Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies

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Unusual left ventricular dilatation without functional or biochemical impairment in normotensive extremely overweight Japanese professional sumo wrestlers

To explore the physiologic limit of left ventricular (LV) enlargement, we performed echocardiography and air displacement plethysmography to respectively assess LV dimension and function and the body composition of Japanese professional sumo wrestlers. After excluding subjects with cardiovascular disease, hypertension, plasma brain natriuretic peptide (BNP) > or =17.9 pg/ml, diabetes mellitus, or asthma, 331 subjects (mean +/- SD age, 21.6 +/- 3.7 years; height 179.2 +/- 5.3 cm; weight 1,17.9 +/- 21.5 kg; percent fat, 29.6 +/- 6.6%) were analyzed. LV end-diastolic dimension averaged 58.4 +/- 3.7 mm and was within the generally regarded normal limit (< or =54 mm) in 14.5% of subjects, but was > or =60 mm in 41.1% of subjects. LV septal and posterior wall thicknesses were 10.3 +/- 0.9 and 10.2 +/- 0.9 mm, respectively. Peak E- and A-wave velocities, E/A ratio, LV fractional shortening, and BNP were 96 +/- 16 and 51 +/- 13 cm/s, 2.0 +/- 0.7, 33.5 +/- 4.5%, and 3.1 +/- 3.7 pg/ml, respectively. LV end-diastolic dimension was not correlated with these indexes of LV function or with plasma BNP levels, but was significantly correlated with height, weight, body surface area, fat-free mass, and fat mass. These results show that among very large, highly trained, professional athletes, LV end-diastolic dimension frequently exceeds the traditionally accepted upper limit of normal for the general population. This increase in LV end-diastolic dimension may thus represent an extreme example of the physiologic adaptation of the athlete's heart.     

Disseminated gonococcal infection in a Japanese man with complement 7 deficiency with compound heterozygous variants: A case report

Rationale:Complement deficiency are known to be predisposed to disseminated gonococcal infection (DGI). We herein present a case of DGI involving a Japanese man who latently had a complement 7 deficiency with compound heterozygous variants.Patient concerns:A previously healthy 51-year-old Japanese man complained of sudden-onset high fever. Physical examination revealed various skin lesions including red papules on his trunk and extremities, an impetigo-like pustule on left forearm, and tendinitis of his right forefinger.Diagnosis:Blood culture testing detected gram-negative cocci, which was confirmed to be Neisseria gonorrhoeae based on mass spectrometry and a pathogen-specific PCR test.Interventions:Screening tests for underlying immunocompromised factors uncovered that complement activities (CH50) was undetectable. With a suspicion of a congenital complement deficiency, genetic analysis revealed rare single nucleotide variants in complement 7 (C7), including c.281-1G>T and a novel variant c.1454C>T (p.A485V). CH50 was normally recovered by adding purified human C7 to the patient''s serum, supporting that the patient has C7 deficiency with compound heterozygous variants.Outcomes:Under a diagnosis of DGI, the patient underwent an antibiotic treatment with cefotaxime for a week and was discharged without any sequela.Lessons:DGI is a rare sexually-transmitted infection that potentially induces systemic complications. Complement immunity usually defeats N. gonorrhoeae and prevents the organism from causing DGI. This case highlighted the importance of suspecting a complement deficiency when a person develops DGI.     

Physiological and morphometric analyses of neuropathy in sucrose-fed OLETF rats

To investigate the characteristic features of diabetic neuropathy in type 2 diabetes mellitus, Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human type 2 diabetes mellitus, and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with or without sucrose and/or an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl] acetic acid (TAT), for 24 weeks, and physiological, biochemical and morphological assessments were performed. Sucrose administration caused remarkable hyperglycemia in OLETF rats but not in LETO rats. Sucrose-fed OLETF rats demonstrated delayed nerve conduction velocity, decreased coefficient of variation of R-R interval, reduced sciatic nerve blood flow, increased platelet aggregation activity, a lower concentration of erythrocyte 2,3-diphosphoglycerate, and decreased Na+/K+-ATPase activity in sciatic nerves, compared with the non-sucrose-fed OLETF and LETO rats. TAT prevented all these deficits except hyperglycemia. Sorbitol and fructose accumulation and myo-inositol depletion in tail nerves of sucrose-fed OLETF rats were ameliorated by TAT. Myelinated fiber size and density in sural nerves of sucrose-fed OLETF rats were decreased and increased, respectively, compared with non-sucrose-fed OLETF and LETO rats. These morphological abnormalities were normalized by TAT. These observations suggest that the sucrose-fed OLETF rat developed diabetic neuropathy not only electrophysiologically but also histologically, and that an aldose reductase inhibitor, TAT, possesses therapeutic value for the treatment of diabetic neuropathy.     

