Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children

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Velocardiofacial syndrome in a mother and daughter: variability of the clinical phenotype.

We report a mother and daughter with features of the velocardiofacial (VCF) syndrome and monosomy for 22q11 identified using molecular techniques. The mother had surgery as a child for a cleft palate and a congenital heart defect, and her facial features were consistent with the diagnosis. The daughter had developmental delay, absent speech, scoliosis, and similar facial features, but no cleft palate or congenital heart defect. These cases illustrate the considerable intrafamilial variability of the phenotype of VCF syndrome. The clinical and molecular diagnosis of this syndrome is discussed. The phenotypic variability of the VCF syndrome means that many cases may be undiagnosed.     

Comparative study of oral and intramuscular atropine sulphate as a premedicant in paediatric age group

The use of atropine sulphate in the paediatric age group as a premedicant orally in a dosage of 0.02 mg/kg body weight 70 minutes prior to surgery was found to be as effective as atropine sulphate given intramuscularly 35 minutes prior to surgery in a dosage of 0.01 mg/kg body weight. This avoids the unpleasant memory of needle prick; The duration of effect as studied in the normal healthy children not subjected to surgery was found to be 2 1/2-3 hours.     

Mutations in VMK1, a mitogen-activated protein kinase gene, affect microsclerotia formation and pathogenicity in Verticillium dahliae

Verticillium dahliae is an important soil-borne fungal pathogen that causes vascular wilt diseases in a large variety of important crop plants. Due to its persistence in the soil, control of Verticillium wilt relies heavily on soil fumigation. The global ban on methyl bromide, a highly effective soil fumigant, poses an urgent need to develop alternative control measures against Verticillium wilt; and these might be more forthcoming with a better understanding of the molecular and cellular mechanisms that underpin the pathogenicity of V. dahliae. In this study, we assessed the role in growth, development, and pathogenicity of VMK1, a gene encoding a mitogen-activated protein (MAP) kinase (hence, Verticillium MAP Kinase 1). Disruption of VMK1 via Agrobacterium tumefaciens-mediated transformation, in two V. dahliae isolates, one from lettuce and the other from tomato, resulted in severely reduced virulence in diverse host plants, suggesting that VMK1 is essential for pathogenicity and that the MAP kinase-mediated signaling pathway has a conserved role in fungal pathogenicity. The vmk1 mutants also exhibited reduced conidiation and microsclerotia formation, suggesting that the gene is important for multiple cellular processes. P.R. and R.G.B. equally contributed to the work     

Optimal field splitting for large intensity-modulated fields

The multileaf travel range limitations on some linear accelerators require the splitting of a large intensity-modulated field into two or more adjacent abutting intensity-modulated subfields. The abutting subfields are then delivered as separate treatment fields. This workaround not only increases the treatment delivery time but it also increases the total monitor units (MU) delivered to the patient for a given prescribed dose. It is imperative that the cumulative intensity map of the subfields is exactly the same as the intensity map of the large field generated by the dose optimization algorithm, while satisfying hardware constraints of the delivery system. In this work, we describe field splitting algorithms that split a large intensity-modulated field into two or more intensity-modulated subfields with and without feathering, with optimal MU efficiency while satisfying the hardware constraints. Compared to a field splitting technique (without feathering) used in a commercial planning system, our field splitting algorithm (without feathering) shows a decrease in total MU of up to 26% on clinical cases and up to 63% on synthetic cases.     

Ghrelin expression in hyperplastic and neoplastic proliferations of the enterochromaffin-like (ECL) cells

Ghrelin, a recently discovered peptide isolated from the gastric corpus mucosa, is believed to be important in the regulation of growth hormone secretion and has been shown to increase appetite and food intake as well. It may also have other gastrointestinal and cardiac functions. Because a cell of origin for ghrelin has not been convincingly identified in the gastric mucosa thus far, we studied the immunohistochemical expression of ghrelin in proliferative lesions of the enterochromaffin-like (ECL) cells—a cell that is not only exclusively confined to the gastric corpus mucosa but is its dominant endocrine cell type as well. Formalin-fixed, paraffin embedded tissues from three cases of gastric ECL cell hyperplasia and five ECL carcinoids (three with coexisting foci of diffuse, linear, and micronodular hyperplasia) were immunohistochemically stained for ghrelin, using a commercially available antibody. The Sevier-Munger stain for ECL cells and immunohistochemical stains for chromogranin, gastrin, serotonin, somatostatin, and vesicular monoamine transporter-2 (VMAT-2) were performed on parallel sections for correlation with the ghrelin staining results. All ECL cell carcinoids and hyperplastic lesions were positive for both the Sevier-Munger and the immunohistochemical stains for chromogranin and VMAT-2. Immunoreactivity for ghrelin was seen in 4/5 ECL carcinoids, all cases of ECL cell hyperplasia, as well as in all areas with linear and micronodular hyperplasia adjacent to the ECL cell carcinoids. In each instance, such staining was confined to the Sevier-Munger, and VMAT-2 positive cells only. Our findings indicate that the ECL cells are either the ghrelin-producing cells of the gastric mucosa or acquire the capability to synthesize ghrelin during proliferative states encompassing the entire hyperplasia to neoplasia spectrum. In view of the orexigenic and other known actions of ghrelin, the functional and/or biologic significance of ghrelin production in such ECL cell proliferations needs to be investigated further.     

