A prospective and comparative cohort study on efficacy and drug resistance during long-term lamivudine treatment for various stages of chronic hepatitis B and cirrhosis

Background and Aims: A prospective , non‐randomized cohort study on long‐term lamivudine treatment , comparing efficacy, drug resistance, and prognosis for various stages of chronic hepatitis B virus (HBV)–related liver disease was performed to elucidate the significance and indication of lamivudine for individual patients at each stage of disease. Methods: A total of 158 cases consisting of 87 chronic hepatitis, 28 compensated cirrhosis, and 43 decompensated cirrhosis, with serum HBV‐DNA > 5 log₁₀ copies/mL and with elevated alanine aminotransferase (ALT) over twice the upper normal limit or complications of hepatic insufficiency, were administered 100 mg of lamivudine daily and monitored for HBV markers, biochemistry, and prognosis. Results: Lamivudine reduced HBV‐DNA and ALT equally in all groups. Serum albumin, prothrombin time (%), and platelet count increased in all groups. The increased margin of albumin was the highest in the decompensated cirrhosis and higher in the compensated cirrhosis than the chronic hepatitis groups. Cumulative incidence of virologic breakthrough was 16%, 42%, 49%, and 53% at 12, 24, 36, and 48 months, respectively, and the strongest predictive factor for lamivudine resistance was persistent HBV‐DNA at 3 months. Ascites, encephalopathy, and jaundice improved in the majority of patients with decompensated cirrhosis. On the other hand, hepatic failure developed or deteriorated in 10 patients after virologic breakthrough, and nine of them had decompensated cirrhosis. Conclusions: Lamivudine was effective in reducing HBV‐DNA and improving hepatic reserve at all stages and was most beneficial and significant for decompensated cirrhosis. Meanwhile, close monitoring of viral load and immediate rescue treatment for lamivudine resistance is necessary to prevent hepatic failure in decompensated cirrhosis.     

