Autosomal linkage analysis of a Japanese single multiplex schizophrenia pedigree reveals two candidate loci on chromosomes 4q and 3q.

We analyzed a large multiplex schizophrenia pedigree collected in mid-eastern Japan using 322 microsatellite markers distributed throughout the whole autosome. Under an autosomal-dominant inheritance model, the highest pairwise LOD score (LOD = 1.69) was found at 4q (D4S2431: theta = 0.0), and LOD scores at two other loci 3q (ATA34G06) and 8q (D8S1128) were 1.62 and 1.46, respectively. In multipoint analysis, LOD scores of the regions on 4q and 3q remained at a similar level; however, the LOD score of the region on 8q apparently decreased. Additional dense map analysis revealed haplotypes on 4q and 3q regions shared by affected individuals. On chromosome 4q, the haplotype spanning about 8 centiMorgans (cM) was shared by four of six genotyped individuals with schizophrenia and one affected individual whose haplotype was estimated. On 3q, the haplotype spanning about 20 cM was shared by five genotyped individuals with schizophrenia. We obtained two candidate regions of major susceptibility loci for schizophrenia on chromosomes 3q and 4q.     

Bloom''s syndrome with porokeratosis of Mibeili and multiple cancers of the skin, lung and colon

A 38-year-old Japanese male with Bloom's syndrome (BS) and porokeratosis of Mibelli (PM) developed multiple carcinomas of the skin and lung. There were multiple, spontaneous chromosomal aberrations and frequent sister chromatid exchanges (SCE). Cutaneous delayed-type hypersensitivity reactions were defective and serum IgM was decreased. The lung cancer was treated with radiation, which was effective but caused a severe pulmonary atelectasis and esophageal stricture. The patient expired one-and-a-half years later because of pneumonia. Autopsy disclosed an adenocarcinoma of the colon. The concurrent PM was considered responsible for the occurrence of multiple skin cancers.     

Simultaneous determination of tryptamine analogues in designer drugs using gas chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry

In recent years, a large number of tryptamine-based designer drugs have been encountered in forensic samples. We have developed simultaneous analytical methods for 14 tryptamine analogues using gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–tandem mass spectrometry (LC–MS–MS). Trimethylsilyl (TMS) derivatives of the analytes were separated on a DB-1ms column within 15 min. The structural isomers could be differentiated by electron ionization GC–MS. LC–MS–MS with a C₁₈ column could separate structural isomers of tryptamines except for a combination of 5-methoxy-N,N-diethyltryptamine and 5-methoxy-N-methyl-N-isopropyltryptamine. Higher collision energy gave different product ion spectra between the structural isomers. The results indicate that GC–MS is the first choice for identification of tryptamines, preferably after TMS derivatization, and LC–MS–MS can be used as a complementary approach for the unequivocal differentiation of tryptamine isomers.     

Micro-segmental hair analysis: detailed procedures and applications in forensic toxicology

Forensic Toxicology - Since the 1980s, the detection sensitivity of mass spectrometers has increased by improving the analysis of drugs in hair. Accordingly, the number of hair strands required for...     

Thin-layer chromatography on silver nitrate-impregnated silica gel for analysis of homemade tetrahydrocannabinol mixtures

Forensic Toxicology - Various forms of cannabidiol (CBD)-containing products are sold in Japan. CBD is easily converted to mixtures of ?9-tetrahydrocannabinol (?9-THC) and its isomer,...     

Novel ACOX1 mutations in two siblings with peroxisomal acyl-CoA oxidase deficiency

Peroxisomal acyl-CoA oxidase (ACOX1) deficiency is a rare autosomal recessive single enzyme deficiency characterized by hypotonia, seizures, failure to thrive, developmental delay, and neurological regression starting from approximately 3 years of age.Here, we report two siblings with ACOX1 deficiency born to non-consanguineous Japanese parents. They showed mild global developmental delay from infancy and began to regress at 5 years 10 months and 5 years 6 months of age respectively. They gradually manifested with cerebellar ataxia, dysarthria, pyramidal signs, and dysphasia. Brain MRI revealed T2 high-intensity areas in the cerebellar white matter, bilateral middle cerebellar peduncle, and transverse tracts of the pons, followed by progressive atrophy of these areas.Intriguingly, the ratios of C24:0, C25:0, and C26:0 to C22:0 in plasma, which usually increase in ACOX1 deficiency were within normal ranges in both patients. On the other hand, whole exome sequencing revealed novel compound heterozygous variants in ACOX1: a frameshift variant (c.160delC:p.Leu54Serfs*18) and a missense variant (c.1259 T > C:p.Phe420Ser). The plasma concentration of individual very long chain fatty acids (C24:0, C25:0, and C26:0) was elevated, and we found that peroxisomes in fibroblasts of the patients were larger in size and fewer in number as previously reported in patients with ACOX1 deficiency. Furthermore, the C24:0 β-oxidation activity was dramatically reduced.Our findings suggest that the elevation of individual plasma very long chain fatty acids concentration, genetic analysis including whole exome analysis, and biochemical studies on the patient’s fibroblasts should be considered for the correct diagnosis of ACOX1 deficiency.     

