Nutritional Assessment in Patients after Gastric Electrical Stimulation (GES).

BACKGROUND: Gastric electrical stimulation (GES) is used for patients with drug-refractory gastroparesis (Gp) symptoms. Approximately two-thirds of patients with Gp symptoms are either overweight or obese. We aimed to assess symptoms and nutritional status pre-GES and post-GES placement in a large sample of drug-refractory Gp patients. METHODS: We conducted a chart review of 282 patients with drug-refractory Gp who received temporary followed by permanent GES at an academic medical center. Gastrointestinal symptoms were collected by a traditional standardized PRO (0-4, 0 being asymptomatic and 4 being worst symptoms), baseline nutritional status by BMI plus subjective global assessment (SGA score A, B, C, for mild, moderate, and severe nutritional deficits), ability to tolerate diet, enteral tube access, and parenteral therapy were assessed at baseline and after permanent GES placement. RESULTS: Comparing baseline with permanent, GES was found to significantly improve upper GI symptoms in all quartiles. Of the 282 patients with baseline body mass index (BMI) information, 112 (40%) patients were severely malnourished at baseline, of which 36 (32%) patients' nutritional status improved after GES. Among all patients, 76 (68%) patients' nutritional status remained unchanged. Many patients with high BMI were malnourished by SGA. CONCLUSION: We conclude that symptomatic patients of different BMIs showed improvement in their GI symptoms irrespective of baseline nutritional status. Severely malnourished patients were found to have an improvement in their nutritional status after GES therapy. We conclude that BMI, even if high, is not by itself a contraindication for GES therapy for symptomatic patients.

Non-surgical local treatments of digital ulcers in systemic sclerosis: a systematic literature review.

INTRODUCTION: Digital ulcers (DUs) are difficult to treat in patients with systemic sclerosis (SSc) and systemic (i.e., pharmacological) therapy is currently considered the 'standard of care'. Our aim was to examine the safety and efficacy of local, non-surgical treatment for SSc-DUs. METHODS: A systematic literature review (SLR) of original research articles up to August, 29 2022 was performed according to the PICO framework. References were independently screened by two reviewers and risk of bias was assed using validated tools. Due to study heterogeneity narrative summaries are used to present data. RESULTS: Among 899 retrieved references, 14 articles were included (2 randomised trials (RTs), and 12 observational (OBS) studies). The most frequently studied procedure (5 studies) was botulin A toxin (hand or single finger) injection with a reported healing rate (HR) of 71%-100%. Amniotic and hydrocolloid membranes were examined in one study each and associated with a good HR. Tadalafil 2% cream was studied in a single study with a reduction in the number of DUs. Vitamin E gel was associated with a reduction in ulcer healing time. Low-level light therapy, hydrodissection and corticosteroid injection, extracorporeal shock wave (ESW) and photobiomodulation were evaluated in a single study each and showed a positive trend. Dimethyl sulfoxide was associated with significant local toxicity. CONCLUSIONS: A range of non-surgical, local treatments for SSc-DUs have been explored and showed efficacy to some extent. We have identified methodological flaws that should be avoided in the design of future studies to explore locally-acting treatments for SSc-DUs.

Dietary Iron Intake and HIV-Related Outcomes Among Adults Initiating Antiretroviral Therapy in Tanzania.