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

For normal fertilization in mammals, it is important that functionally mature sperm are motile and have a fully formed acrosome. The glycosyltransferase-like gene, human polypeptide N-acetylgalactosaminyltransferase-like protein 5 (GALNTL5), belongs to the polypeptide N-acetylgalactosamine-transferase (pp-GalNAc-T) gene family because of its conserved glycosyltransferase domains, but it uniquely truncates the C-terminal domain and is expressed exclusively in human testis. However, glycosyltransferase activity of the human GALNTL5 protein has not been identified by in vitro assay thus far. Using mouse Galntl5 ortholog, we have examined whether GALNTL5 is a functional molecule in spermatogenesis. It was observed that mouse GALNTL5 localizes in the cytoplasm of round spermatids in the region around the acrosome of elongating spermatids, and finally in the neck region of spermatozoa. We attempted to establish Galntl5-deficient mutant mice to investigate the role of Galntl5 in spermiogenesis and found that the heterozygous mutation affected male fertility due to immotile sperm, which is diagnosed as asthenozoospermia, an infertility syndrome in humans. Furthermore, the heterozygous mutation of Galntl5 attenuated glycolytic enzymes required for motility, disrupted protein loading into acrosomes, and caused aberrant localization of the ubiquitin–proteasome system. By comparing the protein compositions of sperm from infertile males, we found a deletion mutation of the exon of human GALNTL5 gene in a patient with asthenozoospermia. This strongly suggests that the genetic mutation of human GALNTL5 results in male infertility with the reduction of sperm motility and that GALNTL5 is a functional molecule essential for mammalian sperm formation.O-glycosylation begins by the addition of N-acetylgalactosamine to the serine or threonine residues in the target protein. This first step occurs in the Golgi apparatus, and is mediated by UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (pp-GalNAc-T; EC 2.4.1.41), which transfer GalNAc from the nucleotide sugar to the acceptor residues (1). Polypeptide N-acetylgalactosaminyltransferase-like protein 5 [GALNTL5, also described as pp-GalNac-T19 (2) or GalNac-T20 (3); Refseq accession no.: {"type":"entrez-protein","attrs":{"text":"NP_660335.2","term_id":"281485547","term_text":"NP_660335.2"}}NP_660335.2] is classified as a member of the pp-GalNAc-T family because GALNTL5 possesses highly conserved catalytic domains of pp-GalNAc-T, whereas it uniquely lacks the conserved lectin domain at the C terminus. Thus far, 20 distinct pp-GalNAc-T genes have been identified in the human genome (2, 4–6). The in vitro enzymatic activities as a glycosyltransferase have been confirmed for 14 members of this family using acceptor peptide substrates (2, 7), but not identified for the other 6 members, including GALNTL5. During the preparation of this paper, it was reported that the transferase activity of GALNTL5 (GalNAc-T20) could not be detected using in vitro assays (3). The in vivo functions of these isoforms are poorly understood because of the absence of specific enzymatic activity. Meanwhile, O-fucosyltransferase 1, a member of a fucosyltransferase family, exhibits chaperon activity specific to Notch folding in Drosophila (8). One possibility is that the isoforms lacking enzymatic activities may have functions other than characteristics of glycosyltransferases, despite having typical glycosyltransferase motifs.Spermatogenesis is a complex process in which spermatogonial stem cells form spermatozoa through the proliferative phase (spermatogonia), the meiotic phase (spermatocytes), and the differentiation or spermiogenic phase (spermatids). Spermatids are connected by intercellular bridges, through which cytoplasmic constituents are shared among haploid spermatids (9). In the last spermiogenic phase, the round haploid spermatids differentiate into spermatozoa where acrosomes and tails unique and necessary for fertilization are developed. Spermatozoa are released through the seminiferous lumen into the epididymis, where they undergo further maturation and acquire motility. Sperm motility is an important factor in normal fertilization, whereas over 80% of sperm samples from infertile men demonstrate asthenozoospermia, poor sperm motility (10). Although defects of many potential genes are reported in mouse models exhibiting asthenozoospermia (11), it is rare that mutations in these genes are identified in human patients with asthenozoospermia.To investigate the biochemical machineries and biological functions of glycosylation, we performed comprehensive identification of the mammalian glycosyltransferase genes using various approaches and confirmed their enzymatic activity in vitro using biochemical methods (12). During these studies, we identified a unique isoform of the human GALNTL5 gene restricted to the human testis. However, we could not confirm the glycosyltransferase activity of GALNTL5, including whether it is a functional molecule in spermatogenesis. Therefore, using the mouse Galntl5 gene, we attempted to elucidate the biological role of GALNTL5 in spermatogenesis and found that the heterozygous mutation of Galntl5 causes male infertility by reducing sperm motility, which highly resembles human asthenozoospermia. In reference to the aberrant protein compositions of sperm from the Galntl5 heterozygous mutant mice (Ht mice), we found a patient with asthenozoospermia carrying one heterozygous nucleotide deletion at the sixth exon of the human GALNTL5 gene. Together with these data, we speculate that the function of GALNTL5 is indispensable for mature sperm formation and that GALNTL5 might have a unique role in mammalian spermiogenesis.     

Comparison of Expression and Proliferative Effect of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its Receptors on Human Astrocytoma Cell Lines

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide considered to be a potent regulator of astrocytes. It has been reported that PACAP also affects astrocytoma cell properties, but the proliferative effects of this peptide in previous reports were inconsistent. The purpose of this study was to search for correlations between malignant potential, PACAP/PACAP receptor expression, and the proliferative potential of four astrocytoma cell lines (KNS-81, KINGS-1, SF-126, and YH-13). Immunohistochemical observations were performed using astrocyte lineage markers with a view to establishing malignant potential, which is inversely correlated to differentiation status in astrocytoma cells. YH-13 showed the most undifferentiated astrocyte-like status, and was immunopositive to a cancer stem cell marker, CD44. These observations suggest that YH-13 is the most malignant of the astrocytoma cell lines tested. Moreover, the strongest PAC1-R immunoreactivity was observed in YH-13 cells. Using real-time PCR analysis, no significant differences among cell lines were detected with respect to PACAP mRNA, but PAC1-R and VPAC1-R mRNA levels were significantly increased in YH-13 cells compared with the other cell lines. Furthermore, when cell lines were treated with PACAP (10^?11 M) for 3 days, the YH-13 cell line, but not of the other cell lines, exhibited a significantly increased cell number. These results suggest that PACAP receptor expression is correlated with the malignant and proliferative potential of astrocytoma cell lines.     

