative behavioral development and the pathophysiology of developmental disorders.

Early Antiretroviral Therapy in HIV-Infected Children Is Associated with Diffuse White Matter Structural Abnormality and Corpus Callosum Sparing.

BACKGROUND AND PURPOSE: Fractional anisotropy in the frontal white matter, corpus callosum, and internal capsule is abnormal in human immunodeficiency virus-positive (HIV+) adults. We describe the distribution and nature of white matter abnormalities in a cohort of children who started antiretroviral therapy within the first year of life and the benefit of early treatment by using DTI measures (fractional anisotropy and mean, axial, and radial diffusion). MATERIALS AND METHODS: DTI was performed on children in a neurodevelopmental substudy from the Children with HIV Early Antiretroviral trial. Voxel-based group comparisons were obtained to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children. Associations of DTI parameters with the timing of antiretroviral therapy initiation were examined. RESULTS: Thirty-nine HIV+ children (15 boys; mean age, 5.4 years) and 13 controls (5 boys; mean age, 5.7 years) were scanned. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group, with symmetric distribution predominantly due to increased radial diffusion, suggestive of decreased myelination. Corticospinal tracts rather than the corpus callosum were predominantly involved. Children on early-interrupted antiretroviral therapy had lower fractional anisotropy compared with those receiving continuous treatment. CONCLUSIONS: HIV+ children at 5 years of age have white matter abnormalities measured by fractional anisotropy, despite early antiretroviral therapy, suggesting that early antiretroviral therapy does not fully protect the white matter from either peripartum or in utero infection. In contrast to adults, the corticospinal tracts are predominantly involved rather than the corpus callosum, possibly due to early antiretroviral therapy. Continuous early antiretroviral therapy can limit white matter damage.

Salmonella spp. in patients suffering from enteric fever and food poisoning in Thamar city, Yemen

Salmonella remains a public health concern around the world, including Yemen although data on its incidence are few. This study determined the incidence of Salmonella infection in 250 enteric fever and 210 food poisoning cases attending Thamar general hospital and Dar Alshafaa medical clinic in 2008. In total, 773 clinical specimens were taken: 250 blood, 187 urine and 336 stool samples. Of the patients with enteric fever and food poisoning, 16.4% and 15.2% respectively were infected with Salmonella. The serovars isolated were: Salmonella Typhi [45.6%], Salmonella Enteritidis [24.4%], Salmonella Paratyphi B [14.4%], Salmonella Typhimurium [13.3%] and Salmonella Paratyphi A [2.2%]. The distribution of somatic groups was: D [70%], B [27.7%] and A [2.2%]. None of the isolates was resistant to ciprofloxacin, sparfloxacin, ceftriaxone or moxifloxacin, while 71.1% were resistant to cotrimoxazole, 62.2% to gentamicin, 56.6% to ampicillin and 35.5% to nalidixic acid

Specific liver autoreactivity in schistosomiasis mansoni.

To investigate the possible involvement of autoimmune mechanisms in the development of hepatosplenic schistosomiasis (HSS), 234 patients with chronic Schistosoma mansoni infections were screened for a wide range of non-organ-specific autoantibodies as well as for antibodies reacting with the GOR peptide and with a liver-specific autoantigen, the hepatic asialoglycoprotein receptor (ASGP-R). Thirty-five (15.0%) were seropositive for antinuclear, smooth muscle or gastric parietal cell antibodies at low titres (< or = 1:80), and 15/176 (8.5%) had anti-GOR, all of whom had concomitant hepatitis C viral (HCV) infections. Anti-ASGP-R was found in 64 (27.4%) of the 234 patients at titres similar to those found in 18 untreated auto-immune hepatitis patients studied concurrently. Anti-ASGP-R seropositivity occurred significantly (P < 0.005) more frequently in patients with HSS (62/190, 32.6%) than in those with hepatointestinal schistosomiasis (2/44, 4.5%), but did not correlate with severity of liver disease or with the presence of the non-organ-specific autoantibodies. Anti-ASGP-R was found significantly (P < < 0.0005) less frequently in HSS patients who had had a splenectomy for portal hypertension (5/86, 5.8%) than in those who had not had a splenectomy (57/104, 54.8%). The findings suggest that liver-specific autoreactivity may play a role in the development of HSS.