Molecular Genetics of Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by the clonal expansion of glycosylphosphatidylinositol (GPI)-deficient cells that leads to complement-mediated hemolysis. A somatic mutation in the PIG-A gene involved in GPI biosynthesis causes a deficiency of GPI-anchored proteins. However, it is evident that the clonal expansion of GPI-deficient cells is not caused by only the PIG-A mutation and that other changes should be involved in the development of PNH. Some patients with aplastic anemia (AA) develop PNH. Furthermore, it has been reported that most patients with AA and refractory anemia (RA) who carry HLA-DRB1*15 and show a good response to immunosuppressive therapies have an expanded population of GPI-deficient clones. This finding, together with recent data showing resistance of GPI-deficient cells to cytotoxic cells, suggests that GPI-deficient cells escape immunologic attack and are positively selected in the autoimmune environment. However, GPI-deficient clones found in AA and RA are generally small and do not increase to near-complete dominance. Therefore, 1 or more additional genetic abnormalities that confer the growth phenotype on GPI-deficient cells are probably required for fully developed PNH or so-called florid PNH. The next 10 years should witness the discovery of the molecular mechanisms of immunologic selection and the identification of abnormalities involved in the further clonal expansion of PNH cells.     

A Simple, 10-minute Procedure for Transforaminal Injection under Ultrasonic Guidance to Effect Cervical Selective Nerve Root Block

The aim is to provide a detailed procedure of a simple and 10-minute cervical nerve root block (CNRB) under ultrasonic guidance, and to report the clinical outcomes, disorders, and complications. Records of patients who had undergone CNRB, were reviewed under ultrasonic guidance at the hospital from 2010 through 2012. The procedure is described in detail. Arm and shoulder pain was evaluated by use of the visual analogue scale (VAS). Forty-three patients agreed to undergo CNRB under ultrasonic guidance. Nerve roots from C5 to C8 were affected in 41, and these nerve roots were readily distinguished. Two of the 43 participants did not receive injections because impediments in visualizing the affected nerve root. Of the 41 who received injections, radicular pain immediately disappeared in 39, who continued to feel pain relief 1 month later. However, pain recurred in 15 patients (38%), of whom 11 underwent cervical spine surgery. The rest of 24 patients felt sustained pain relief longer than 3 months after the injection, significantly. Although one patient had recurrent radicular pain 10 months later, the pain could be controlled by medication. At the final follow-up periods, 17.2 (10–24 months), the median VAS score of the patients, 23 (0 to 71 mm), was significantly improvement (P = 0.001) in comparison to before injection 88 (range; 56–100). No complications occurred. The cervical nerve root block under ultrasonic guidance simply, safely, and efficaciously decreased radicular pain for 17.2 months in 62% patients with intolerable radicular pain.     

Inhibitory neurons in the anterior piriform cortex of the mouse: Classification using molecular markers

The primary olfactory cortex (or piriform cortex, PC) is attracting increasing attention as a model system for the study of cortical sensory processing, yet little is known about inhibitory neurons in the PC. Here we provide the first systematic classification of GABA‐releasing interneurons in the anterior PC of mice, based on the expression of molecular markers. Our experiments used GAD67‐GFP transgenic mice, in which gamma‐aminobutyric acid (GABA)‐containing cells are labeled with green fluorescent protein (GFP). We first confirmed, using paired whole‐cell recordings, that GFP⁺ neurons in the anterior PC of GAD67‐GFP mice are functionally GABAergic. Next, we performed immunolabeling of GFP⁺ cells to quantify their expression of every possible pairwise combination of seven molecular markers: calbindin, calretinin, parvalbumin, cholecystokinin, neuropeptide Y, somatostatin, and vasoactive intestinal peptide. We found that six main categories of interneurons could be clearly distinguished in the anterior PC, based on the size and laminar location of their somata, intensity of GFP fluorescence, patterns of axonal projections, and expression of one or more of the seven markers. A number of rarer categories of interneurons could also be identified. These data provide a road map for further work that examines the functional properties of the six main classes of interneurons. Together, this information elucidates the cellular architecture of the PC and provides clues about the roles of GABAergic interneurons in olfactory processing. J. Comp. Neurol. 518:1670–1687, 2010. © 2009 Wiley‐Liss, Inc.