SARS-CoV-2 and Influenza Virus Co-Infection Cases Identified through ILI/SARI Sentinel Surveillance: A Pan-India Report

SARS-CoV-2/influenza virus co-infection studies have focused on hospitalized patients who usually had grave sequelae. Here, we report SARS-CoV-2/influenza virus co-infection cases from both community and hospital settings reported through integrated ILI/SARI (Influenza Like Illness/Severe Acute Respiratory Infection) sentinel surveillance established by the Indian Council of Medical Research. We describe the disease progression and outcomes in these cases. Out of 13,467 samples tested from 4 July 2021–31 January 2022, only 5 (0.04%) were of SARS-CoV-2/influenza virus co-infection from 3 different sites in distinct geographic regions. Of these, three patients with extremes of age required hospital admission, but none required ICU admission or mechanical ventilation. No mortality was reported. The other two co-infection cases from community settings were managed at home. This is the first report on SARS-CoV-2/Influenza virus co-infection from community as well as hospital settings in India and shows that influenza viruses are circulating in the community even during COVID-19. The results emphasize the need for continuous surveillance for multiple respiratory pathogens for effective public health management of ILI/SARI cases in line with the WHO (World Health Organization) recommendations.     

Effect of group vs. single housing on phenotypic variance in C57BL/6J mice

OBJECTIVE: To determine if group housing affects the variance of body composition parameters in a highly inbred mouse strain. RESEARCH METHODS AND PROCEDURES: Thirty 3-week-old male C57BL/6J mice were obtained from the Jackson Laboratory. Fifteen mice were housed individually, and 15 mice were housed in groups of 5/cage. Animals were fed ad libitum and maintained in the same room under a 12:12-hour light/dark photoperiod at 22 degrees C for 9 weeks. Animals were killed, and fat mass, soft-lean tissue mass, bone mineral density (BMD), and bone mineral content (BMC) were determined by DXA. At necropsy, weights of the paired epididymal fat pads, paired retroperitoneal fat pads, right inguinal fat pad, liver, kidneys, paired testes, and seminal vesicles were obtained. RESULTS: Relative to mice housed singly, group-housed mice showed significantly greater variance in percentage of body fat, testes weight, and BMC. Group-housed mice tended to show greater variance in liver weights and BMD. Mice housed singly were smaller, had less soft-lean tissue mass and BMC, and lower BMD when compared with group-housed mice. DISCUSSION: These results suggest that with respect to body composition parameters, mice housed singly are more similar to one another than are group-housed mice, most likely because of a reduction in environmental (predominately behavioral/social) effects. Thus, mice housed singly may be more representative of genotypic effects on body composition than group-housed mice. Whether other inbred strains of mice show similar responses to housing condition is unknown.     

Activating FLT3 mutations are rare in children with juvenile myelomonocytic leukemia

BACKGROUND: Activating mutations of FLT3 have been identified in multiple myeloid malignancies. Two types of activating mutations have been described: (1) the internal tandem duplication (FLT3-ITD) and (2) point mutations within the activating loop (FLT3-ALM). Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder of early childhood. Mutations and other genetic abnormalities of RAS, NF1, and PTPN11 have been implicated as causative events in JMML, but approximately 25% of JMML patients harbor none of these abnormalities. We investigated whether FLT3 mutations might also contribute to JMML pathogenesis, and if present, whether FLT3 status would correlate with disease natural history and prognosis. PROCEDURES: Genomic DNA was isolated from peripheral blood and bone marrow samples of 60 patients meeting international JMML diagnostic criteria. Samples were analyzed for FLT3-ITD and FLT3-ALM using polymerase chain reaction and restriction endonuclease digestion. RESULTS: FLT3-ALM was found in 1/60 (1.7%) patients analyzed. Direct sequencing confirmed a C836G mutation. Clinical and laboratory characteristics of the JMML patient with the FLT3-ALM did not differ from the remainder of the cohort. No FLT3-ITD mutations were detected. CONCLUSIONS: This first reported mutational analysis for both FLT3-ITD and FLT3-ALM performed in JMML documents the presence of FLT3 mutations within JMML, but at a sufficiently low prevalence as to be clinically insignificant for most patients. Despite the poor prognosis and limited therapeutic options for JMML patients with refractory disease, compassionate therapy with targeted FLT3 inhibitors should not be considered in this patient population until adequate safety and efficacy data become available.     

Postsurgical disparity in survival between African Americans and Caucasians with colonic adenocarcinoma

