Three dimensional coupled reaction–diffusion modeling of calcium and inositol 1,4,5-trisphosphate dynamics in cardiomyocytes

Nanoparticles have shown great promise in improving cancer treatment efficacy by changing the intracellular calcium level through activation of intracellular mechanisms. One of the mechanisms of the killing of the cancerous cell by a nanoparticle is through elevation of the intracellular calcium level. Evidence accumulated over the past decade indicates a pivotal role for the IP₃ receptor mediated Ca²⁺ release in the regulation of the cytosolic and the nuclear Ca²⁺ signals. There have been various studies done suggesting the role of IP₃ receptors (IP₃R) and IP₃ production and degradation in cardiomyocytes. In the present work, we have proposed a three-dimensional unsteady-state mathematical model to describe the mechanism of cardiomyocytes which focuses on evaluation of various parameters that affect these coupled dynamics and elevate the cytosolic calcium concentration which can be helpful to search for novel therapies to cure these malignancies by targeting the complex calcium signaling process in cardiomyocytes. Our study suggests that there are other factors involved in this signaling which can increase the calcium level, which can help in finding treatment for cancer. The cytosolic calcium level may be controlled by IP₃ signaling, leak, source influx of calcium (σ) and maximum production of IP₃ (V_P). We believe that the proposed model suggests new insight into finding treatment for cancer in cardiomyocytes through elevation of the cytosolic Ca²⁺ concentration by various parameters like leak, σ, V_P and especially by other complex cell signaling dynamics, namely IP₃ dynamics.

We propose a three-dimensional unsteady-state mathematical model to describe the mechanism of cardiomyocytes.     

Diabetes in pregnancy: a review of current evidence

PURPOSE OF REVIEW: There is controversy about the best approach to screening and management for gestational diabetes. In the recent Confidential Enquiry in Maternal and Child Health (CEMACH) the outcome of women with diabetes compared with women without diabetes. The results were exceptionally poor, suggesting the need for a new management approach. The aim of this review is to address these findings and our suggested care pathways. RECENT FINDINGS: The CEMACH report showed the congenital malformation rate was four to 10-fold higher, the perinatal mortality rate was four to seven-fold higher, stillbirth was five times more common, and babies were three times more likely to die in the first 3 months of life. Only 39% of women with established diabetes took folic acid and only 37% had some documentation of glycaemic control before pregnancy. Overall, less than a fifth of NHS trusts in the UK had any kind of multidisciplinary preconception services. The results for women with type 2 diabetes were as bad as those for type 1. Caesarean delivery rates were very high (67%). SUMMARY: Prepregnancy counselling and multidisciplinary team management is the key in achieving good pregnancy outcomes. There is emerging evidence about the safety and efficacy of oral hypoglycaemics like metformin in pregnancy.     

SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings from the COV-AD Study

Background

Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood.

Objectives

COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination.

Methods

Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs.

Results

A total of 5.6% (n?=?320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n?=?168) compared with 100% of healthy controls (n?=?205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p?=?0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p?=?0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine.

Conclusion

SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.

     

A systematic review of the relationship between glycemic control and necrobiosis lipoidica diabeticorum in patients with diabetes mellitus

The association of specific skin disorders with diabetes mellitus (DM) has been well established. Current literature suggests that approximately 30–91% of patients with diabetes will experience at least one cutaneous manifestation of this systemic disease in their lifetime. To date, there are limited articles summarizing the link between necrobiosis lipoidica diabeticorum (NLD) prognosis and glycemic control in patients with diabetes. The objective of the study is to summarize and appraise the available evidence assessing the relationship between glycemic control and NLD. A literature search was conducted based on MEDLINE (1946–2015), EMBASE (1980–2015), Google Scholar, and PubMed for publications that described the results of diabetes control and NLD. Further studies were identified from bibliographies of all relevant studies, gray literature, and annual scientific assemblies. All studies investigating the relationship between DM (type 1 and type 2) management and NLD were included. Two reviewers independently extracted data including demographics, type of diabetes management measures (glucose, HbA1c, insulin), comorbidities, and outcome. A total of 622 studies were identified, and 10 studies met the inclusion and exclusion criteria: two case series and eight case reports. Of the 24 patients with NLD, 13 patients reported resolution of NLD after implementing various methods of glycemic control (diabetic diet consisting of 1600 kcal/day [1 patient], insulin regimen [3 patients], and pancreatic transplantation [9 patients]). Glycemic control may have a role in influencing the prognosis of necrobiosis lipoidica in patients with diabetes; however, there is currently insufficient evidence to support or refute this claim.     

Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior

OBJECTIVE: To compare the clinical behavior and outcome of uterine carcinosarcomas and grade 3 endometrioid carcinomas. METHODS: Data on patients with grade 3 endometrioid adenocarcinomas and uterine carcinosarcomas, from 1988 to 2004, was obtained from the Surveillance, Epidemiology, and End Results database. Mortality was analyzed using Cox proportional hazards models. Survival analysis was performed with the Kaplan-Meier method and log rank test. RESULTS: The cohort included 8,986 women with 5,024 (56%) grade 3 endometrioid carcinomas and 3,962 (44%) uterine carcinosarcomas. Women with uterine carcinosarcomas were older (aged 70 years compared with 66 years; P<.001) and more often nonwhite (23% compared with 15%; P<.001). These women presented with more advanced disease (stage III/IV 41% compared with 31%; P<.001). Multivariable analysis demonstrated that uterine carcinosarcoma histology, advanced age, nonwhite race, and advanced stage were independent predictors of poor survival. Cancer-specific mortality was 45% lower in women with grade 3 endometrioid carcinomas (hazard ratio 0.55; 95% confidence interval [CI] 0.5-0.6). The 5-year cancer-specific survival was lower for women with uterine carcinosarcoma for each disease stage. Survival for stage IC was 38% (95% CI 33-45%) for uterine carcinosarcoma compared with 68% (95% CI 63-73%) for grade 3 endometrioid carcinoma. For stage III, survival was 22% (95% CI 19-26%) for uterine carcinosarcoma compared with 45% (95% CI 41-49%) for grade 3 endometrioid carcinoma. CONCLUSION: Carcinosarcomas present at more advanced stage and have worse survival than grade 3 endometrioid carcinomas. Carcinosarcomas may represent a distinct biologic entity. LEVEL OF EVIDENCE: II.     

Cytodiagnosis of actinomycetoma

Mycetoma is a late clinical manifestation of a subcutaneous infection produced by bacteria (actinomycetoma) or fungi (eumycetoma). The distinction between eumycetoma and actinomycetoma in Fine Needle Aspiration Cytology (FNAC) is as accurate as histopathology. A 55 year old man presented with a slow growing swelling on the plantar aspect of the right foot which was present for the last 10 years. A clinical diagnosis of soft tissue tumor was made and FNAC was advised. Smears revealed mixed inflammatory infiltrate and foreign body type of giant cells along with clumps of fibrillar organisms. Gram stain done later demonstrated gram positive thin branching filaments. A diagnosis of actinomycetoma was rendered. Histopathology of the excised specimen confirmed the cytologic diagnosis of actinomycetoma. Mycetoma can be accurately diagnosed by FNAC, which is a simple, inexpensive technique for rapid diagnosis. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.