OBJECTIVE: Anemia is highly prevalent among people living with HIV (PLWHIV) and is often due to iron deficiency. This study evaluated the relationship of dietary iron intake levels and sources with mortality and clinical outcomes among adults initiating HAART. DESIGN: We conducted a secondary analysis of a multivitamin supplementation trial among 2293 PLWHIV initiating HAART in Dar es Salaam, Tanzania. METHODS: Dietary iron intake was assessed with a food frequency questionnaire at HAART initiation, and participants followed until death or censoring. Total, animal-, and plant-sourced iron were categorized into quartiles. Intake of food groups was categorized into 0-1, 2-3, and ≥4 servings/wk. Cox proportional hazards models estimated hazard ratios for mortality and incident clinical outcomes. RESULTS: There were 175 deaths (8%). Red meat intake was associated with a lower risk of all-cause mortality (HR: 0.54; 95% CI: 0.35 to 0.83), AIDS-related mortality (HR: 0.49; 95% CI: 0.28 to 0.85), and severe anemia (HR: 0.57; 95% CI: 0.35 to 0.91), when intake ≥4 servings/wk, compared with 0-1 servings/wk. Legume intake was a lower risk of associated with all-cause mortality (HR: 0.49; 95% CI: 0.31 to 0.77) and AIDS-related mortality (HR: 0.37; 95% CI: 0.23 to 0.61), when intake ≥4 servings/wk, compared with 0-1 servings/wk. Although total dietary iron and overall plant-sourced iron intake were not associated with the risk of mortality or HIV-related outcomes, the highest quartile of animal-sourced iron intake was associated with a lower risk of all-cause mortality (HR: 0.56; 95% CI: 0.35 to 0.90) and a lower risk of AIDS-related mortality (HR: 0.50; 95% CI: 0.30 to 0.90), compared with the lowest quartile. CONCLUSION: Intake of iron-rich food groups may be associated with a lower risk of mortality and critical HIV-related outcomes among adults initiating HAART. TRIAL REGISTRATION: The parent trial was registered at Clinicaltrials.gov . Identifier: NCT00383669.

Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide for Peripheral T Cell Lymphoma: The Importance of Graft Source.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus host-disease (GVHD) prophylaxis has revolutionized allogeneic blood or marrow transplantation (alloBMT), but there is limited published experience in peripheral T cell lymphoma (PTCL). We sought to assess outcomes in patients with PTCL who underwent alloBMT with PTCy. We reviewed the charts of all adult patients age ≥18 years who underwent alloBMT with nonmyeloablative conditioning and PTCy-based GVHD prophylaxis at the Sidney Kimmel Comprehensive Cancer Center between January 2004 and December 2020. Sixty-five patients were identified. The median age was 59 years (range, 24 to 75 years). Lymphoma histology included PTCL not otherwise specified (n = 24), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 14), angioimmunoblastic T cell lymphoma (n = 7), enteropathy-associated T cell lymphoma (n = 6), hepatosplenic T cell lymphoma (n = 4), and others (n = 10). Eleven patients were in first complete remission (17%); the remaining patients were in first partial remission or underwent salvage therapy to at least PR prior to transplantation. Forty-eight patients underwent alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (11%). All patients received fludarabine, cyclophosphamide, and total body irradiation (TBI). The graft source was bone marrow (BM) in 46 patients (71%) and peripheral blood (PB) in 19 patients (29%); all patients in the BM cohort received 200 cGy TBI, and most patients in the PB cohort (15 of 19) received 400 cGy TBI. GVHD prophylaxis comprised PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow-up of 2.8 years (range, 290 days to 14.2 years), the 2-year progression-free survival (PFS) for the entire cohort was 49% (95% confidence interval [CI], 38% to 64%), and the 2-year overall survival (OS) was 55% (95% CI, 44% to 69%). Outcomes were significantly improved in those receiving PB compared to those receiving BM, including a 2-year PFS of 79% (95% CI 63% to 100%) versus 39% (95% CI, 27% to 56%), 2-year OS of 84% (95% CI, 69% to 100%) versus 46% (95% CI, 33% to 63%), and 1-year cumulative incidence of relapse of 5% (95% CI, 0 to 16%) versus 33% (95% CI, 19% to 46%), with no difference in GVHD and nonrelapse mortality. AlloBMT with PTCy is safe and well-tolerated in patients with PTCL. Our data suggest that increasing the TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings.

The effect of iron supplementation on maternal iron deficiency anemia does not differ by baseline anemia type among Tanzanian pregnant women without severe iron deficiency anemia.

