Total abdominal colectomy and ileorectal anastomosis for inflammatory bowel disease

PURPOSE: This retrospective study assesses the results of total colectomy and ileorectostomy for inflammatory bowel disease. METHODS: Between January 1974 and December 1990, 90 patients underwent total colectomy and ileorectal anastomosis for chronic ulcerative colitis (n=48) or Crohn's colitis (n=42) at the Mayo Clinic. Patients' records were reviewed retrospectively. Long-term results were assessed by chart reviews and postal questionnaires. Conversion to a permanent ileostomy, with or without proctectomy, was considered a failure of the procedure. The Kaplan-Meier method was used to estimate survivorship free of failure. The log-rank test was used to compare survivorship curves. Ninety-five percent confidence intervals were calculated at selected time points.P values<0.05 were considered to be statistically significant. RESULTS: The main indication for surgery was refractory chronic disease. There were no immediate postoperative deaths. The anastomotic leakage rate was 4.4 percent, and small-bowel obstruction occurred in 15.6 percent. At the time of follow-up (mean, 6.5±4.8 years), 46 patients (58.9 percent) had recurrence or exacerbation of the disease. This was the most common indication for subsequent proctectomy/permanent ileostomy in the follow-up period. There were 8 failures in 48 patients with ulcerative colitis (16.7 percent) and 11 failures in 42 patients with Crohn's disease (26.2 percent), although this difference was not statistically significant. Cumulative probability of having a functioning ileorectal anastomosis at five years was 84.2 percent (95 percent confidence interval, 71–95.9 percent) for ulcerative colitis and 73.8 percent (95 percent confidence interval, 58.6–88.6 percent) for Crohn's disease. In the latter group, females showed a significantly lower cumulative probability of having a functioning ileorectal anastomosis (females, 634 percent; males, 92.3 percent;P =0.04). Crohn's patients 36 years of age or younger also showed a lower probability of success (patients 36 years, 57 percent; patients >36 years, 93.8 percent;P =0.03). In the group with chronic ulcerative colitis, younger patients also seemed to require additional surgery more frequently; however, this difference was not statistically significant. Previous duration of symptoms, with mild or moderate disease in a distensible rectum, had no effect on results in either disease group. Functional results were acceptable in 63.6 and 87.5 percent of patients with Crohn's and ulcerative colitis, respectively. Eighty-four percent of ulcerative colitis patients and 91 percent of Crohn's disease patients reported an improvement in their quality of life, and overall, more than 90 percent considered their health status to be better than before surgery. One patient with ulcerative colitis developed carcinoma of the rectal stump 11.5 years after the colectomy and ileorectal anastomosis (cumulative probability of remaining free of cancer, 85.7 percent at 12 years; 95 percent confidence interval, 57.7–100 percent). CONCLUSIONS: These results demonstrate that, in selected patients with a relatively spared rectum and without severe perineal disease, total colectomy and ileorectal anastomosis still remains a viable option to total proctocolectomy with extensive Crohn's colitis. In addition, ileorectal anastomosis, as a sphincter-saving procedure, continues to have a place in the surgical treatment of chronic ulcerative colitis for high-risk or older patients who are not good candidates for ileal pouch-anal anastomosis, when the latter procedure cannot be done because of technical reasons and in the presence of advanced carcinoma concomitant with colitis, when life expectancy is limited.     

