Protein Kinase A-Mediated Effects of Protein Kinase C Partial Agonist 5-(Hydroxymethyl)Isophthalate 1a3 in Colorectal Cancer Cells.

Colorectal cancer is the third most commonly occurring cancer in men and the second in women. The global burden of colorectal cancer is projected to increase to over 2 million new cases with over 1 million deaths within the next 10 years, and there is a great need for new compounds with novel mechanisms of action. Our group has developed protein kinase C (PKC)-modulating isophthalic acid derivatives that induce cytotoxicity toward human cervical and prostate cancer cell lines. In this study, we investigated the effects of 5-(hydroxymethyl)isophthalate 1a3 (HMI-1a3) on colorectal cancer cell lines (Caco-2, Colo205, and HT29). HMI-1a3 inhibited cell proliferation, decreased cell viability, and induced an apoptotic response in all studied cell lines. These effects, however, were independent of PKC. Using serine/threonine kinome profiling and pharmacological kinase inhibitors, we identified activation of the cAMP/PKA pathway as a new mechanism of action for HMI-1a3-induced anticancer activity in colorectal cancer cell lines. Our current results strengthen the hypothesis for HMI-1a3 as a potential anticancer agent against various malignancies. SIGNIFICANCE STATEMENT: Colorectal cancer (CRC) is a common solid organ malignancy. This study demonstrates that the protein kinase C (PKC)-C1 domain-targeted isophthalatic acid derivative 5-(hydroxymethyl)isophthalate 1a3 (HMI-1a3) has anticancer activity on CRC cell lines independently of PKC. We identified PKA activation as a mechanism of HMI-1a3-induced anticancer effects. The results reveal a new anticancer mechanism of action for the partial PKC agonist HMI-1a3 and thus provide new insights for the development of PKC and PKA modulators for cancer therapy.

Interventions to reduce social isolation and loneliness during COVID-19 physical distancing measures: A rapid systematic review.

BACKGROUND: A significant proportion of the worldwide population is at risk of social isolation and loneliness as a result of the COVID-19 pandemic. We aimed to identify effective interventions to reduce social isolation and loneliness that are compatible with COVID-19 shielding and social distancing measures. METHODS AND FINDINGS: In this rapid systematic review, we searched six electronic databases (Medline, Embase, Web of Science, PsycINFO, Cochrane Database of Systematic Reviews and SCOPUS) from inception to April 2020 for systematic reviews appraising interventions for loneliness and/or social isolation. Primary studies from those reviews were eligible if they included: 1) participants in a non-hospital setting; 2) interventions to reduce social isolation and/or loneliness that would be feasible during COVID-19 shielding measures; 3) a relevant control group; and 4) quantitative measures of social isolation, social support or loneliness. At least two authors independently screened studies, extracted data, and assessed risk of bias using the Downs and Black checklist. Study registration: PROSPERO CRD42020178654. We identified 45 RCTs and 13 non-randomised controlled trials; none were conducted during the COVID-19 pandemic. The nature, type, and potential effectiveness of interventions varied greatly. Effective interventions for loneliness include psychological therapies such as mindfulness, lessons on friendship, robotic pets, and social facilitation software. Few interventions improved social isolation. Overall, 37 of 58 studies were of "Fair" quality, as measured by the Downs & Black checklist. The main study limitations identified were the inclusion of studies of variable quality; the applicability of our findings to the entire population; and the current poor understanding of the types of loneliness and isolation experienced by different groups affected by the COVID-19 pandemic. CONCLUSIONS: Many effective interventions involved cognitive or educational components, or facilitated communication between peers. These interventions may require minor modifications to align with COVID-19 shielding/social distancing measures. Future high-quality randomised controlled trials conducted under shielding/social distancing constraints are urgently needed.

Management of anastomotic leaks after elective colorectal resections: The East of England experience. A retrospective cohort.