PURPOSE: Whether anemia type modifies the risk of pregnancy and newborn outcomes and the effectiveness of iron supplementation is unclear. We examined the association of iron deficiency anemia (IDA) and non-iron deficiency anemia (NIDA) on the risks of these outcomes and the extent to which anemia type modifies the impact of prenatal iron supplementation. METHODS: This was a secondary analysis of a placebo-controlled trial of iron supplementation among 1450 HIV-negative women in Tanzania. Eligibility criteria included gestational age < 27 weeks, hemoglobin > 85 g/L, and ferritin > 12 µg/L. Individuals were categorized as non-anemia, IDA or NIDA using hemoglobin, ferritin and CRP. Analyses were conducted using regression models and likelihood ratio tests. RESULTS: Compared to the non-anemia group, delivery hemoglobin was lower by 15 g/L (95% CI 10.9, 19.3) in the baseline IDA group, and 7.3 g/L (95% CI 3.1, 11.5) in the baseline NIDA group. The RRs of anemia severity, iron deficiency, placental malaria, stillbirths, perinatal mortality, birthweight, and preterm birth were not different among women in the baseline NIDA group (vs. non-anemia) compared to the baseline IDA group (vs. non-anemia). The difference in the mean delivery hemoglobin for iron supplementation and placebo arms was 8 g/L (95% CI 6, 11) in the non-anemia group, 7 g/L (95% CI 2, 13) in the NIDA group, and 16 g/L (95% CI 10, 22) in the IDA group. CONCLUSION: Iron supplementation is effective even among pregnant women with NIDA. TRIAL REGISTRATION: NCT01119612 (May 7, 2010).

Baseline predictive factors for foregut and hindgut response to long-term gastric electrical stimulation using augmented energy.

INTRODUCTION: Gastric electrical stimulation (GES) has been recommended for drug refractory patients with gastroparesis, but no clear baseline predictors of symptom response exist. We hypothesized that long-term predictors to GES for foregut and hindgut symptoms exist, particularly when using augmented energies. PATIENTS: We evaluated 307 patients at baseline, 1 week post temporary GES, and one year after permanent GES. Baseline measures included upper and lower symptoms by patient-reported outcomes (PRO), solid and liquid gastric emptying (GET), cutaneous, mucosal, and serosal electrophysiology (EGG, m/s EG), BMI, and response to temporary stimulation. METHODS: Foregut and hindgut PRO symptoms were analyzed for 12-month patient outcomes. All patients utilized a standardized energy algorithm with the majority of patients receiving medium energy at 12 months. Patients were categorized based on change in average GI symptom scores at the time of permanent GES compared to baseline using a 10% decrease over time as the cutoff between improvers versus non-improvers. RESULTS: By permanent GES implant, average foregut and hindgut GI symptom scores reduced 42% in improved patients (n = 199) and increased 27% in non-improved patients (n = 108). Low BMI, baseline infrequent urination score, mucosal EG ratio, and proximal mucosal EG low-resolution amplitude remained significant factors for improvement status. CONCLUSIONS: GES, for patients responding positively, improved both upper/foregut and lower/hindgut symptoms with most patients utilizing higher than nominal energies. Low baseline BMI and the presence of infrequent urination along with baseline gastric electrophysiology may help identify those patients with the best response to GES/bio-electric neuromodulation.

Prebiotic Inulin Supplementation and Peripheral Insulin Sensitivity in adults at Elevated Risk for Type 2 Diabetes: A Pilot Randomized Controlled Trial.

Prediabetes affects 84.1 million adults, and many will progress to type 2 diabetes (T2D). The objective of this proof-of-concept trial was to determine the efficacy of inulin supplementation to improve glucose metabolism and reduce T2D risk. Adults (n = 24; BMI: 31.3 ± 2.9 kg/m2; age: 54.4 ± 8.3 years) at risk for T2D were enrolled in this controlled feeding trial and consumed either inulin (10 g/day) or placebo (maltodextrin, 10 g/day) for six weeks. Assessments included peripheral insulin sensitivity, fasting glucose, and insulin, HOMA-IR, in vivo skeletal muscle substrate preference, Bifidobacteria copy number, intestinal permeability, and endotoxin concentrations. Participant retention was 92%. There were no baseline group differences except for fasting insulin (p = 0.003). The magnitude of reduction in fasting insulin concentrations with inulin (p = 0.003, inulin = Δ-2.9, placebo = Δ2.3) was attenuated after adjustment for baseline concentrations (p = 0.04). After adjusting for baseline values, reduction in HOMA-IR with inulin (inulin = Δ-0.40, placebo=Δ0.27; p = 0.004) remained significant. Bifidobacteria 16s increased (p = 0.04; inulin = Δ3.1e9, placebo = Δ-8.9e8) with inulin supplementation. Despite increases in gut Bifidobacteria, inulin supplementation did not improve peripheral insulin sensitivity. These findings question the need for larger investigations of inulin and insulin sensitivity in this population.

