Urinary tract pathology attributed to Schistosoma haematobium: does parasite genetics play a role?

Disease outcome in persons infected with Schistosoma haematobium varies dramatically, ranging from mild symptoms to severe damage of the kidneys and/or bladder. We used ultrasonography to characterize the extent of urinary tract pathology of infected children in Zimbabwe, and random genetic markers to examine the relationship between genetic diversity of S. haematobium and clinical outcome. One hundred thirty-three parasite isolates from 12 students with mild lesions and 13 with severe lesions were compared. Using four randomly amplified polymorphic DNA (RAPD) markers, we scored parasite allelic frequencies at 53 loci. Although parasite heterogeneity did not differ, allelic frequencies at eight loci differed significantly between the mild and severe groups. Parasite isolates were analyzed further using a modified cluster analysis that segregated the population into 13 clusters of associated genotypes. Three clusters were significantly over-represented in children with severe lesions. Our findings, although preliminary, suggest that parasite genetic associations may be important in clinical outcome.     

No increase of blocking type anti-thyrotropin receptor antibodies during pregnancy in patients with Graves' disease

Serial changes in serum levels of anti-TSH receptor antibodies were examined during and after pregnancy in six patients with Graves' disease receiving no or minimal maintenance doses of antithyroid drugs. During pregnancy, serum levels of TSH-binding inhibitory Igs (P < 0.001) and thyroid-stimulating antibodies (TSAbs) (P < 0.01) decreased gradually but increased after delivery in all patients. Activities of thyroid-stimulation blocking antibodies (TSBAbs) were lower than the cut-off value in early pregnancy, and values significantly decreased in four patients during pregnancy. The other two patients showed no significant change during pregnancy. In contrast, TSBAb levels increased significantly (P < 0.01) after delivery in all patients. We found that activities of TSH-binding inhibitory Igs, TSAb, and TSBAb decrease during pregnancy and increase after delivery, suggesting that amelioration of Graves' disease during pregnancy is induced by decrease of TSAb but not by the appearance of TSBAb.     

Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation

We investigated the biological effects of the active oxygen produced by P450s. First, we identified which isoforms of P450 efficiently produced active oxygen using electron spin resonance. Eight forms of P450 purified from rat liver were used. Of these, CYP1A2, 2B1, 2C11 and 3A2 produced hydroxyl radicals efficiently. Phenobarbital (PB) which is a typical inducer of CYP2B1 and 3A2 induced production of hydroxyl radicals by rat liver and ketoconazole, an inhibitor of P450, inhibited production of hydroxyl radicals in vitro. PB is a tumor promoter as well as the P450-inducer. We investigated oxidation of the genomic DNA by the hydroxyl radicals produced by PB-inducible P450 in vitro and in vivo. 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation in vivo was assayed by HPLC. PB strongly induced the production of 8-OHdG in the rat liver. While ketoconazole inhibited the production of 8-OHdG in vivo. These results suggest that active oxygen produced by P450 oxidized genomic DNA and induction of P450 increased oxidative stress that may contribute to tumor initiation and promotion.     

Ovarian endometrioid adenocarcinoma arising from endometriosis in a young woman

BACKGROUND: The risk of ovarian cancer increases in women with a long history of ovarian endometriosis, particularly in postmenopausal women. We present here a case of malignant transformation of endometriosis occurring over a short time in a young woman. CASE: The 27-year-old woman underwent laparoscopic cystectomy and was diagnosed with left ovarian endometrioma with an accompanying high level of serum CA125 (734.6 U/mL). Fourteen months later, she underwent cytoreductive surgery for her ovarian cancer. Histological examination revealed endometrioid adenocarcinoma with transitions between endometriosis and adenocarcinoma. She was diagnosed as having stage IIIc of ovarian cancer with paraaortic lymphnode involvement. CONCLUSION: We suggest that endometrial cyst of the ovary associated with high levels of serum CA125 should be managed with special care even in a young woman.     