INTRODUCTION: Colorectal anastomotic leaks (AL) are associated with high morbidity and mortality. Management of AL and its intra-operative decision making is often difficult. The aim of this multi-centre study is to explore different management strategies, including different surgical options, and analyse rates and patterns of failure of initial management. METHODS: All consecutive patients who had a confirmed AL after elective colorectal resections from 1st January 2014 to 31st December 2019 were included at seven hospitals across the East of England Region. Morbidity (length of stay, and failures) and mortality were compared across the different management strategies, and survival analyses were performed (Clinicaltrials.gov ID: NCT05000580). RESULTS: Across all seven hospitals, a total of 3391 elective resection were done during the study period. 201 (5.9%) consecutive patients with confirmed AL were included. The initial treatment was conservative in 102(50.7%). 19 patients (9.5%) had a radiological procedure, 80 (39.8%) of patients required surgery as an initial treatment post AL. Of those who initially did not have a surgical intervention (n = 121), 10% (n = 12/121) eventually required laparotomy, 2 additional patients required transanal drainage. Ultimately 45.8% (n = 92/201) of the whole population eventually required a laparotomy. Patients managed conservatively had a shorter LOS when compared to either radiological drainage or surgical patients. Patients with a defunctioning stoma are more likely to have a successful conservative management and shorter LOS. 90-day mortality across the entire population was 8.1%. There were no significant differences in mortality or long-terms survival between the different initial treatment modalities or whether the leak was right or left sided. CONCLUSION: Despite initial conservative, antibiotic and radiological intervention being successful in the majority of patients, two out of five patients will still require a laparotomy and over a quarter of patients will have an end stoma.

Case-report: A rare cause of an intra-abdominal mass.

INTRODUCTION: Mesenteric cysts are a rare and often asymptomatic incidental finding on imaging. The diagnosis and management of mesenteric cysts remains a clinical challenge since those presenting with symptoms, often have vague and nonspecific symptoms, owing to variability in cyst location and size. This case report will aim to discuss the presentation, investigation and management options available. PRESENTATION: A 73-year-old female presented with abdominal swelling and a palpable right sided mass. Examination revealed a right sided mass and abdominal distention with vital signs within normal limits. Ultrasound scan (USS) revealed a right-sided 12 cm × 11 cm × 8 cm thin walled cyst. DISCUSSION: Mesenteric cysts are mostly asymptomatic but can cause nonspecific symptoms of abdominal pain, abdominal distension, altered bowel habit, nausea, vomiting and an abdominal mass. Complete surgical excision, either laparoscopically, or through a laparotomy is typically considered first line treatment. If size or location of the cyst precludes complete surgical excision, partial excision with marsupialisation of the opening of the cyst into the abdominal peritoneal cavity is a second option. CONCLUSION: Mesenteric cysts represent a rare cause of intra-abdominal mass. Owing to low prevalence, literature is limited as is guidance on management. Careful pre-operative planning is essential so as to avoid operative complications. Imaging such as USS is of great importance; however Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) may be of more benefit, owing to the complex anatomical relations within which mesenteric cysts can present. Surgical excision is widely reported as the surgical treatment of choice for symptomatic cysts.

Primary resection anastomosis versus Hartmann's procedure in Hinchey III and IV diverticulitis.

Introduction: Surgical management of Hinchey III and IV diverticulitis utilizes either Hartmann's procedure (HP) or primary resection anastomosis (PRA) with or without fecal diversion. The aim of this meta-analysis is to determine which of the two procedures has a more favorable outcome. Methods: A systematic review of the existing literature was performed using the PRISMA guidelines. A meta-analysis was carried out using a Mantel-Haenszel, random effects model, and forest plots were generated. The Newcastle-Ottawa and Jadad scoring tools were used to assess the included studies. Results: A total of 25 studies involving 3546 patients were included in this study. The overall mortality in the HP group was 10.8% across the observational studies and 9.4% in the randomized controlled trials (RCTs). The mortality rate in the PRA group was lower than that in the HP group, at 8.2% in the observational studies and 4.3% in the RCTs. A comparison of PRA vs HP demonstrated a 40% lower mortality rate in the PRA group than in the HP (OR 0.60, 95% CI 0.38-0.95, p = 0.03) when analyzing the observational studies. However, meta-analysis of the three RCTs did not demonstrate any difference in mortality, (OR 0.44 (95% CI 0.14-1.34, p = 0.15). Wound infection rates between the two groups were comparable (OR 0.75, 95% CI 0.20-2.78, p = 0.67). Conclusion: Analysis of observational studies suggests that PRA may be associated with a lower overall mortality. There were no differences in wound infection rates. Based on the current evidence, both surgical strategies appear to be acceptable.