The combination of plasmid interleukin-12 with a single DNA vaccine is more effective than Mycobacterium bovis (bacille Calmette-Guèrin) in protecting against systemic Mycobacterim avium infection

Sub‐unit vaccines utilizing purified mycobacterial proteins or DNA vaccines induce partial protection against mycobacterial infections. For example, immunization with DNA vaccines expressing the gene for the immunodominant 35 000 MW protein, common to Mycobacterium avium and Mycobacterium leprae but absent from the Mycobacterium tuberculosis complex, conferred significant protection against infection with either virulent M. avium or M. leprae in mice. However, the level of protection was equivalent to that obtained with the viable, attenuated vaccine, Mycobacterium bovis, bacille Calmette–Guèrin (BCG). The cytokine, interleukin (IL)‐12, is essential for priming naïve CD4⁺ T lymphocytes to differentiate into interferon‐γ (IFN‐γ)‐secreting T cells. We have used a novel self‐splicing vector expressing both chains of murine IL‐12 to determine if plasmid IL‐12 would increase the efficacy of a vaccine expressing the M. avium 35 000 MW protein (DNA‐Av35). Co‐immunization with p2AIL‐12 and DNA‐Av35 led to a significant increase in the number of antigen‐specific IFN‐γ secreting cells and total amount of IFN‐γ released, but a concomitant fall in the antibody response to the 35 000 MW protein. This pattern of response was associated with enhanced clearance of M. avium from the liver and spleen of coimmunized mice, and was significantly more effective than BCG or DNA‐Av35. alone. Following M. avium challenge there was significant increase in the expansion of the 35 000 MW antigen‐reactive T cells in the coimmunized mice. Therefore, plasmid‐delivered IL‐12 acts as an effective adjuvant to increase the protective efficacy of a single DNA vaccine against M. avium infection above that achieved by BCG, and this strategy may improve the efficacy of subunit vaccines against M. leprae and M. tuberculosis.     

A critical function for type I interferons in cancer immunoediting

'Cancer immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-gamma (IFN-gamma) is known to be involved in this process, the involvement of type I interferons (IFN-alpha/beta) has not been elucidated. We now show that, like IFN-gamma, endogenously produced IFN-alpha/beta was required for the prevention of the growth of primary carcinogen-induced and transplantable tumors. Although tumor cells are important IFN-gamma targets, they are not functionally relevant sites of the actions of the type I interferons. Instead, host hematopoietic cells are critical IFN-alpha/beta targets during development of protective antitumor responses. Therefore, type I interferons are important components of the cancer immunoediting process and function in a way that does not completely overlap the functions of IFN-gamma.     

Monozygotic twins with a severe form of Alagille syndrome and phenotypic discordance

Alagille syndrome is an autosomal dominant disorder affecting multiple organ systems, predominantly the liver, heart, skeleton, eye, face, and kidney. The phenotype in Alagille syndrome is highly variable both within and between families. We report monozygotic twins with Alagille syndrome concordant for a mutation in Jagged1 but discordant for clinical phenotype. The twins' monozygosity was confirmed by molecular testing. A de novo splice site mutation was identified in exon 6 (1329 + 2T --> G) in both children. Both twins display a severe form of Alagille syndrome; however, one twin has a severe pulmonary atresia with mild liver involvement, while the other has tetralogy of Fallot and severe hepatic involvement, which has required liver transplantation. Potential mechanisms for phenotypic variability among monozygotic twins are discussed. This is the first reported case of discordance in phenotype in monozygotic twins with Alagille syndrome. This case implies that genotypic variations alone do not explain the clinical variability seen in Alagille syndrome and supports the contributory role of nongenetic factors in phenotype determination.