Hypertrophic obstructive cardiomyopathy with infundibular stenosis treated by alcohol ablation therapy

This report describes an uncommon case of hypertrophic obstructive cardiomyopathy (HOCM) accompanying infundibular stenosis of the right ventricle treated by alcohol ablation therapy, in a 28-yr-old male patient presenting with dyspnea on exertion. HOCM with infundibular stenosis was detected by echocardiogram and cardiac catheterization and patient has dynamic obstructions of both ventricular outflow tracts. We performed alcohol ablation therapy to improve clinical symptoms and to relieve dynamic obstructions of both ventricular outflow tracts. This is the first case in which HOCM with infundibular stenosis of the right ventricle was treated by alcohol ablation therapy.     

Gene conversion is a likely cause of mutation in PKD1

Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease ( PKD1 ) is replicated in several highly homologous copies located more proximally on chromosome 16. We recently have described a novel technique for mutation detection in the duplicated region of PKD1 that circumvents the difficulties posed by these homologs. We have used this method to identify two patients with a nearly identical cluster of base pair substitutions in exon 23. Since pseudogenes are known to be reservoirs for mutation via gene conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a result of this mechanism. Using changes in restriction digest patterns, we were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. This is the first example of gene conversion in PKD1 , and our findings highlight the importance of using gene-specific reagents in defining PKD1 mutations.      

Predominance of null mutations in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.      

Acute effect of ethanol on firing patterns of Purkinje cells in the rat cerebellar slice preparation

This study examined the acute effects of ethanol (EtOH) on the firing patterns of Purkinje cells (PCs) using an intracellular recording in slice preparation of rat cerebellum. The experiments were performed in sagittal cerebellar slices (400 micrometer) of adult Sprague-Dawley rats (80-100g). Ethanol was applied by a bath superfusion with a known concentration expressed as the percentage of solution by volume (v/v) at 0.1, 0.5, 1, 2, and 4%. The result of the Chi-square test illustrated that the firing patterns were altered significantly after EtOH (p=0.007). However, the firing patterns that were altered by EtOH application were not affected by EtOH concentration (p= 0.1296). Among the 54 PCs tested, 30 PCs did not display any spontaneous firing activity and 24 PCs displayed spontaneous spike activity, either spiking in the simple manner (n=14) or cyclicly oscillating (n=10). In the presence of EtOH, 31 PCs were quiet, 22 PCs exhibited simple spiking activity and 1 PC continued to oscillate. Most PCs that displayed spontaneous activity before EtOH application progressively slowed their spike activity after EtOH superfusion. Especially, it was evident that 9 out of 10 oscillating PCs stopped their regular cyclic activity. In addition, 9 out of 14 PCs that displayed simple spike activity ceased to fire after EtOH application. Eleven out of 30 quiet PCs began to fire irregularly after EtOH application and this phenomenon usually occurred with membrane depolarization. EtOH induced spontaneous activity in 36.7% (11/30) of the quiescent PCs. In conclusion, there was differential EtOH sensitivity in the vitro slice preparation. EtOH depressed the endogenously generated spontaneous activity, especially the oscillatory firing activity. In contrast, the silent PCs were excited after EtOH application. Since this differential sensitivity persists in the presence of tetrodotoxin (TTX), it is suggested that this differential sensitivity is peculiar to the PCs.     

The reliability and validity of Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version- Korean version (K-SADS-PL-K)

In order to develop a structured and objective diagnostic instrument, authors completed: (1) the translation and back translation of the Korean version of the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL) and (2) the examination of its validity and reliability of the K-SADS-PL-Korean version (K-SADS- PL) when used with Korean children. A total of 91 study subjects were recruited from child and adolescent psychiatry outpatient clinics. Clinical diagnoses were used as a gold standard for the examination of validity of K-SADS-PL-K. Consensual validity of threshold and sub-threshold diagnoses were good to excellent for attention-deficit/hyperactivity disorder (ADHD), fair for tic and oppositional defiant disorders, and poor to fair for anxiety and depressive disorders. Inter-rater and test-retest reliabilities were fair to excellent for ADHD and tic disorder. The significant correlations between the K-SADS-PL-K and Korean Child Behavior Checklist (K-CBCL) were found, which provided additional support for the concurrent validity of the K-SADS-PL-K. Sensitivities varied according to the diagnostic categories, but specificities remained high over all diagnoses, suggesting that the K-SADS-PL-K is a desirable confirmatory diagnostic tool. The results of this study suggest that the K-SADS-PL-K is an effective instrument for diagnosing major child psychiatric disorders, including ADHD, behavioral disorders and tic disorders in Korean children. Future studies will examine the validity and reliability of the K-SADS-PL-K in larger samples, including adolescents and community samples on a variety of child and adolescent psychiatric disorders.     