Case-report: A rare cause of an intra-abdominal mass.

INTRODUCTION: Mesenteric cysts are a rare and often asymptomatic incidental finding on imaging. The diagnosis and management of mesenteric cysts remains a clinical challenge since those presenting with symptoms, often have vague and nonspecific symptoms, owing to variability in cyst location and size. This case report will aim to discuss the presentation, investigation and management options available. PRESENTATION: A 73-year-old female presented with abdominal swelling and a palpable right sided mass. Examination revealed a right sided mass and abdominal distention with vital signs within normal limits. Ultrasound scan (USS) revealed a right-sided 12 cm × 11 × cm × 8 cm thin walled cyst. DISCUSSION: Mesenteric cysts are mostly asymptomatic but can cause nonspecific symptoms of abdominal pain, abdominal distension, altered bowel habit, nausea, vomiting and an abdominal mass. Complete surgical excision, either laparoscopically, or through a laparotomy is typically considered first line treatment. If size or location of the cyst precludes complete surgical excision, partial excision with marsupialisation of the opening of the cyst into the abdominal peritoneal cavity is a second option. CONCLUSION: Mesenteric cysts represent a rare cause of intra-abdominal mass. Owing to low prevalence, literature is limited as is guidance on management. Careful pre-operative planning is essential so as to avoid operative complications. Imaging such as USS is of great importance; however Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) may be of more benefit, owing to the complex anatomical relations within which mesenteric cysts can present. Surgical excision is widely reported as the surgical treatment of choice for symptomatic cysts.

Dietary micronutrient intakes among women of reproductive age in Mumbai slums.

OBJECTIVES: To (1) describe micronutrient intakes among women of reproductive age living in Mumbai slums; (2) assess the adequacy of these intakes compared with reference values; (3) identify important dietary sources of micronutrients. SUBJECTS/METHODS: Participants were 6426 non-pregnant women aged 16-39 years, registered in a randomised controlled trial of a food-based intervention set in the Bandra, Khar and Andheri areas of Mumbai, India. Cross-sectional quantified food frequency questionnaire (FFQ) data were collected. Vitamin (n = 9) and mineral (n = 6) intakes were calculated and analysed in relation to dietary reference values (DRVs). Important dietary sources were identified for each micronutrient. RESULTS: Median intakes of all micronutrients, except vitamin E, were below the FAO/WHO reference nutrient intake (RNI). Intakes of calcium, iron, vitamin A and folate were furthest from the RNI. For seven of the micronutrients, over half of the women had intakes below the lower reference nutrient intake (LRNI); this figure was over 75% for calcium and riboflavin. The majority of women (93%) had intakes below the EAR for 5 or more micronutrients, and 64% for 10 or more. Adolescents had lower intakes than women aged >19 years. Less than 1% of adult women and no adolescents met the EAR for all micronutrients. Animal source foods and micronutrient-rich fruit and vegetables were consumed infrequently. CONCLUSIONS: These women had low intakes of multiple micronutrients, increasing their risk of insufficiency. There is a need to determine the factors causing poor intakes, to direct interventions that improve diet quality and nutritional sufficiency.

"It's not all in my head!" - The complex relationship between rare diseases and mental health problems.

The incidence of mental health disorders is significantly higher in individuals with a rare disease, compared to the general population. This letter considers the possible reasons for this in terms of the many ways in which a rare disease impacts on an individual's life, and how these impacts can be strongly related to factors which predispose to mental health difficulties.Furthermore, issues surrounding mental health can also play a significant role in the process of diagnosing a rare disease. The unusual nature of such diseases intrinsically predisposes an individual to obtain an inaccurate diagnosis of a psychosomatic disorder, a diagnosis which can often be further complicated by the presence of genuine psychiatric symptoms.This letter argues that these common experiences of rare disease patients have impacts upon the way in which their psychiatric care should be offered and managed, and that sensitivity and understanding surrounding these issues should be considered a necessary part of effective care for rare disease patients.