A case of intrahepatic splenosis: usefulness of splenic scintigraphy

Abdominal Radiology - We report a 39-year-old male with intrahepatic and peritoneal splenosis, focusing on scintigraphic findings. Dynamic computed tomography (CT) showed a 3 cm lesion in...     

Mitral valve prolapse in sickle cell disease: Manifestation of a generalized connective tissue disorder

Previous studies have shown an association of sickle cell disease with generalized connective tissue disorders such as pscudoxanthoma elasticum. We recently documented an unexpectedly high prevalence of mitral valve prolapse, a connective tissue disorder, in sickle cell discase. To investigate this association, skin biopsies were analyzed from 32 sickle cell disease patients, 11 of whom had mitral prolapse. Total and type III collagen, collagen solubility, and uronic acid were not different between the patients with or without mitral prolapse (p > 0.05). Computerized morphometric quantitation of the volume fraction of elastic fibers was greater in sickle cell disease patients than in 10 normals (3.1 ± 0.1 mean ± SEM vs 2.0 ± 0.3%; p < 0.01) but less than in three patients with pseudoxanthoma elasticum (9.7 0.6%; p < 0.001). Desmosine radioimmunoassay (an index of elastic fibers) was greater in sickle cell disease patients with mitral prolapse than those without (239.3 ± 9.3 vs 171.7 ± 25.4 ng/mg wet weight; p < 0.02). Histopathologic grading showed a similar trend (p = 0.07). The combined probabilities of these three independent tests of elastic fiber quantity showed an increased elastic fiber concentration in mitral prolapse patients compared to those without mitral prolapse (p < 0.02). Thus, there is no evidence for a specific collagen defect; rather, sickle cell disease appears to be associated with a spectrum of elastic tissue disorders, a feature that could predispose to mitral valve prolapse.     

The effects of histamine on the concentrations of immunoreactive thyrotropin-releasing hormone in the stomach and hypothalamus in rats

The effects of histamine and its related compounds on the concentrations of immunoreactive thyrotropin-releasing hormone (ir-TRH) in the stomach, gastric juice and hypothalamus in rats were studied. Histamine, ranitidine or ethanolamine was injected intraperitoneally, and the rats were decapitated at various times after the injection. Ir-TRH concentrations in the stomach, gastric juice and hypothalamus were measured by a radioimmunoassay. Ir-TRH concentrations in the stomach decreased significantly after histamine injection and increased significantly after ranitidine injection in a dose-dependent manner, but did not change with ethanolamine. Ir-TRH concentrations in the gastric juice increased in a dose-dependent manner, peaking at 30 min after histamine injection, and its effect was blocked with ranitidine. Ir-TRH concentrations in the hypothalamus elevated significantly after histamine injection and reduced significantly after ranitidine injection, but did not change with ethanolamine. The effects of histamine on ir-TRH concentrations in the stomach and hypothalamus were significantly blocked with ranitidine, but not with ethanol-amine. These findings suggest that histamine stimulates ir-TRH release from the stomach and inhibits ir-TRH release from the hypothalamus, and that these effects of histamine on ir-TRH release are mediated via an H₂-receptor. Portions of this work were presented at the 75th annual meeting of Japanese Society of Gastroenterology. March 1989 in Yokohama, Japan.     

Associations between Chest CT Abnormalities and Clinical Features in Patients with the Severe Fever with Thrombocytopenia Syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus. It involves multiple organ systems, including the lungs. However, the significance of the lung involvement in SFTS remains unclear. In the present study, we aimed to investigate the relationship between the clinical findings and abnormalities noted in the chest computed tomography (CT) of patients with SFTS. The medical records of 22 confirmed SFTS patients hospitalized in five hospitals in Nagasaki, Japan, between April 2013 and September 2019, were reviewed retrospectively. Interstitial septal thickening and ground-glass opacity (GGO) were the most common findings in 15 (68.1%) and 12 (54.5%) patients, respectively, and lung GGOs were associated with fatalities. The SFTS patients with a GGO pattern were elderly, had a disturbance of the conscious and tachycardia, and had higher c-reactive protein levels at admission (p = 0.009, 0.006, 0.002, and 0.038, respectively). These results suggested that the GGO pattern in patients with SFTS displayed disseminated inflammation in multiple organs and that cardiac stress was linked to higher mortality. Chest CT evaluations may be useful for hospitalized patients with SFTS to predict their severity and as early triage for the need of intensive care.