New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a.

Recent studies have focused on whether different hepatitis C virus (HCV) genotypes are associated with different profiles of pathogenicity, infectivity, and response to antiviral therapy. The establishment of a simple and precise genotyping system for HCV is essential to address these issues. A new genotyping system based on PCR of the core region with genotype-specific PCR primers for the determination of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a was developed. A total of 607 samples (379 from Japan, 63 from the United States, 53 from Korea, 35 from Taiwan, 32 from China, 20 from Hong Kong, 15 from Australia, 6 from Egypt, 3 from Bangladesh, and 1 from South Africa) were tested by both the assay of Okamoto et al. (H. Okamoto, Y. Sugiyama, S. Okada, K. Kurai, Y. Akahane, Y. Sugai, T. Tanaka, K. Sato, F. Tsuda, Y. Miyamura, and M. Mayumi, J. Gen. Virol. 73:673-679, 1992) and this new genotyping system. Comparison of the results showed concordant results for 539 samples (88.8%). Of the 68 samples with discordant results, the nucleotide sequences of the HCV isolates were determined in 23, and their genotypes were determined by molecular evolutionary analysis. In all 23 samples, the assignment of genotype by our new genotyping system was correct. This genotyping system may be useful for large-scale determination of HCV genotypes in clinical studies.

Usefulness and limitation of phylogenetic analysis for hepatitis C virus core region: application to isolates from Egyptian and Yemeni patients.

We report here the nucleotide sequences of the core region of HCV isolates from Egyptian and Yemeni patients and the method for classifying these HCV isolates by phylogenetic analysis. Sequence comparison suggested that the genotypes of these isolates were the same. Preliminary phylogenetic analysis of the HCV core region indicated that the genotypes of both isolates were 1c. However, an additional phylogenetic tree of the HCV core region constructed using a greater number of HCV isolates than that used in the preliminary analysis and on the basis of alignment of nucleotide sequences in an appropriate length indicated that the genotypes of these isolates were 4 and not 1c. For a more detailed analysis, the nucleotide sequences of the HCV E1 region as well as the core region for the same Yemeni patient were determined. A phylogenetic tree of the E1 region confirmed that the genotype of the HCV isolate from the Yemeni patient was 4. These data indicate that even when classifying HCV isolates using phylogenetic analysis, the misclassification would occur if care is not taken regarding the number and sequence lengths of the isolates included in the analysis.

Hepatitis C virus infection in Schistosomiasis mansoni in Brazil.

The involvement of the hepatitis C virus (HCV) in the severity of liver disease in chronic schistosomiasis was investigated in 215 Brazilian patients with S. mansoni infections, but without evidence of hepatitis B surface antigen (HBsAg). Forty-three had hepatointestinal (HIS) and 172 had hepatosplenic schistosomiasis (HSS), and 135 had compensated (HSSC), and 37 had decompensated (HSSD) liver disease. Fifty-two (24%) were found to have evidence of HCV infection (seropositive for anti-HCV antibodies and/or HCV-RNA). These comprised 35 (95%) of the 37 with HSSD, 16 (12%) of the 135 with HSSC, and 1 (2.4%) of the 43 with HIS, compared with only 1 (2%) of 50 control patients without S. mansoni. Testing of matched liver tissue and peripheral blood mononuclear cells (PBMCs) from 25 patients (6 HSSC and 19 HSSD) with HCV infections showed that 17 (68%) had "active" viral infections, in that negative strand HCV-RNA (the presumed replicative intermediate of the virus) could be detected in liver and/or PBMCs. Among these 25, negative strand HCV-RNA was found in 16 (84%) of the 19 with chronic active hepatitis, but in only 1 (17%) of the 6 with mild or inactive disease (P < 0.01). HCV-RNA was detected in matched spleen specimens from 9 of 10 patients (all of whom were also positive in PBMCs), suggesting that the spleen is an important extrahepatic reservoir of the virus.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ribavirin on intrahepatic and extrahepatic expression of hepatitis C virus in interferon nonresponsive patients.