A Model Example: Coexisting Superior Mesenteric Artery Syndrome and the Nutcracker Phenomenon.

Superior mesenteric artery (SMA) syndrome is a rare cause of gastrointestinal obstruction, caused by external compression of the third part of the duodenum by the SMA. It may be associated with the Nutcracker phenomenon: external compression of the left renal vein. To our knowledge, there are few reports in the literature describing the coexistence of these two conditions and so we take this opportunity to highlight a rare cause of the acute abdomen that might otherwise be overlooked in cases of nonspecific abdominal findings and potentially unremarkable initial investigations. We report a case of SMA syndrome and Nutcracker phenomenon in a 19-year-old female who presented to our emergency department with a short history of epigastric pain and emesis. The SMA syndrome is thought to develop as the result of an abnormally narrow angle between the proximal SMA and the aorta, for which a number of predisposing factors have been described. Surgical options exist; however, the SMA syndrome is typically managed conservatively in the first instance, consistent with the approach described in this case. The Nutcracker phenomenon may give rise to the Nutcracker syndrome in the presence of typical clinical manifestations; however, these did not feature in this case.

Teaching and learning about food and nutrition through science education in Brazilian schools: an intersection of knowledge.

Science teachers are the main professionals in schools who address health-related subjects, though food and nutrition education (FNE) projects are mainly planned by health professionals, especially nutritionists. The objective of this study is to create a transdisciplinary approximation between scientific research fields and practical fields from the analysis of an integrated case study conducted in Brazilian schools. In 2011, 10 days of observation were programmed in six schools in five cities. Semi-structured interviews were carried out with different social actors and data was analyzed using the complex thinking theory and the bricolage method of educational research. Planting of vegetable gardens or projects to improve table manners during mealtimes were identified in the schools. The results describe educational approaches used by science teachers to include FNE in school activities, even when not described in the official curriculum. Health professionals can identify actions to support health education in schools starting with that already undertaken by science teachers. The successful initiatives also involved professionals with practical knowledge and experience of life.

Teaching and learning about food and nutrition through science education in Brazilian schools: an intersection of knowledge / Ensinando e aprendendo sobre alimentação e nutrição através da educação em ciências: uma interseção de conhecimentos

Science teachers are the main professionals in schools who address health-related subjects, though food and nutrition education (FNE) projects are mainly planned by health professionals, especially nutritionists. The objective of this study is to create a transdisciplinary approximation between scientific research fields and practical fields from the analysis of an integrated case study conducted in Brazilian schools. In 2011, 10 days of observation were programmed in six schools in five cities. Semi-structured interviews were carried out with different social actors and data was analyzed using the complex thinking theory and the bricolage method of educational research. Planting of vegetable gardens or projects to improve table manners during mealtimes were identified in the schools. The results describe educational approaches used by science teachers to include FNE in school activities, even when not described in the official curriculum. Health professionals can identify actions to support health education in schools starting with that already undertaken by science teachers. The successful initiatives also involved professionals with practical knowledge and experience of life.

Professores de ciências são os principais profissionais nas escolas dedicados a temas de saúde, mas projetos de educação alimentar e nutricional (EAN) são planejados principalmente por profissionais de saúde, em especial, por nutricionistas. O objetivo deste estudo foi construir uma aproximação transdisciplinar entre campos de pesquisa científica e campos de prática, a partir da análise de um estudo de caso integrado realizado em escolas brasileiras. Em 2011, foram realizados 10 dias de observação em seis escolas de cinco cidades. Entrevistas semiestruturadas foram realizadas com diversos atores sociais e os dados analizados a partir da teoria do pensamento complexo e da metodologia da bricolagem em pesquisa. O cultivo de hortas, ou projetos que visavam a bons hábitos nas refeições, foram identificados nas escolas. Os resultados descrevem abordagens educativas utilizadas por professores de ciências para incluir EAN nas atividades escolares, mesmo quando não estão previstas no currículo formal. Profissionais de saúde podem identificar propostas de educação em saúde nas escolas que partam de atividades já realizadas por professores de ciências. As iniciativas bem sucedidas envolveram também profissionais com o conhecimento prático e a experiência de vida.