CD14 expression and Kupffer cell dysfunction in non-alcoholic steatohepatitis: superparamagnetic iron oxide-magnetic resonance image and pathologic correlation

Background and Aim: Kupffer cell (KC) function and CD14 expression contributes to pathogenesis of non‐alcoholic steatohepatitis (NASH). However, these relationships remain unclear. We investigated the relationship of KC function with superparamagnetic iron oxide‐enhanced magnetic resonance imaging (SPIO‐MRI), histopathological severity of NASH, and number of CD14‐positive KCs in NASH. Methods: This retrospective study included 32 patients (24 with NASH and eight with simple steatosis) who had previously undergone SPIO‐MRI with T2‐weighted gradient‐recalled echo sequence. All subjects were diagnosed pathologically and were evaluated for necroinflammation grade, fibrosis stage, and number of CD14‐positive KCs. Patients with NASH and simple steatosis were compared by using the Mann–Whitney test to determine differences in percent reduction of liver‐to‐muscle signal intensity ratio (reduction‐%LMR), as a surrogate parameter of KC function, and number of CD14‐positive KCs. Kruskal–Wallis test and Pearson's correlation coefficient were used to analyze relation among reduction‐%LMR, histopathological severity and number of CD14‐positive KCs. Results: There were statistically significant differences in reduction‐%LMR and number of CD14‐positive KCs between NASH and simple steatosis patients (Mann–Whitney test, P < 0.001 for all comparisons). Reduction‐%LMR decreased with an increase in necroinflammation grade or fibrosis stage. The number of CD14‐positive KCs increased with an increase in necroinflammation grade and fibrosis stage (Kruskal–Wallis test, both, P < 0.001). A high correlation was seen between number of CD14‐positive KCs and reduction‐%LMR (Pearson r = 0.81; P < 0.001). Conclusions: KC phagocytic function evaluated with SPIO‐MRI correlated with histopathological severity and number of CD14‐positive KCs. These results support the concept that KC phagocytic dysfunction contributes to the pathogenesis of NASH.     

Fish to meat intake ratio and cooking oils are associated with hepatitis C virus carriers with persistently normal alanine aminotransferase levels

Aim: Dietary habits are involved in the development of chronic inflammation; however, the impact of dietary profiles of hepatitis C virus carriers with persistently normal alanine transaminase levels (HCV‐PNALT) remains unclear. The decision‐tree algorithm is a data‐mining statistical technique, which uncovers meaningful profiles of factors from a data collection. We aimed to investigate dietary profiles associated with HCV‐PNALT using a decision‐tree algorithm. Methods: Twenty‐seven HCV‐PNALT and 41 patients with chronic hepatitis C were enrolled in this study. Dietary habit was assessed using a validated semiquantitative food frequency questionnaire. A decision‐tree algorithm was created by dietary variables, and was evaluated by area under the receiver operating characteristic curve analysis (AUROC). Results: In multivariate analysis, fish to meat ratio, dairy product and cooking oils were identified as independent variables associated with HCV‐PNALT. The decision‐tree algorithm was created with two variables: a fish to meat ratio and cooking oils/ideal bodyweight. When subjects showed a fish to meat ratio of 1.24 or more, 68.8% of the subjects were HCV‐PNALT. On the other hand, 11.5% of the subjects were HCV‐PNALT when subjects showed a fish to meat ratio of less than 1.24 and cooking oil/ideal bodyweight of less than 0.23 g/kg. The difference in the proportion of HCV‐PNALT between these groups are significant (odds ratio 16.87, 95% CI 3.40–83.67, P = 0.0005). Fivefold cross‐validation of the decision‐tree algorithm showed an AUROC of 0.6947 (95% CI 0.5656–0.8238, P = 0.0067). Conclusion: The decision‐tree algorithm disclosed that fish to meat ratio and cooking oil/ideal bodyweight were associated with HCV‐PNALT.     

Treatment When Prognostic Factors Do Not Match St. Gallen Recommendations: Profiling of Prognostic Factors among HR(+) and HER2(−) Breast Cancer Patients

Background

The St. Gallen consensus provides treatment recommendations for breast cancer based on prognostic factors. Although many patients’ prognostic patterns are not easily matched with the prognostic patterns listed in the St. Gallen consensus, there has been no systematic investigation reporting the gap between treatment recommendations and actual postoperative treatment choices in clinical practice.

Methods

Four hundred seventy-one patients with hormone receptor-positive [HR(+)] and human epidermal growth factor receptor type 2-negative [HER2(?)] breast cancer were analyzed. These patients were classified into either the “crisp treatment group” or “fuzzy treatment group” based on the definitiveness of postoperative treatment selection based on St. Gallen treatment recommendations. The patients in the fuzzy treatment group were further classified into strata in which patients within each stratum shared the same prognostic factor patterns with similar recurrence rates.

Results

A total of 87.3 % of HR(+)HER2(?) patients were designated to the fuzzy treatment group. Four prognostic strata were constructed according to the survival tree model, and revealed that patients with poor prognostic profiles tended to receive endocrine therapy with chemotherapy. This suggests that postoperative chemotherapy is useful, although there was no statistical significance.

Conclusions

We constructed prognostic profiles of patients in the fuzzy treatment group and examined the recurrence rates associated with two treatment regimens within each prognostic profile. These findings are exploratory, but they may be useful for planning prospective studies of the effectiveness of postoperative treatment regimens among patients with a heterogeneous combination of prognostic factors.