Temporal bone histopathological and quantitative analysis of mitochondrial DNA in MELAS

OBJECTIVES/HYPOTHESIS: Although hearing loss is common in MELAS (syndrome of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes), the histopathology of the temporal bone has not been reported. The majority of cases of MELAS are linked to a mitochondrial DNA (mtDNA) mutation at nucleotide 3243. In MELAS, normal mtDNA and mutant mtDNA coexist in a heteroplasmic manner. The purpose of the study was to report the otopathological findings from two patients with MELAS and quantitative mtDNA analysis in the inner ear of one of these patients. STUDY DESIGN: Basic scientific histopathological examination and quantitative mtDNA analysis of the temporal bone. METHODS: Temporal bones were embedded in celloidin and sectioned for light microscopic study. Graphic reconstruction of the cochlea was performed using the method described by Schuknecht. For quantitative mtDNA analysis, total DNA from the membranous part of the inner ear was collected, amplified by polymerase chain reaction, and digested with the restriction enzyme. The percentage of mutant/total mtDNA was measured by the ratio of fluorescence intensity. RESULTS: Histopathological examination revealed severe degeneration of the stria vascularis and degenerative change of spiral ganglion cells in both patients. The quantitative DNA studies showed that the proportion of mutant to wild-type mtDNA was similar in both histologically affected and histologically unaffected tissues within the inner ear. CONCLUSION: Dysfunction of the stria vascularis and spiral ganglion cells causes sensorineural hearing loss in MELAS.     

Formation of advanced glycosylation end products and oxidative stress in young patients with type 1 diabetes

Increased production of advanced glycosylation end products (AGEs) and augmented oxidative stress may contribute to vascular complications in diabetes. Little is known about the formation and accumulation of AGEs in young patients with type 1 diabetes. The aim of the present study was to investigate whether AGE production and oxidative stress are augmented in young patients with type 1 diabetes at early clinical stages of the disease. Urine samples of 38 patients with type 1 diabetes [mean age (+/-SD), 12.8 +/- 4.5 y; diabetes duration, 5.7 +/- 4.3 y; HbA1c, 8.0 +/- 1.6%; urinary albumin excretion, 12.6 +/- 14.4 mg/g creatinine (Cr)] and those of 60 age-matched healthy control subjects were assayed for AGEs, pentosidine and pyrraline, and markers of oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and acrolein-lysine. Of these four markers, urinary concentrations of pentosidine, 8-OHdG, and acrolein-lysine were significantly higher in the patients with diabetes than in the healthy control subjects. For the patient group, pentosidine correlated significantly with 8-OHdG and acrolein-lysine, and pyrraline correlated significantly with acrolein-lysine. Urinary pentosidine, 8-OHdG, and acrolein-lysine but not pyrraline correlated significantly with urinary albumin excretion. Patients with microalbuminuria (> or =15 mg/g Cr) showed significantly higher levels of all four markers than did normoalbuminuric patients and control subjects. The present study indicates that accumulation of AGEs, whose formation is closely linked to oxidative stress, and resultant endothelial dysfunction may start early in the course of type 1 diabetes. This means that the risk of vascular complications may be present at an early age and that the best possible glycemic control should be emphasized from the diagnosis of diabetes.     

CDR3 spectratyping analysis of the T cell receptor repertoire in Guillain-Barré and Fisher syndromes