Response to ribavirin therapy (1,000-1,200 mg/day for 6 months) was evaluated in nine patients with chronic hepatitis C virus (HCV) infections who had previously failed to respond to a 6-month course of alpha-interferon. All had chronic active hepatitis with elevated serum aminotransferase activities (mean +/- SD = 138 +/- 66IU/I). During ribavirin therapy, three showed a complete response (normalized serum aminotransferase), although in one patient this returned to the pretreatment level 2 months after treatment was stopped. Three others showed a partial response (serum aminotransferase reduction by > or = 50%) and the remainder showed no response. There were no consistent changes in HCV-RNA (positive strand) in serum, liver, or peripheral blood mononuclear cells during therapy, but two patients lost HCV-RNA from serum and three of five patients with negative strand HCV-RNA in their livers lost this putative replicative form of the virus. The findings suggest that ribavirin may exert its effects by suppressing viral replication rather than by eradicating the virus, at least in this group of patients, and that the drug may have some benefit in selected cases of chronic hepatitis C that are resistant to interferon. However, peripheral blood mononuclear cells represent a major extrahepatic reservoir of HCV and the present regimen of ribavirin therapy did not significantly affect this situation. More prolonged therapy may be required to eradicate the virus from this large pool of cells with the potential to continually reinfect the liver.

Hepatic and extrahepatic hepatitis C virus replication in relation to response to interferon therapy.

Response to a 1-yr course of interferon-alpha 2b was assessed in 18 patients with chronic hepatitis C virus infection in relation to clinical, biochemical and histological parameters and to the presence or absence of hepatitis C virus RNA and the presumed replicative form of the virus (negative-strand hepatitis C virus RNA) in serum, liver and peripheral blood mononuclear cells. The findings were compared with those in seven untreated patients studied over the same period. At the start of the study, positive-strand hepatitis C virus RNA was found in sera of all 25 patients, in livers of 24 and in peripheral-blood mononuclear cells of 19 of 22 tested; negative strand was found in livers of 11 and in peripheral-blood mononuclear cells of 15 of 22. Negative-strand hepatitis C virus RNA was not found in the serum of any patient at any stage. All of the five treated patients considered to show complete response during the study period cleared hepatic hepatitis C virus RNA, and four also became seronegative, but three had evidence suggestive of viral replication in their peripheral-blood mononuclear cells; two of these last patients subsequently relapsed. Loss of hepatic hepatitis C virus RNA was the only significant difference between these five and the seven partial and six nonresponders, but it is uncertain whether the observed changes were due specifically to interferon-induced modulation of virus expression because similar (apparently spontaneous) changes were seen in four of the untreated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

High prevalence of hepatitis C virus in the normal Libyan population.

The prevalence of hepatitis C virus (HCV) in Libya has been investigated by seeking evidence of HCV infection in 266 healthy Libyan subjects (147 females, 119 males; age range 1-78 years), 76 of whom were registered blood donors. None had any history of blood transfusions, surgery, homosexuality, drug misuse or other risk factor for viral hepatitis. Sera from all subjects were tested for anti-HCV antibodies by enzyme-linked immunosorbent assay against synthetic structural and non-structural HCV peptides from the HCV core, envelope, NS1, NS3/NS4 and NS5 regions. Eighteen (6.8%), all of whom were seronegative for hepatitis B surface antigen (HBsAg), were found to be anti-HCV positive (including 5 blood donors). The patterns of reactivity against the individual peptides varied between subjects as follows: core (14 subjects), envelope (11), NS1 (9), NS3/NS4 (10), and NS5 (6). Fourteen of the 18 had elevated serum aminotransferase activities (AST/ALT) but so also did 9 other subjects who were seronegative for both HBsAg and anti-HCV. Twelve of the 18 anti-HCV positive subjects, including 3 of the 5 anti-HCV positive blood donors, had circulating HCV RNA detected by the polymerase chain reaction. HCV RNA was also detected in 3 of the 9 anti-HCV negative cases with elevated AST/ALT. The finding that 21 (7.9%) of the 266 subjects had evidence of HCV infection indicates that there is a very high frequency of 'community-acquired' HCV in the normal Libyan population, and this has major implications for blood transfusion in that country.

