SGLT2 inhibitor versus carbohydrate-restricted isocaloric diet: reprogramming substrate oxidation in type 2 diabetes.

OBJECTIVE: Based on the whole-body energy metabolism and insulin action, the difference between increased excretion of carbohydrate in urine by SGLT2i and reduced same amount of oral carbohydrate intake are scarce. This study aimed to compare the effect of carbohydrate availability with reduced oral intake (carbohydrate-restricted isocaloric diet: CRIC diet) or lost in urine, as urinary glucosuria on sodium/glucose cotransporter-2 inhibitor (SGLT2i) treatment, focus on the insulin requirement and the macronutrient oxidation within insulin treated type 2 diabetes. METHODS: This is randomized 3-arm open-label prospective study. Subjects treated with titrated basal-bolus insulin regimen subsequent to three diet regimens, control diet (CON), administration of canagliflozin 100 mg/day to CON (SGLT2i), or CRIC diet, with a week admission to the endocrinology ward followed by 12 weeks outpatients' management. The main outcome measures including the total insulin dose (TID) required to achieve euglycemia, fasting and postprandial energy expenditure (EE) and respiratory quotient (RQ) at 1-week and 12-week. RESULTS: We enrolled 23 patients with type 2 diabetes (male/female: 14/9, age: 53.6 ± 14.2 years, body mass index: 26.9 ± 4.8 kg/m2, HbA1c: 12.5 ± 1.6%). The TID was similar with CON and SGLT2i at both 1 and 12-weeks. Although comparable net carbohydrate availability in SGLT2i and CRIC groups, the TID was significantly higher in the CRIC (p = 0.02) compare to the SGLT2i at both 1 and 12-weeks. Fasting EE was similar in all groups, postprandial EE was significantly elevated in the SGLT2i and CRIC groups compared to the CON group (p = 0.03 and 0.04). Compare to the CON, lower basal fasting RQ (p = 0.049) and decreased delta-RQ (postprandial RQ/fasting RQ) indicated continuous lipid substrate utilization in the SGLT2i (p = 0.04) and CRIC (p = 0.03) groups. CONCLUSION: The CRIC diet resulted in a similar fasting and postprandial EE and substrate oxidation compared to the SGLT2i. The increased insulin requirement in the CRIC diet indicates that a relatively highly lipid and protein consumption, compared to the SGLT2i and CON, may influence insulin requirement.

Robot-assisted training using hybrid assistive limb ameliorates gait ability in patients with amyotrophic lateral sclerosis.

OBJECTIVE: The Hybrid Assistive Limb (HAL; CYBERDYNE, Inc., Japan) is a wearable robot device that provides effective gait assistance according to voluntary intention by detecting weak bioelectrical signals of neuromuscular activity on the surface of the skin. We used HAL for patients with amyotrophic lateral sclerosis (ALS) to determine whether HAL training had an effect on their gait ability. METHODS: We conducted a single-center, single-arm, observational study. Patients with ALS underwent HAL training once per day (20-40 min per session) for 9-10 days for at least 4 weeks. Gait ability was evaluated using the 2-minute walk test, the 10-meter walk test without the assistance of HAL, and activities of daily living (ADL) using the Barthel Index and Functional Independence Measures before and after a full course of HAL training. RESULTS: There were no dropouts or adverse events during the observation period. Gait function improved after HAL training. The 2-minute walk test revealed a mean gait distance of 73.87 m (36.65) at baseline and 89.9m (36.70) after HAL training (p = 0.004). The 10-meter walk test showed significantly improved cadence, although gait speed, step length on the 10-m walk, or ADL measurements did not change significantly. CONCLUSIONS: Although HAL is not a curative treatment for ALS, our data suggest that HAL may be effective in ameliorating and preserving gait ability in patients with ALS.

Contradictory Responses to the COVID-19 Pandemic in Amyotrophic Lateral Sclerosis Patients and Their Families and Caregivers in Japan.

Objective The coronavirus disease 2019 (COVID-19) pandemic has resulted in a shortage of medical resources, including ventilators, personal protective equipment, medical staff, and hospital beds. We investigated the impact of COVID-19 in amyotrophic lateral sclerosis (ALS) patients, their families, caregivers, and medical experts. Methods We conducted a nationwide ALS webinar about COVID-19 in May 2020 and sent a questionnaire to those enrolled. Results A total of 135 participants (31 ALS patients; 23 families and caregivers of ALS patients; 81 medical experts) responded to this cross-sectional self-report questionnaire. The results showed that tracheostomy and invasive ventilation (TIV) was used in 22.6% of ALS patients, whereas 77.4% of ALS patients were not under TIV. Among non-TIV patients (n=24), 79.2% did not want TIV in the future. However, 47.4% of non-TIV patients not wanting a tracheostomy in advanced stages replied that they would want an emergency tracheostomy if they developed COVID-19-related pneumonia. These results suggest that ALS patients may be receptive to emergency treatments for reasons other than ALS. In addition, approximately half of the ALS patients agreed with the policy of not ventilating the elderly or ALS patients in case of a ventilator shortage. Furthermore, compared with medical experts, few ALS patients reported that the chance for ALS patients to obtain work was higher due to the increasing availability of remote work. Conclusions This survey indicates that the COVID-19 pandemic might be associated with increased distress about access to care and work, inducing contradictory responses and potential hopelessness among ALS patients.

Curcumin Inhibits Age-Related Vascular Changes in Aged Mice Fed a High-Fat Diet.