Several autoimmune and infectious disorders show oligoclonal expansion of particular T cell phenotypes. The extent of T cell involvement in the pathogenesis of Guillain-Barré syndrome (GBS), a post-infectious autoimmune neuropathy, however, is not clear. To identify the pathogenic T cell phenotypes in GBS and Fisher syndrome (FS), variations in T cell receptor use of the V beta 1-24 and V delta 1-5 chain genes were analyzed at complementarity-determining region 3 level in 119 patients with GBS or FS. Overall, V beta and V delta spectratypes were expanded more frequently in patients with GBS (V beta in 77%, V delta in 53%) or FS (V beta in 75%, V delta in 65%) than in the healthy controls (V beta in 59%, V delta in 38%). No particular spectratype was significantly associated with GBS or FS. Subgrouping the patients by Campylobacter jejuni serology and anti-ganglioside IgG antibodies also failed to detect particular spectratype gene use. The frequency of V beta 5.2 expansion tended to be higher in patients with positive Haemophilus influenzae serology (50%) than in the controls (7%), but the difference was not significant. Our findings show that oligoclonal expansion of T cells bearing particular type T cell receptor V beta and V delta genes frequently occurs in GBS and FS, suggestive that T cells mediate the development of these neuropathies. The predominant phenotypes vary, even within subgroups of patients with a syndrome of single etiological origin or those with uniform serological features.     

No clinical correlation between bilirubin levels and severity of retinopathy of prematurity

PURPOSE: To evaluate the hypothesis that bilirubin has a protective effect against the development of severe retinopathy of prematurity (ROP). METHODS: An assessment of 76 infants born at 24 and 25 weeks' gestation and admitted to the level III neonatal intensive care unit at Saitama Children's Medical Center was made. Indirect ophthalmoscopy fundus examinations were performed on all infants to identify the degree and progression to threshold ROP. We analyzed the daily bilirubin levels and grouped the patients according to the severity of ROP based on the infant's worst ROP examination. The first group was comprised of infants with less than stage 3 ROP and infants with stage 3 ROP. The second group was infants with less than prethreshold ROP or prethreshold ROP, and infants with threshold ROP. Next, we divided the infants into 3 groups: less than prethreshold ROP, prethreshold ROP, and threshold ROP. The daily changes in serum bilirubin concentrations during the first 14 days of life were determined for each infant. Three groups (less than prethreshold ROP, prethreshold ROP, and threshold ROP) were comparable as to their basic data, clinical characteristics, and treatments. RESULTS: ROP was found in 76 infants. There were no statistical differences in the clinical characteristics and treatments, excluding the duration of phototherapy, among the 3 groups. During the first 14 days of age, there were no significant differences in the daily mean bilirubin concentrations according to the groups separated by severity of ROP. CONCLUSION: These results indicate that there is no distinct protective effect of bilirubin on the development of severe ROP.     

A new prognostic scoring system involving des-gamma-carboxy prothrombin as a useful marker for predicting prognosis in patients with hepatocellular carcinoma

A staging system for hepatocellular carcinoma was reported from Italy (CLIP). In this study, we evaluate the CLIP scoring system and establish a new scoring system for predicting the prognosis of patients with hepatocellular carcinoma. Patients (n=141) who were diagnosed and who underwent initial treatment at our single institution were recruited retrospectively into this study. We evaluated markers for prognosis, using a stratified Cox proportional hazard regression model and Kaplan-Meier survival analysis. CLIP score differentiated patients with different survival experiences by Kaplan-Meier estimated survival analysis. However, with respect the CLIP score, more than two thirds of patients were included in the early stage (CLIP 0-1), and the group with better prognosis than the survival rate of all patients was the only one with CLIP 0. Multivariate analysis revealed that des-gamma-carboxy prothrombin (DCP) >/=100 mAU/ml (relative risk, 2.06; P=0.0218) was statistically significant as a predictor of poor survival. A new prognostic scoring system included DCP classified patients to 6 well-balanced groups (score 0-5). The new prognostic scoring system 0 group (14.9% of the cohort) and the CLIP score 0 group (34.0% of the cohort) had a median survival of 66.9 and 61.6 months. The new prognostic scoring system performs better for prediction of survival than either the CLIP score or the Child-Pugh stage. In conclusion, the described scoring system provides more accurate prognostic information than the CLIP scoring system. It may help physicians decide more appropriate clinical and therapeutic management.