Educating and Training a Workforce for Nutrition in a Post-2015 World

Nearly all countries in the world today are burdened with malnutrition, manifesting as undernutrition, micronutrient deficiencies, and/or overweight and obesity. Despite some progress, efforts to alleviate malnutrition are hampered by a shortage in number, skills, and geographic coverage, of a workforce for nutrition. Here, we report the findings of the Castel Gandolfo workshop, a convening of experts from diverse fields in March 2014 to consider how to develop the capacity of a global cadre of nutrition professionals for the post-2015 development era. Workshop participants identified several requirements for developing a workforce for nutrition, including an ability to work as part of a multisectoral team; communication, advocacy, and leadership skills to engage decision makers; and a set of technical skills to address future challenges for nutrition. Other opportunities were highlighted that could immediately contribute to capacity development, including the creation of a consortium to link global North and South universities, online training modules for middle managers, and practical, hands-on experiences for frontline nutrition workers. Institutional and organizational support is needed to enable workshop recommendations on education and training to be effectively implemented and sustained. The findings from the Castel Gandolfo workshop can contribute to the delivery of successful nutrition-relevant actions in the face of mounting external pressures and informing and attaining the forthcoming Sustainable Development Goals.     

Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

Rationale

Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown.

Objective

This study aims to pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2).

Methods

Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9 % ethanol?+?2 % sucrose (ethanol) or 2 % sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0–1.7 μg/side) in PFC, NAC, or AMY prior to self-administration.

Results

pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg?=?1.21 g/kg; BAC?=?54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 μg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions.

Conclusions

Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC, and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.

     

The dietary inflammatory index,obesity, type 2 diabetes,and cardiovascular risk factors and diseases

An unhealthy diet is a recognized risk factor in the pathophysiology of numerous chronic noncommunicable diseases (NCD), including obesity, type 2 diabetes (T2DM), and cardiovascular diseases (CVD). This is, at least in part, due to unhealthy diets causing chronic low-grade inflammation in the gut and systemically. To characterize the inflammatory potential of diet, we developed the Dietary Inflammatory Index (DII®). Following this development, around 500 papers have been published, which examined the association between the DII, energy-adjusted DII (E-DII?), and the children's DII (C-DII?) and many chronic NCDs including obesity and cardiometabolic diseases. Although a previous narrative review published in 2019 briefly summarized the evidence in this area, there was a significant increase in papers on this topic since 2020. Therefore, the purpose of this narrative review is to provide an in-depth updated review by including all papers until July 2021 on DII and its relationship with obesity, T2DM, and CVD. Furthermore, we aim to identify potential gaps in the literature and provide future directions for research. Most studies found that DII was associated with an increased risk of obesity, T2DM, and CVD with some relationships being sex-specific. However, we identified the paucity of papers describing associations between dietary inflammation and T2DM and its risk factors. Few studies used gold-standard measures of cardiometabolic risk factors. We also identified the lack of interventional studies designed to change the inflammatory potential of diets and study its effect on cardiometabolic risk factors and diseases. We recommend that such interventional studies are needed to assess if changes in DII, representing the inflammatory potential of diet, independently of changes in body composition can modulate cardiometabolic risk factors and diseases.     

In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease.

Protease inhibitors are another class of compounds for treatment of human immunodeficiency virus (HIV)-caused disease. The emergence of resistance to the current anti-HIV drugs makes the determination of potential resistance to protease inhibitors imperative. Here we describe the isolation of an HIV type 1 (HIV-1) resistant to an HIV-protease inhibitor. Serial passage of HIV-1 (strain RF) in the presence of the inhibitor, [2-pyridylacetylisoleucylphenylalanyl-psi (CHOH)]2 (P9941), failed to yield a stock of virus with a resistance phenotype. However, variants of the virus with 6- to 8-fold reduced sensitivity to P9941 were selected by using a combination of plaque assay and endpoint titration. Genetic analysis and computer modeling of the variant proteases revealed a single change in the codon for amino acid 82 (Val-->Ala), which resulted in a protease with lower affinity and reduced sensitivity to this inhibitor and certain, but not all, related inhibitors.     

