Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: report of a case

We report a rare case with pheochromocytoma as the first manifestation of multiple endocrine neoplasia type 2A with RET mutation S891A. Bilateral pheochromocytomas were identified in a 54-year-old woman. Screening for RET revealed a rare S891A mutation located in the intracellular tyrosine kinase domain. This mutation was previously recognized as one of the mutations only in cases manifesting solely medullary thyroid carcinomas (MTCs). Since calcitonin stimulation test indicated positive result, total thyroidectomy was performed 1 year after the bilateral adrenalectomy, and C-cell hyperplasia was diagnosed by histopathological examination. Our report suggests that cases with S891A mutation, akin to those with other RET mutations, require screening for pheochromocytoma. In addition, it is indicated that calcitonin stimulation test should be performed even in the unaffected elder cases with S891A mutation although the mutation is classified as lowest risk group on MTC in guidelines.     

Survival of rabid rabbits after intrathecal immunization

Rabies is a fatal zoonotic disease for which no effective treatment measures are currently available. Rabies virus (RABV) has anti‐apoptotic and anti‐inflammatory properties that suppress nerve cell damage and inflammation in the CNS. These features imply that the elimination of RABV from the CNS by appropriate treatment could lead to complete recovery from rabies. Ten rabbits showing neuromuscular symptoms of rabies after subcutaneous (SC) immunization using commercially available vaccine containing inactivated whole RABV particles and subsequent fixed RABV (CVS strain) inoculation into hind limb muscles were allocated into three groups. Three rabbits received no further treatment (the SC group), three rabbits received three additional SC immunizations using the same vaccine, and four rabbits received three intrathecal (IT) immunizations, in which the vaccine was inoculated directly into the cerebrospinal fluid (the SC/IT group). An additional three naïve rabbits were inoculated intramuscularly with RABV and not vaccinated. The rabbits exhibited neuromuscular symptoms of rabies within 4–8 days post‐inoculation (dpi) of RABV. All of the rabbits died within 8–12 dpi with the exception of one rabbit in the SC group and all four rabbits in SC/IT group, which recovered and started to respond to external stimuli at 11–18 dpi and survived until the end of the experimental period. RABV was eliminated from the CNS of the surviving rabbits. We report here a possible, although still incomplete, therapy for rabies using IT immunization. Our protocol may rescue the life of rabid patients and prompt the future development of novel therapies against rabies.     

SARS-CoV-2 Disinfection of Air and Surface Contamination by TiO2 Photocatalyst-Mediated Damage to Viral Morphology,RNA, and Protein

SARS-CoV-2 is the causative agent of COVID-19, which is a global pandemic. SARS-CoV-2 is transmitted rapidly via contaminated surfaces and aerosols, emphasizing the importance of environmental disinfection to block the spread of virus. Ultraviolet C radiation and chemical compounds are effective for SARS-CoV-2 disinfection, but can only be applied in the absence of humans due to their toxicities. Therefore, development of disinfectants that can be applied in working spaces without evacuating people is needed. Here we showed that TiO₂-mediated photocatalytic reaction inactivates SARS-CoV-2 in a time-dependent manner and decreases its infectivity by 99.9% after 20 min and 120 min of treatment in aerosol and liquid, respectively. The mechanistic effects of TiO₂ photocatalyst on SARS-CoV-2 virion included decreased total observed virion count, increased virion size, and reduced particle surface spike structure, as determined by transmission electron microscopy. Damage to viral proteins and genome was further confirmed by western blotting and RT-qPCR, respectively. The multi-antiviral effects of TiO₂-mediated photocatalytic reaction implies universal disinfection potential for different infectious agents. Notably, TiO₂ has no adverse effects on human health, and therefore, TiO₂-induced photocatalytic reaction is suitable for disinfection of SARS-CoV-2 and other emerging infectious disease-causing agents in human habitation.     