Hepatitis B virus infection in schistosomiasis mansoni.

Schistosomiasis and hepatitis B virus (HBV) infection are very common in Brazil but the interrelationships between the two infections are poorly understood. We have undertaken a detailed serological study of the prevalence of HBV markers in 189 Brazilian patients with chronic schistosomiasis mansoni, 46 with hepatointestinal (HIS) and 143 with hepatosplenic (HSS) schistosomiasis, 12 of the latter having decompensated liver disease (HSSD), and in 50 control patients. Sera were tested for HBsAg, anti-e, anti-HBc, anti-HBs and HBV-DNA. Eighty-three (44%) of the 189 schistosoma patients had at least one marker of HBV infection, 18 of whom (10%) were seropositive for HBsAg. All the controls were HBsAg negative, but ten (20%) had anti-HBc and anti-HBs. There was no significant difference in the frequency of these markers between HIS (14/46, 30.4%), HSSC (43/131, 34.5%), and the controls. Among the HBsAg-positive patients, one had HIS (HBV-DNA negative), seven had HSSC (one HBV-DNA positive) and ten had HSSD (six HBV-DNA positive), a significant association of HBV carriage with HSSD (P << 0.001). Mean (+/- SD) ALT values were significantly (P < 0.001) higher in HBsAg-positive HSSD patients (70.7 +/- 18 IU/liter) than in those with HSSC (29.5 +/- 15 IU/liter). Liver biopsies were performed in 12 HBsAg-positive patients (one with HIS, three with HSSC, and eight with HSSD) and in 50 HBsAg-negative HSSC patients. Seven of the eight HSSD patients had chronic active hepatitis with cirrhosis, and one had inactive cirrhosis. All three patients with HSSC and the one with HIS had chronic persistent hepatitis, with periportal fibrosis in three.(ABSTRACT TRUNCATED AT 250 WORDS)

Virus-induced autoimmunity in hepatitis C virus infections: a rare event.

Serial serum samples from 16 Italian patients presenting with acute hepatitis C virus (HCV) infections (which progressed to chronic hepatitis in six) were screened for the non-organ-specific autoantibodies most frequently associated with autoimmune hepatitis (AIH), as well as for antibodies against the hepatic asialoglycoprotein receptor (ASGP-R) and against the GOR peptide. One patient had low titres (1:10-1:80) of liver-kidney microsomal (LKM-1) antibodies during the recovery phase and three others had transient low titres of anti-smooth muscle (IgM class, 1:10) or anti-ASGP-R (1:150-1:300). Anti-GOR was detected in 43 (65%) of 66 sera from 13 of these patients. There was no correlation between any of these findings and progression to chronicity. By comparison, 18 patients with AIH studied concurrently before institution of immunosuppressive therapy all had antinuclear and/or smooth muscle antibodies, or LKM-1, at 1:40-1:640 and anti-ASGP-R at 1:300-1:2,100. None of these 18 had evidence of HCV infection and all were seronegative for anti-GOR. The findings indicate that the autoantibodies usually associated with AIH are rare in HCV infections but the virus can very occasionally induce a transient autoimmune response. Anti-GOR appears to be an antibody specifically related to HCV infection and is probably not a marker of induced autoimmunity, and it does not predict progression to chronic hepatitis.