Drug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial.

BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs). METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability. RESULTS: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens. CONCLUSIONS: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.

In vitro intestinal toxicity of commercially available spray disinfectant products advertised to contain colloidal silver.

The use of colloidal silver-containing products as dietary supplements, immune boosters and surface disinfectants has increased in recent years which has elevated the potential for human exposure to silver nanoparticles and ions. Product mislabeling and long-term use of these products may put consumers at risk for adverse health outcomes including argyria. This study assessed several physical and chemical characteristics of five commercial products as well as their cytotoxicity using a rat intestinal epithelial cell (IEC-6) model. Concentrations of silver were determined for both the soluble and particulate fractions of the products. Primary particle size distribution and elemental composition were determined by transmission electron microscopy (TEM) and energy-dispersive X-ray spectroscopy (EDS), respectively. Hydrodynamic diameters were measured using nanoparticle tracking analysis (NTA) and dynamic light scattering (DLS). The effect of gastrointestinal (GI) simulation on the colloidal silver products was determined using two systems. First, physical and chemical changes of the silver nanoparticles in these products was assessed after exposure to Synthetic Stomach Fluid (SSF) resulting in particle agglomeration, and the appearance of AgCl on the surfaces and between particles. IEC-6 cells were exposed for 24 h to dilutions of the products and assessed for cell viability. The products were also treated with a three-stage simulated GI system (stomach and intestinal fluids) prior to exposure of the IEC-6 cells to the isolated silver nanoparticles. Cell viability was affected by each of the consumer products. Based on the silver nitrate and commercial silver nanoparticle dose response, the cytotoxicity for each of the colloidal silver products was attributed to the particulate silver, soluble silver or non­silver matrix constituents.

Effects of Gastric Neuromodulation on Crohn's Disease in Patients With Coexisting Symptoms of Gastroparesis.

INTRODUCTION: Crohn's Disease (CD) results from chronic inflammation of the gastrointestinal (GI) tract involving TNF-α release. Gastrointestinal electrical stimulation (GES), a form of neuromodulation used to treat upper GI motility symptoms (UGI Sx), exerts an anti-inflammatory effect via TNF-α suppression. We hypothesized patients with CD symptoms in patients with gastroparesis (GP) may respond to GES. METHODS: We retrospectively examined 284 patients with symptomatic gastroparesis (Gp Sx), who underwent GES placement. Patients with Gp Sx were evaluated by validated GI Sx patient reported outcome. Scores were obtained at baseline, after temporary GES placement and after permanent GES placement. Eleven patients from this cohort with coexisting CD were analyzed for improvements in their CD symptomatology using the Harvey Bradshaw Index (HBI). HBI scores were compared from before GES to after two sequential applications of electrical stimulation (temporary then permanent). A 3-point decrease in HBI indicated a clinical response and an HBI <5 indicated clinical remission after GES. An unadjusted repeated measures model was used in the analysis with statistical significance set at p ≤ 0.05. RESULTS: Our cohort prevalence of CD was 3.9% (2 M & 9 F, mean age 49.8 yrs.). Within both the Gp + CD & Gp subgroups, UGI Sx substantially improved after temporary and permanent GES. Furthermore, 55% of the GP + CD subgroup demonstrated a clinical response by HBI, while one patient achieved clinical remission (p < 0.01). CD medications were reviewed before and after GES placement, and any interval changes are unlikely to explain the improved HBI scores. DISCUSSION: We conclude that both UGI and CD symptoms in GP + CD patients responded well to GES. The interaction of Gp and CD and the effects of neuromodulation on CD symptoms warrant additional investigation.