Mutagenesis studies with four stereoisomeric N2-dG benzo[a]pyrene adducts in the identical 5'-CGC sequence used in NMR studies: G->T mutations dominate in each case

Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon (PAH) and a potent mutagen/carcinogen found ubiquitously in the environment. B[a]P is primarily metabolized to diol epoxides, which react principally at N2-dG in DNA. B[a]P-N2-dG adducts have been shown to induce a variety of mutations, notably G-->T, G-->A, G-->C and -1 frameshifts. Four stereoisomers of B[a]P-N2-dG (designated: [+ta]-;, [+ca]-, [-ta] and [-ca]) were studied by NMR in duplex 11mers in a 5'-CGC sequence context, and each adopted a different adduct conformation (Geacintov, et al. (1997) Chem. Res. Toxicol., 10, 111). Herein these four identical B[a]P-containing 11mers are built into duplex plasmid genomes and mutagenesis studied in Escherichia coli following SOS-induction. In nucleotide excision repair (NER) proficient E.coli, no adduct-derived mutants are detected. In NER deficient E.coli, G-->T mutations dominate for all four stereoisomers [+ta]-, [+ca]-, [-ta] and [-ca]-B[a]P-N(2)-dG, and mutation frequency is similar. Thus, the mutagenic pattern for these four B[a]P-N2-dG stereoisomers is the same, in spite of the fact that they adopt dramatically different conformations in ds-oligonucleotides as determined by NMR. These findings suggest that adduct conformation must be fluid enough in the 5'-CGC sequence that the duplex DNA conformation can interconvert to mutagenic and non-mutagenic conformations during lesion-bypass. A comparison of all published studies with these four B[a]P-N2-dG stereoisomers in E.coli reveals that B[a]P-N2-dG adduct stereochemistry tends to have a lesser impact on mutagenic pattern (e.g. G-->T versus G-->A mutations) than does DNA sequence context, which is discussed.     

Amino acid substitutions within the heptad repeat domain 1 of murine coronavirus spike protein restrict viral antigen spread in the central nervous system

Targeted recombination was carried out to select mouse hepatitis viruses (MHVs) in a defined genetic background, containing an MHV-JHM spike gene encoding either three heptad repeat 1 (HR1) substitutions (Q1067H, Q1094H, and L1114R) or L1114R alone. The recombinant virus, which expresses spike with the three substitutions, was nonfusogenic at neutral pH. Its replication was significantly inhibited by lysosomotropic agents, and it was highly neuroattenuated in vivo. In contrast, the recombinant expressing spike with L1114R alone mediated cell-to-cell fusion at neutral pH and replicated efficiently despite the presence of lysosomotropic agents; however, it still caused only subclinical morbidity and no mortality in animals. Thus, both recombinant viruses were highly attenuated and expressed viral antigen which was restricted to the olfactory bulbs and was markedly absent from other regions of the brains at 5 days postinfection. These data demonstrate that amino acid substitutions, in particular L1114R, within HR1 of the JHM spike reduced the ability of MHV to spread in the central nervous system. Furthermore, the requirements for low pH for fusion and viral entry are not prerequisites for the highly attenuated phenotype.     

Supradiaphragmatic ectopic adrenocorticotropic hormone-secreting adenoma

A 22-year-old woman with Cushing's syndrome, caused by an extremely rare suprasellar ectopic pituitary adenoma, is presented. Magnetic resonance imaging and computed tomography revealed a well-circumscribed mass in the right suprasellar region. Endocrinological tests showed elevated s-adrenocorticotropic hormone level and hypercortisolemia. The tumor was totally removed by right subfrontal approach. At the time of the operation, the tumor was in continuity with the distal pituitary stalk but not with the pituitary gland. The diaphragma sellae was intact. Histologic diagnosis of the tumor specimen was confirmed as a pituitary adenoma. After surgical removal of the tumor, continued improvement in the patient's laboratory results and disappearance of her endocrine symptoms strongly indicated the absence of adenoma cells in the pituitary gland or stalk. Six years post-surgery, there was no evidence of recurrence in the patient's clinical and laboratory examination. This tumor probably originated from aberrant anterior pituitary cells of the pituitary stalk.     

PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted,but Functional in Patients with COVID-19

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Clear cell sarcoma of the kidney--a case report

Clear cell sarcoma of the kidney (CCSK) is a highly malignant childhood tumor, distinguished from classic Wilms' tumor by its propensity to metastasize to the skeletal system. Authors described a case of CCSK from a 3-year-old boy in the right kidney, showing various histologic features, such as classic, epithelioid, trabecular, neurilemmoma-like, cystic and entrapped collecting tubular pattern. Ultrastructurally epithelial differentiation was absent. Immunohistochemically, none of the intrinsic tumor cells showed positive staining with the antibodies against the keratin, S-100 protein, carcinoembryonic antigen, vimentin, desmin and myoglobin, suggesting primitive mesenchymal cell in origin.