Fc-rosette inhibition by hypocomplementaemic systemic lupus erythematosus sera

Morito, T., Tanimoto, K., Hashimoto, Y., Horiuchi, Y., and Juji, T. (1976).Annals of the Rheumatic Diseases, 35, 415-421. Fc-rosette inhibition by hypocomplementaemic systemic lupus erythematosus sera. Human red cells sensitized with one of the Rh antisera (Ripley) form rosettes (Fc-rosette) with human B lymphocytes and the rosettes are well inhibited by aggregated human IgG. Since sera of hypocomplementaemic patients with systemic lupus erythematosus (SLE) have frequently been reported to contain immune complexes, they were used for the inhibition of Fc-rosette formation in this study.

The results of Fc-rosette inhibition rates of the sera were inversely correlated with the serum CH₅₀ levels. When the sera were separated into top, middle, and bottom fractions by ultracentrifugation, the bottom fractions showed more effective inhibitions than the others. Similarly, the strongest inhibition was found in the void volume of the serum separated by Sephadex G200 gel filtration. Reduction and alkylation of IgG resulted in the loss of reactivity with Fc receptor of B lymphocytes, and the rosette inhibiting activities of the SLE sera were markedly reduced after reduction and alkylation. Some of anti-HLA sera were inhibitory for the Fc-rosette formation, while the tested sera did not contain anti-HLA activity assessed by the microcytotoxicity test. These results indicated that circulating immune complexes contained in the sera inhibit the rosette formation, and that the Fc-rosette inhibition test is a simple and relatively sensitive method for the detection of circulating immune complexes.

Antinuclear antibody activities of the sera were tested by the indirect immunofluorescent method; however, clear correlations were not obtained between Fc-rosette inhibition rates and staining patterns of antinuclear antibodies. On the other hand, the positive groups of LE-test exhibited slightly greater inhibition rates of the rosette than the negative groups.

     

Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood

Refractory cytopenia of childhood is the most common subtype of myelodysplastic syndrome in children. In this study, we compared the outcome of immunosuppressive therapy using horse antithymocyte globulin (n=46) with that using rabbit antithymocyte globulin (n=49) in 95 patients with refractory cytopenia of childhood and hypocellular bone marrow. The response rate at 6 months was 74% for horse antithymocyte globulin and 53% for rabbit antithymocyte globulin (P=0.04). The inferior response in the rabbit antithymocyte globulin group resulted in lower 4-year transplantation-free (69% versus 46%; P=0.003) and failure-free (58% versus 48%; P=0.04) survival rates in this group compared with those in the horse antithymocyte globulin group. However, because of successful second-line hematopoietic stem cell transplantation, overall survival was comparable between groups (91% versus 85%; P=ns). The cumulative incidence of relapse (15% versus 9%; P=ns) and clonal evolution (12% versus 4%; P=ns) at 4 years was comparable between groups. Our results suggest that the outcome of immunosuppressive therapy with rabbit antithymocyte globulin is inferior to that of horse antithymocyte globulin. Although immunosuppressive therapy is an effective therapy in selected patients with refractory cytopenia of childhood, the long-term risk of relapse or clonal evolution remains. (ClinicalTrial.gov identifiers: {"type":"clinical-trial","attrs":{"text":"NCT00662090","term_id":"NCT00662090"}}NCT00662090)     

Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism

Background

In a genome-wide association study of autism, zinc finger protein 804A (ZNF804A) single nucleotide polymorphisms (SNPs) were found to be nominally associated in verbally deficient individuals with autism. Zinc finger protein 804A copy number variations (CNVs) have also been observed in individuals with autism. In addition, ZNF804A is known to be involved in theory of mind (ToM) tasks, and ToM deficits are deemed responsible for the communication and social challenges faced by individuals with autism. We hypothesized that ZNF804A could be a risk gene for autism.