Companion Animals and Health in Older Populations: A Systematic Review.

OBJECTIVES: . The aim of this systematic literature review (SLR) was to investigate the effect of companion animals (whether simply as pets or used in more formal intervention approaches) on the physical and mental health of older adults (aged 60+). METHODS: . The reviewers identified key search terms and conducted a systematic search of the PsycINFO and PubMed databases. The 70 articles reviewed were evaluated through tabular and thematic analysis. RESULTS: . In 52 of the studies examined, companion animals positively contributed to the mental and/or physical health of older adults. With respect to mental health, involvement with a companion animal improved participant quality of life and effectively attenuated symptoms of depression, anxiety, cognitive impairment, and the behavioral and psychiatric symptoms of dementia (BPSD). In relation to physical health, marked increases in physical activity and improvements in blood pressure and heart rate variability were the only consistent physical health improvements observed from companion animal interactions. CONCLUSIONS: . Animal companionship can benefit the mental and physical health of older adults, although more and better controlled research on this topic is required. CLINICAL IMPLICATIONS: . Use of companion animals has the potential to be an effective treatment or adjunct therapy to improve the health status and quality of life of older individuals.

Flavanol supplementation protects against obesity-associated increases in systemic interleukin-6 levels without inhibiting body mass gain in mice fed a high-fat diet.

Weight gain and obesity are associated with increased levels of proinflammatory cytokines. Studies have demonstrated the ability of dietary flavanols to reduce the severity of metabolic derangements due to high-fat (HF) feeding. The degree of polymerization of the flavanols appears to play a role in determining the extent of these protective effects. This study evaluated the preventative effects of grape seed and pine bark flavanol supplementation, with significantly different flavanol degree of polymerization, in the context of an HF diet. For 13 weeks, mice were given 35 mg/kg body weight per day grape seed or pine bark as part of an HF diet and compared to mice fed a low-fat diet and control HF diet. All flavanol-supplemented groups and the HF control incurred significantly higher weight gain compared to the lean control, and the grape seed group gained significantly more weight than the HF control. Increased weight gain of treatment groups was likely caused by hyperphagia. Despite lack of improvements to weight gain and glycemic control, it was observed that all flavanol treatment groups were able to significantly reduce interleukin-6 compared to HF control. The grape seed group, which gained the most weight overall, also exhibited the lowest levels of interleukin-6 compared to other groups. Overall, low-dose flavanol extract supplementation, regardless of mean degrees of polymerization, blunted cytokine production despite increased weight gain. This obesity-independent effect suggests flavanols may be used as complementary interventions to ameliorate increased inflammatory tone in the contexts of obesity and diabetes. Furthermore, flavanol-induced hyperphagia may have use for attenuation of cachexia.

Gastroparesis syndromes: Response to electrical stimulation.

BACKGROUND AND AIMS: Factors underlying gastroparesis are not well defined, nor is the mechanism of action of gastric electrical stimulation (GES). We hypothesized that GES acts via several mechanisms related to underlying disordered pathophysiology. METHODS: We studied 43 consecutive eligible patients with gastroparetic symptoms, previously evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal; and also categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. We then studied 41 patients who underwent temporary GES for 5-7 days. Thirty-six of those patients were implanted and 30 were followed up at 6 months after permanent GES. RESULTS: In previous but separately reported work, patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status and all patients demonstrated abnormalities in each of the five areas studied. After GES, patients showed early and late effects of electrical stimulation with changes noted in multiple areas, categorized by improvement status. CONCLUSION: Patients with symptoms of gastroparesis have multiple abnormalities, including systemic inflammation and disordered hormonal status. GES affects many of these abnormalities. We conclude electrical stimulation improves symptoms and physiology with (a) an early and sustained anti-emetic effect; (b) an early and durable gastric prokinetic effect in delayed emptying patients; (c) an early anti-arrhythmic effect that continues over time; (d) a late autonomic effect; (e) a late hormonal effect; (f) an early anti-inflammatory effect that persists; and (g) an early and sustained improvement in health-related quality of life. This study is registered with Clinicaltrials.gov under study # NCT03178370 (https://clinicaltrials.gov/ct2/show/NCT03178370).