BACKGROUND: Studies of colorectal adenocarcinoma (CRC) indicate a higher mortality rate for African Americans compared with Caucasians in the United States. In the current study, the authors evaluated the racial differences in survival based on tumor location and pathologic stage between African-American patients and Caucasian patients who underwent surgery alone for CRC. METHODS: All 199 African American patients and 292 randomly selected, non-Hispanic Caucasian patients who underwent surgery between 1981 and 1993 for first primary sporadic CRC at the University of Alabama-Birmingham (Birmingham, AL) or an affiliated Veterans Affairs hospital were assessed for differences in survival. None of these patients received preoperative or postoperative neoadjuvant or adjuvant therapy. Survival curves were generated using the Kaplan-Meier method, and hazard ratios with 95% confidence intervals (95% CI) were estimated from Cox proportional hazards models, adjusting for demographic and tumor characteristics. RESULTS: African Americans were 1.67 (95% CI, 1.21-2.33) and 1.52 (95% CI, 1.12-2.07) times more likely to die of colonic adenocarcinoma (CAC) within 5 years and 10 years of surgery, respectively, compared with Caucasians. Racial differences in survival were observed among patients with Stage II, III, and IV CAC; however, the strongest and statistically significant association was observed among patients with Stage II CAC. There were no significant racial differences in survival in patients with rectal adenocarcinomas. CONCLUSIONS: The current findings suggest that the decreased overall survival at 5 years and 10 years postsurgery observed in African-American patients with CAC may not be attributable to tumor stage at diagnosis or treatment but may be due to differences in other biologic or genetic characteristics between African-American patients and Caucasian patients.     

Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor

Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy.     

Predictors of outcome in small cell carcinoma of the cervix--a case series

OBJECTIVE: The objective of this study was to determine whether clinicopathologic findings or the immunohistochemical presence of molecular markers are predictive of clinical outcome in patients with small cell carcinoma of the cervix (SCCC). METHODS: A retrospective review of cases of carcinoma of the cervix was conducted to identify SCCC. From 1978 to 1999, 16 patients were identified at our institution with the diagnosis of SCCC. Microscopic sections of paraffin-embedded tissue specimens were evaluated for confirmation of diagnosis. Specimens were immunohistochemically stained with antibodies to three neuroendocrine markers: neuron-specific enolase, chromagranin (CGR), and synaptophysin. Specimens were also stained for protein expression of p53, erbB2, proliferating cell nuclear antigen, and c-myc. The relationship between molecular markers and clinical outcome was determined. RESULTS: All 16 cases met the histologic criteria for SCCC. Fourteen of 16 tumors (88%) stained positive for neuroendocrine differentiation. Eleven of 16 patients (69%) died from disease with a median survival of 19 months; there were 3 long-term survivors (greater than 5 years). CGR was positive in 8 (50%) specimens and was found to be highly predictive of death (P = 0.001). Complete loss of p53 protein was seen in 8 patients, 7 of whom died with a median survival of 20 months. CONCLUSION: Immunohistochemistry can be helpful in confirming difficult cases of SCCC. Further studies are necessary to define molecular markers that may be predictive of outcome in patients with SCCC.     

Insulin treatment reduces pre-prandial plasma ghrelin concentrations in children with type 1 diabetes.

BACKGROUND: Ghrelin is well recognized as a key factor in regulating appetite and energy homeostasis. The aim of the present study is to characterize the plasma ghrelin concentrations in children with type 1 diabetes at the time of diagnosis and to determine the effect of metabolic control after insulin therapy on circulating ghrelin levels. Also, the relationship between the simultaneous blood glucose concentrations and fasting plasma ghrelin concentrations was explored. MATERIAL/METHODS: This prospective study assessed the changes in pre-prandial plasma ghrelin levels after treatment of type 1 diabetes with insulin. Results: The study comprised 19 children with new onset diabetes mellitus. Mean plasma ghrelin levels declined by 29% in diabetic children post insulin treatment (p=0.007). There was a significant correlation between plasma ghrelin and body mass index (BMI) in children with type 1 diabetes at diagnosis (r=-0.54), but not at follow up. The difference in ghrelin at diagnosis and at 3 month follow up demonstrated an inverse relationship to difference in plasma glucose (r=-0.48). CONCLUSIONS: Plasma ghrelin concentrations could be suppressed in untreated type 1 diabetic children by improved glycemic control following insulin replacement.     

Engineered herpes simplex virus expressing bacterial cytosine deaminase for experimental therapy of brain tumors

Lack of effective therapy of primary brain tumors has promoted the development of novel experimental approaches utilizing oncolytic viruses combined with gene therapy. Towards this end, we have assessed a conditionally replication-competent, gamma(1)34.5-deleted herpes simplex virus type 1 (HSV-1) expressing cytosine deaminase (CD) for treatment of malignant brain tumors. Our results are summarized as follows: (i) a recombinant HSV (M012) was constructed in which both copies of the gamma(1)34.5 gene were replaced with the bacterial CD gene, under the control of the cellular promoter Egr-1; (ii) M012-infected cells in vitro efficiently convert 5-fluorocytosine (5-FC) to 5-fluorouracil, thereby enhancing cytotoxicity of neighboring, uninfected cells; (iii) both direct and bystander cytotoxicity of murine neuroblastoma and human glioma cell lines after infection with M012 were demonstrated; (iv) direct intracerebral inoculation of A/J mice demonstrated lack of neurotoxicity at doses similar to G207, a gamma(1)34.5-deleted HSV with demonstrated safety in human patient trials and (v) intratumoral injection of M012 into Neuro-2a flank tumors in combination with 5-FC administration significantly reduced tumor growth versus tumors treated with R3659 combined with 5-FC, or treated with M012 alone. Thus, M012 is a promising new oncolytic HSV vector with an enhanced prodrug-mediated, antineoplastic effect that is safe for intracranial administration.