Methods

We examined the genetic association and CNVs of ZNF804A in 841 families in which 1 or more members had autism. We compared the expression of ZNF804A in the postmortem brains of individuals with autism (n = 8) and controls (n = 13). We also assessed in vitro the effect of ZNF804A silencing on the expression of several genes known to be involved in verbal efficiency and social cognition.

Results

We found that rs7603001 was nominally associated with autism (p = 0.018). The association was stronger (p = 0.008) in the families of individuals with autism who were verbally deficient (n = 761 families). We observed ZNF804A CNVs in 7 verbally deficient boys with autism. In ZNF804A knockdown cells, the expression of synaptosomal-associated protein, 25kDa (SNAP25) was reduced compared with controls (p = 0.009). The expression of ZNF804A (p = 0.009) and SNAP25 (p = 0.009) were reduced in the anterior cingulate gyrus (ACG) of individuals with autism. There was a strong positive correlation between the expression of ZNF804A and SNAP25 in the ACG (p < 0.001).

Limitations

Study limitations include our small sample size of postmortem brains.

Conclusion

Our results suggest that ZNF804A could be a potential candidate gene mediating the intermediate phenotypes associated with verbal traits in individuals with autism.     

s‐Afadin binds more preferentially to the cell adhesion molecules nectins than l‐afadin

l‐Afadin was originally purified from rat brain as an actin filament (F‐actin)‐binding protein that was homologous to the AF‐6 gene product. Concomitantly, s‐afadin that did not show an F‐actin‐binding capability was copurified with l‐afadin. Structurally, s‐afadin lacks the C‐terminal F‐actin‐binding domain but has two short sequences that were not present in l‐afadin. The properties and roles of l‐afadin have intensively been investigated, but those of s‐afadin have poorly been understood. We show here an additional difference in their biochemical properties other than binding to F‐actin between l‐afadin and s‐afadin. Both l‐afadin and s‐afadin bound to nectins, immunoglobulin‐like cell adhesion molecules, whereas s‐afadin more preferentially bound to nectins than l‐afadin. The PDZ domain of l‐afadin and s‐afadin was essential for their binding to nectin‐3. The dilute domain of l‐afadin negatively regulated its binding to nectin‐3, but the deletion of the C‐terminal F‐actin‐binding domain of l‐afadin did not increase the binding of l‐afadin to nectin‐3. These results indicate that the s‐afadin‐specific C‐terminal inserts may be involved in its preference of binding to nectin‐3 and raise the possibility that there are proteins other than nectins that more preferentially bind s‐afadin than l‐afadin.     

A Population Association Study of Four Candidate Genes (Hexokinase II,Glucagon-like Peptide-1 Receptor,Fatty Acid Binding Protein-2, and Apolipoprotein C-II) with Type 2 Diabetes and Impaired Glucose Tolerance in Japanese Subjects

In order to define the major genetic factor(s) for the development of Type 2 (non-insulin-dependent) diabetes mellitus in Japanese subjects, a population association study of candidate genes involved in either glucose or lipid metabolism was carried out using microsatellite DNA polymorphisms. Each polymorphic locus near the four candidate genes, hexokinase II (HKII), glucagon-like peptide-1 receptor (GLP1R), fatty acid binding protein-2 (FABP-2), and apolipoprotein C-II (apoC-II) genes, were amplified by polymerase chain reaction (PCR) using ³²P-labelled primers and each subject was genotyped for the association study. The HKII, GLP1R, FABP-2, and apoC-II polymorphisms exhibited 18, 10, 7, and 10 alleles, respectively. While polymorphism information contents (PICs) of these polymorphisms were relatively high, allele frequencies in these polymorphisms did not differ among subjects with Type 2 diabetes, impaired glucose tolerance (IGT) and non-diabetic controls. These results suggest that the HKII, GLP1R, FABP-2, and apoC-II genes are not the major inherited factors for the development of Type 2 diabetes or IGT in Japanese subjects, although minor contributions cannot be ruled out.