The Effect of Gastric Electrical Stimulation on Small Bowel Motility in Patients With Gastroparesis and Concomitant Pancreatic and Small Bowel Dysfunction: From Animal Model to Human Application.

BACKGROUND/AIMS: Patients with gastroparesis often have biliary/pancreatic and small bowel symptoms but the effects of gastric electrical stimulation on small bowel electrical activity of the mid-gut have not been studied. Animal model aim: Establish gastric and upper small bowel/biliary slow wave activity relationships with electrical stimulation. Human study aim: Demonstrate improvement in symptoms associated with proximal small bowel dysmotility in gastric stimulated patients. MATERIALS AND METHODS: Animal model: In vivo evoked responses of duodenal and Sphincter of Oddi measures recorded during gastric electrical stimulation in a nonsurvival swine model (N = 3). High-resolution electrical slow wave mapping of frequency, amplitude, and their ratio, for duodenal and Sphincter of Oddi electrical activity were recorded. Human study: Patients (N = 8) underwent temporary gastric stimulation with small bowel electrodes. Subjective and objective data was collected before and after temporary gastric stimulation. Symptom scores, gastric emptying times, and mucosal electrograms via low-resolution mapping were recorded. RESULTS: Animal gastric stimulation resulted in some changes in electrical activity parameters, especially with the highest energies delivered but the changes were not statistically significant. Human study revealed improvement in symptom and illness severity scores, and changes in small bowel mucosal slow wave activity. CONCLUSIONS: Gastric electrical stimulation in an animal model seems to show nonsignificant effects small bowel slow wave activity and myoelectric signaling, suggesting the existence of intrinsic neural connections. Human data shows more significance, with possible potential for therapeutic use of electrical stimulation in patients with gastroparesis and pancreato-biliary and small bowel symptoms of the mid-gut. This study was limited by the nonsurvival pig model, small sample size, and open label human study.

From the Cover: Genomic Effects of Androstenedione and Sex-Specific Liver Cancer Susceptibility in Mice.

Current strategies for predicting carcinogenic mode of action for nongenotoxic chemicals are based on identification of early key events in toxicity pathways. The goal of this study was to evaluate short-term key event indicators resulting from exposure to androstenedione (A4), an androgen receptor agonist and known liver carcinogen in mice. Liver cancer is more prevalent in men compared with women, but androgen-related pathways underlying this sex difference have not been clearly identified. Short-term hepatic effects of A4 were compared with reference agonists of the estrogen receptor (ethinyl estradiol, EE) and glucocorticoid receptor (prednisone, PRED). Male B6C3F1 mice were exposed for 7 or 28 days to A4, EE, or PRED. EE increased and PRED suppressed hepatocyte proliferation, while A4 had no detectable effects. In a microarray analysis, EE and PRED altered >3000 and >670 genes, respectively, in a dose-dependent manner, whereas A4 did not significantly alter any genes. Gene expression was subsequently examined in archival liver samples from male and female B6C3F1 mice exposed to A4 for 90 days. A4 altered more genes in females than males and did not alter expression of genes linked to activation of the mitogenic xenobiotic receptors AhR, CAR, and PPARα in either sex. A gene expression biomarker was used to show that in female mice, the high dose of A4 activated the growth hormone-regulated transcription factor STAT5b, which controls sexually dimorphic gene expression in the liver. These findings suggest that A4 induces subtle age-related effects on STAT5b signaling that may contribute to the higher risk of liver cancer in males compared with females.

Treating an oft-unrecognized and troublesome entity: using gastric electrical stimulation to reduce symptoms of malignancy-associated gastroparesis.