Alcohol Self-Administration: Further Examination of the Role of Dopamine Receptors in the Nucleus Accumbens

One of the functions of the mesolimbic dopamine (DA) system is to regulate the process of reinforcement, a process that is thought to influence drug self-administration. This study tested the effects of centrally administered DA receptor ligands on ethanol self-administration behavior. Long-Evans rats were trained to lever press on a fixed-ratio 4 schedule of ethanol (10% v/v) reinforcement. DA agonists and antagonists were then bilaterally microinjected (0.5 μ/side) into the nucleus accumbens (N Acc) 10-min before sessions to test for effects on the onset, maintenance, and termination of ethanol self-administration. Infusions of the D₁-like agonist SKF 38393 (0.03 to 3.0 μg) produced no effect on ethanol self-administration. The D₁-like antagonist SCH 23390 (0.5 to 2.0 μg) reduced total responding by decreasing the time course of self-administration without altering response rate. The D₂-like agonist quinpirole produced a biphasic effect on self-administration. Quinpirole (1.0 μg) increased total responses and response rate, whereas higher doses (4.0 to 10.0 μg) decreased total responding as a result of early termination. The D₂-like antagonist raclopride (0.1 to 1.0 μg) reduced total responding by decreasing time course and response rate. Co-administration of either SKF 38393 or SCH 23390 with quinpirole prevented the behavioral effects observed with the low doses of quinpirole. Thus, in the N ACC either increased activation of D₁-like receptors or their blockade can affect the expression of the behavioral effects of the D₂-like agonist. This suggests that some intermediate level of D₁ activation is required to observe the D₂ effect. The decreases in total responding produced by raclopride were enhanced by co-administration of SKF 38393, but not altered by SCH 23390, thus suggesting that D₁-like and D₂-like receptors in the N Acc interact in the regulation of ethanol self-administration in a manner similar to their interactive regulation of other behaviors.     

Infarct size determination by technetium 99m sestamibi single-photon emission computed tomography predicts survival in patients with chronic coronary artery disease

BACKGROUND: The prognostic value of infarct size quantification by technetium 99m sestamibi single-photon emission computed tomography (SPECT) in patients with chronic coronary artery disease (CAD) has not been established.Methods And Results Between September 1994 and May 1995, 1323 patients with known or suspected CAD were referred for perfusion imaging for clinical reasons and had infarct size determined by quantitative SPECT imaging. Patients underwent exercise stress (61%), pharmacologic stress (37%), and rest imaging (3%). Patients were excluded if they had cardiomyopathy, valvular heart disease, or myocardial infarction within 3 weeks of the SPECT study. There were 1224 patients who formed the study group. Follow-up was 94% complete at a median of 1.9 +/- 0.4 years. Sixty-five percent of patients had no measurable infarct. Among the patients with measurable infarcts, the mean infarct size by sestamibi imaging was 15.0% +/- 14.5% of the left ventricle (25% of infarcts /=19% of the left ventricle). By using stepwise regression analysis, age, diabetes, and hypercholesterolemia were all clinical predictors of overall death (P <.05). For cardiac death, only age and diabetes were significant. After adjusting for these clinical variables, infarct size remained an independent predictor of overall death (P =. 001) and survival free of cardiac death (P =.0002). However, when first-pass left ventricular ejection fraction was added to the models, infarct size was no longer significant. CONCLUSIONS: Infarct size determination by SPECT (99m)Tc sestamibi can predict subsequent death in patients with chronic CAD, although ejection fraction appears to have greater prognostic value.     

A search for heterogeneity in insulin dependent diabetes mellitus (IDDM): HLA and autoimmune studies in simplex, multiplex and multigenerational families

HLA antigens (A, B, C and DR loci), serum islet cell antibodies, thyrogastric antibodies, and insulin antibodies were studied in 77 families (25 simplex, 42 multiplex, and 10 multigenerational). In order to test for intrafamilial constancy and intergroup variation, we compared simplex with multiplex families, HLA identical and non identical siblings within families, as well as groups of families characterized by different DR alleles (DR3, DR4, and DR3/DR4) for various immunologic and clinical characteristics. These comparisons did not reveal all the distinct subgroups suggested by different cross-sectional population studies, but did provide evidence for a compound form having an aggregation of different high risk alleles. This study suggests that in many cases (and possibly especially in families with multiple affected individuals), there are several different genetic influences leading to IDDM.