Selective Serotonin Reuptake Inhibitors and Poststroke Epilepsy: A Population-Based Nationwide Study

Objective

To investigate the effects of selective serotonin reuptake inhibitors (SSRIs) on poststroke epilepsy in a population-based nationwide study.

Identification of mutations in the gene for glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a.

Glycogen storage disease (GSD) type 1a is an autosomal recessive inborn error of metabolism caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis. Southern blot hybridization analysis using a panel of human-hamster hybrids showed that human G6Pase is a single-copy gene located on chromosome 17. To correlate specific defects with clinical manifestations of this disorder, we identified mutations in the G6Pase gene of GSD type 1a patients. In the G6Pase gene of a compound heterozygous patient (LLP), two mutations in exon 2 of one allele and exon 5 of the other allele were identified. The exon 2 mutation converts an arginine at codon 83 to a cysteine (R83C). This mutation, previously identified by us in another GSD type 1a patient, was shown to have no detectable phosphohydrolase activity. The exon 5 mutation in the G6Pase gene of LLP converts a glutamine codon at 347 to a stop (Q347SP). This Q347SP mutation was also detected in all exon 5 subclones (five for each patient) of two homozygous patients, KB and CB, siblings of the same parents. The predicted Q347SP mutant G6Pase is a truncated protein of 346 amino acids, 11 amino acids shorter than the wild type G6Pase of 357 residues. Site-directed mutagenesis and transient expression assays demonstrated that G6Pase-Q347SP was devoid of G6Pase activity. G6Pase is an endoplasmic reticulum (ER) membrane-associated protein containing an ER retention signal, two lysines (KK), located at residues 354 and 355. We showed that the G6Pase-K355SP mutant containing a lysine-355 to stop codon mutation is enzymatically active. Our data demonstrate that the ER protein retention signal in human G6Pase is not essential for activity. However, residues 347-354 may be required for optimal G6Pase catalysis.     

Fibromyalgia and Risk of Dementia—A Nationwide,Population-Based,Cohort Study

Background

Fibromyalgia is a syndrome of chronic pain and other symptoms and is associated with patient discomfort and other diseases. This nationwide matched-cohort population-based study aimed to investigate the association between fibromyalgia and the risk of developing dementia, and to clarify the association between fibromyalgia and dementia.

Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation for Multiple Myeloma: Results from the Japan Myeloma Study Group

We conducted a retrospective survey of multiple myeloma (MM) patients who underwent reduced-intensity conditioning allogeneic stem cell transplantation (RIST) at 11 hospitals participating in the Japan Myeloma Study Group. Forty-five patients (median age, 53 years) were included in this study. The conditioning regimen consisted of a fludarabine-based regimen in 24 patients and a regimen based on total body irradiation (1-2 Gy) in 18 patients. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and tacrolimus in 28 and 17 patients, respectively. All patients showed myeloid engraftment. Complete chimerism was obtained in 42 patients. Grade II to IV acute GVHD developed in 28 (65%) of 43 patients evaluated, and chronic GVHD developed in 31 (76%) of 41 patients. Early death before day 100 was observed in 4 patients (8.8%). A complete response (CR) was obtained in 12 patients. The factors affecting overall survival were severe acute GVHD and the response after RIST. To date, 18 patients are alive, with 9 patients remaining in CR at a median follow-up of 25 months. The overall and progression-free survival rates at 3 years were 38.5% and 18.8%, respectively. These observations suggest that RIST is feasible with reliable donor engraftment and relatively low transplantation-related mortality in Japanese MM patients.     

Functional profiling of a human cytomegalovirus genome

Human cytomegalovirus (HCMV), a ubiquitous herpesvirus, causes a lifelong subclinical infection in healthy adults but leads to significant morbidity and mortality in neonates and immunocompromised individuals. Its ability to grow in different cell types is responsible for HCMV-associated diseases, including mental retardation and retinitis, and vascular disorders. To globally assess viral gene function for replication in cells, we determined the genomic sequence of a bacterial artificial chromosome (BAC)-based clone of HCMV Towne strain and used this information to delete each of its 162 unique ORFs and generate a collection of viral mutants. The growth of these mutants in different cultured cells was examined to systematically investigate the necessity of each ORF for replication. Our results showed that 45 ORFs are essential for viral replication in fibroblasts and 117 are nonessential. Some genes were found to be required for viral replication in retinal pigment epithelial cells and microvascular endothelial cells, but not in fibroblasts, indicating their role as tropism factors. Interestingly, several viral mutants grew 10- to 500-fold better than the parental strain in different cell types, suggesting that the deleted ORFs encode replication temperance or repressing functions. Thus, HCMV encodes supportive and suppressive growth regulators for optimizing its replication in human fibroblasts, epithelial, and endothelial cells. Suppression of viral replication by virus-encoded temperance factors represents a novel mechanism for regulating the growth of an animal virus, and may contribute to HCMV's optimal infection of different tissues and successful proliferation among the human population.     

Trousseau's syndrome in a patient with advanced stage gastric cancer

Patients with cancer are at high risk for thrombotic events,which are known collectively as Trousseau's syndrome. Herein,we report a 66-year-old male patient who was diagnosed with terminal stage gastric cancer and liver metastasis and who had an initial clinical presentation of upper gastrointestinal bleeding. Acute ischemia of the left lower leg that resulted in gangrenous changes occurred during admission. Subsequent angiography of the left lower limb was then performed. This procedure revealed arterial thrombosis of the left common iliac artery with extension to the external iliac artery,the left common iliac artery,the posterior tibial artery,and the peroneal artery,which were occluded by thrombi. Aspiration of the thrombi demonstrated that these were not tumor thrombi. The interesting aspect of our case was that the disease it presented as arterial thrombotic events,which may correlate with gastric adenocarcinoma. In summary,we suggested that the unexplained thrombotic events might be one of the initial presentations of occult malignancy and that thromboprophylaxis should always be considered.