PURPOSE: Malignancy-associated gastroparesis (MAG) is a cause of morbidity in cancer patients but therapies are lacking. Gastric electrical stimulation (GES) is a novel treatment for MAG. Here, we describe 19 patients with MAG who underwent temporary GES placement. PATIENTS AND METHODS: Nineteen patients (6 males, 13 females) with various malignancies were reviewed for symptom scores and physiologic measures at baseline and after temporary GES placement. Symptoms were scored by three variables: nausea (N), vomiting (V), and GI total symptom score (TSS). Physiologic profiles were measured by solid and liquid phase gastric emptying scans (GET) at 1, 2, and 4 h and cutaneous electrogastrogram (EGG) and mucosal electrogram (EG) frequencies. Symptoms were measured for 5 days after temporary endoscopic GES placement, and measures were repeated post GES placement. RESULTS: Baseline GET results displayed delayed gastric emptying in 16 of 19 patients (mean solid retention 21.7 % at 4 h, normal <10 %; mean liquid retention 10.4 % at 4 h, normal <5 %). Cutaneous EGG (mean frequency 5.5 cpm) and EG (mean proximal frequency 5.1 cpm; mean distal frequency 5.1 cpm) showed evidence of neuromuscular dysfunction (normal 2.5-3.3 cpm). Symptom scores in N, V, and TSS showed statistically significant reduction after GES placement. CONCLUSION: A small sample of patients with MAG and receiving temporary GES experienced symptom improvement, with less change on gastric emptying time or gastric electrical amplitude or frequency. GES may provide a potential therapeutic option for symptomatic management of MAG and evaluation of these MAG patients after permanent GES placement is ongoing. Prospective studies of MAG using temporary and permanent GES may be warranted.

Mini-laparotomy with Adjunctive Care versus Laparoscopy for Placement of Gastric Electrical Stimulation.

We compared outcomes for two gastric electrical stimulation placement strategies, minilaparotomy with adjunctive care (MLAC) versus laparoscopy without adjunctive care (LAPA). For electrode placement, the peritoneal cavity was accessed with either a single 2.5 to 3.0 cm midline incision (MLAC) or three trocar incisions (LAPA). For both groups, generator was placed subcutaneously over the anterior rectus sheath. For MLAC, adjunctive pain control measures were used for placement of both electrode and generator (transversus abdominus plane block). For LAPA, those that could not be completed by laparoscopy were converted to traditional open approach and kept in the analysis. MLAC (n = 128) resulted in shorter operative times than LAPA (n = 37) (median operative time: 87.5 vs 137.0 minutes, P ≤ 0.01). Hospital length of stay was also shorter for MLAC than for LAPA (median: 2.0 vs 3.0 days, P ≤ 0.01) without any increase in readmission rates to the hospital within 30 days of discharge (11.0 vs 16.2%, P = 0.39). After equalizing learning curves, these differences were even greater (median operative time: 84.5 vs 137.0 minutes, P < 0.01; median length of stay: 1.0 vs 3.0 days; P < 0.01) without increasing 30-day readmission rates (9.1 vs 16.2%, P = 0.25). For implantation of gastric electrical stimulators, minilaparotomy can result in improved outcomes when coupled with adjunctive pain control measures.

Calcium channel blockers for primary Raynaud's phenomenon.

BACKGROUND: Calcium channel blockers are the most commonly prescribed drugs for people with primary Raynaud's phenomenon. Primary Raynaud's phenomenon is a common condition characterised by an exaggerated vasospastic response to cold or emotion: classically the digits (fingers and toes) turn white, then blue, then red. This is an update of the review first published in 2014. OBJECTIVES: To assess the effects of different calcium channel blockers for primary Raynaud's phenomenon as determined by attack rates, severity scores, participant-preference scores and physiological measurements. SEARCH METHODS: For this update the Cochrane Vascular Trial Search Co-ordinator searched the Specialised Register (last searched January 2016) and the Cochrane Register of Studies (CENTRAL) (2015, Issue 12). In addition the TSC searched clinical trials databases. SELECTION CRITERIA: Randomised controlled trials evaluating the effects of oral calcium channel blockers for the treatment of primary Raynaud's phenomenon. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the trials for inclusion and their quality, and extracted the data. Data extraction included adverse events. We contacted trial authors for missing data. MAIN RESULTS: We included seven randomised trials with 296 participants. Four trials examined nifedipine and the remainder nicardipine. Comparisons were with placebo in six trials and with both dazoxiben and placebo in one trial (only the nifedipine versus placebo data were used within this review). Treatment with oral calcium channel blockers was minimally effective in primary Raynaud's phenomenon at decreasing the frequency of attacks (standardised mean difference of 0.23; 95% confidence interval (CI) 0.08 to 0.38, P = 0.003). This translates to 1.72 (95% CI 0.60 to 2.84) fewer attacks per week on calcium channel blockers compared to placebo. One trial provided details on duration of attacks reporting no statistically significant difference between the nicardipine and placebo groups (no P value reported). Only two trials provided any detail of statistical comparisons of (unvalidated) severity scores between treatment groups: one of these trials (60 participants) reported a mean severity score of 1.55 on placebo and 1.36 on nicardipine, difference 0.2 (95% CI of difference 0 to 0.4, no P value reported) and the other trial (three participants only with primary Raynaud's phenomenon) reported a median severity score of 2 on both nicardipine and placebo treatment (P > 0.999) suggesting little effect on severity. Participant-preference scores were included in four trials, but in only two were results specific to participants with primary Raynaud's phenomenon, and scoring systems differed between trials: scores differed between treatments in only one trial, in which 33% of participants on placebo and 73% on nifedipine reported improvement in symptoms (P < 0.001). Physiological measurements were included as outcome measures in five trials (different methodologies were used in each): none of these trials found any statistically significant between-treatment group differences. Treatment with calcium channel blockers appeared to be associated with a number of adverse reactions, including headaches, flushing and oedema (swelling). Overall, the trials were classed as being at low or unclear risk of bias; and the quality of the evidence presented was moderate for number of attacks, very low for duration of attacks, high for severity scores and low for patient preference scores. AUTHORS' CONCLUSIONS: The randomised controlled trials included in this review provide moderate quality evidence that oral calcium channel blockers are minimally effective in the treatment of primary Raynaud's phenomenon as measured by the frequency of attacks and high-quality evidence that they have little effect on severity. We are unable to comment on duration of attacks or on patient preference due to the very low and low quality of evidence as a result of small sample sizes in the included studies and the variable data quality of outcome measures.

Emergence of differentially regulated pathways associated with the development of regional specificity in chicken skin.

BACKGROUND: Regional specificity allows different skin regions to exhibit different characteristics, enabling complementary functions to make effective use of the integumentary surface. Chickens exhibit a high degree of regional specificity in the skin and can serve as a good model for when and how these regional differences begin to emerge. RESULTS: We used developing feather and scale regions in embryonic chickens as a model to gauge the differences in their molecular pathways. We employed cosine similarity analysis to identify the differentially regulated and co-regulated genes. We applied low cell techniques for expression validation and chromatin immunoprecipitation (ChIP)-based enhancer identification to overcome limited cell availabilities from embryonic chicken skin. We identified a specific set of genes demonstrating a high correlation as being differentially expressed during feather and scale development and maturation. Some members of the WNT, TGF-beta/BMP, and Notch family known to be involved in feathering skin differentiation were found to be differentially regulated. Interestingly, we also found genes along calcium channel pathways that are differentially regulated. From the analysis of differentially regulated pathways, we used calcium signaling pathways as an example for further verification. Some voltage-gated calcium channel subunits, particularly CACNA1D, are expressed spatio-temporally in the skin epithelium. These calcium signaling pathway members may be involved in developmental decisions, morphogenesis, or epithelial maturation. We further characterized enhancers associated with histone modifications, including H3K4me1, H3K27ac, and H3K27me3, near calcium channel-related genes and identified signature intensive hotspots that may be correlated with certain voltage-gated calcium channel genes. CONCLUSION: We demonstrated the applicability of cosine similarity analysis for identifying novel regulatory pathways that are differentially regulated during development. Our study concerning the effects of signaling pathways and histone signatures on enhancers suggests that voltage-gated calcium signaling may be involved in early skin development. This work lays the foundation for studying the roles of these gene pathways and their genomic regulation during the establishment of skin regional specificity.