Inhibiting the onset of arteriosclerotic disease, which has been increasing due to the westernized diet and aging, is a significant social challenge. Curcumin, a type of polyphenol, has anti-oxidative effects and anti-inflammatory action and is expected to treat and to have prophylactic effects on different diseases. In this study, we examined the effects of long-term administration of curcumin on vascular aging and chronic inflammation-the causes of arteriosclerotic disease. Eight-week-old C57BL/6J mice were fed with high fat diet (HFD) or 0.1% curcumin-mixed HFD (HFD + Cu) until 80 weeks old (n = 20 for each group). After the breeding, we examined the expression of antioxidant enzymes, heme oxygenase-1 (HO-1), oxidative stress, vascular aging, and inflammatory changes in the aorta. In the HFD group, oxidative stress increased with decreased sirt1 expression in the aorta followed by increased senescent cells and enhanced inflammation. Whereas in the HFD + Cu group, HO-1 was induced in the aorta with the suppression of oxidative stress. Additionally, it was shown that sirt1 expression in the aorta in the HFD + Cu group remained at a level comparable to that of the 8-week-old mice with suppression of increased senescent cells and enhanced inflammation. Consequently, disorders associated with HFD were resolved. These results suggest that curcumin might be a food with a prophylactic function against arteriosclerotic disease.

Prognostic significance of high serum p53 antibody titers in patients with esophageal squamous cell carcinoma.

BACKGROUND: The p53 protein overexpression that usually results from genetic alterations reportedly induces serum antibodies against p53. However, little information is available about the prognostic significance of perioperative serum p53 antibody (s-p53-Abs) titers in patients with esophageal squamous cell carcinoma. METHODS: In this study, we retrospectively evaluated the clinical significance of perioperative s-p53-Abs in 135 patients with esophageal squamous cell carcinoma. Of these, 58 patients received neoadjuvant chemotherapy comprising 5-FU and CDDP. While the cutoff level at 1.3 U/ml indicated seropositive patients, level of 13.4 U/ml was used to identify high-titer patients. We monitored serum titers seropositive patients after surgery and evaluated the prognostic significance by the univariate and multivariate analyses. RESULTS: In this study, 29 patients (21.5%) were positive for s-p53-Abs before treatment. The frequency of both seropositive patients and high-titer patients (> 13.4 U/ml) was not significantly associated with tumor progression. While seropositive patients did not demonstrate significant poor overall survival, high-titer patients demonstrated significant poor overall survival based on the multivariate analysis (P < 0.001). Moreover, the s-p53-Abs titer did not correlate with the response to neoadjuvant chemotherapy. Among seropositive patients, the negative conversion of s-p53-Abs more likely led to be long-term survival. CONCLUSIONS: This study determined that the high-titer of s-p53-Abs was an independent risk factor to reduce the overall survival of patients with esophageal cancer patients. The negative conversion of s-p53-Abs could be a good indicator of favorable prognosis.

Prognostic significance of hyperfibrinogenemia in patients with esophageal squamous cell carcinoma.

BACKGROUND: Preoperative hyperfibrinogenemia is associated with inflammatory mediators and a poor prognosis in several types of cancer. However, there is no published information on the monitoring of patients with preoperative hyperfibrinogenemia after surgery. The aim of the study reported here was to assess the clinicopathological and prognostic significance of plasma fibrinogen levels in patients with esophageal squamous cell carcinoma before and after surgical treatment. METHODS: Plasma fibrinogen levels were analyzed before surgical treatment (endoscopic submucosal dissection and surgery) in 82 patients with esophageal squamous cell carcinoma. The clinicopathological significance of plasma fibrinogen levels and the relationship of plasma fibrinogen levels with several biomarkers were evaluated. The cutoff value for hyperfibrinogenemia was 321 mg/dl. Univariate and multivariate analysis using the Cox proportional hazards model were performed to evaluate the prognostic significance of plasma fibrinogen levels. The changing patterns of plasma fibrinogen were monitored after surgical treatment to evaluate prognostic impact. RESULTS: Hyperfibrinogenemia was significantly associated with advanced pathological stage of cancer and high C-reactive protein levels. Plasma fibrinogen levels significantly decreased after surgical treatment in recurrence-free patients but did not decrease in patients with recurrence. The multivariate analysis indicated that preoperative hyperfibrinogenemia was an independent prognostic factor for poor survival (hazard ratio 1.005, 95% confidence interval 1.000-1.010; P = 0.039). CONCLUSION: Preoperative hyperfibrinogenemia was associated with inflammatory mediators, tumor progression, and poor survival in patients with esophageal squamous cell carcinoma. The absence of a decrease in plasma fibrinogen levels after surgical treatment may indicate the possibility of tumor recurrence.

Hyperfibrinogenemia is associated with inflammatory mediators and poor prognosis in patients with gastric cancer.

PURPOSE: Hyperfibrinogenemia is associated with poor prognosis in various cancers; however, its clinical relevance in gastric cancer has not been well analyzed. We conducted this study to assess the clinicopathological significance and prognostic value of hyperfibrinogenemia in patients with gastric cancer. METHODS: Plasma fibrinogen levels were measured preoperatively in 315 patients undergoing surgery for gastric cancer. We then evaluated the clinicopathological significance of hyperfibrinogenemia and its relationship with several biomarkers, including white blood cell (WBC), C-reactive protein (CRP), platelet count, prothrombin time (PT) and activated partial thromboplastin time (APTT). Postoperative plasma levels were compared with preoperative levels. The multivariate prognostic value of hyperfibrinogenemia was calculated using the Cox proportional hazards model. RESULTS: Tumor progression was significantly associated with hyperfibrinogenemia, as were the CRP level and platelet counts. Plasma fibrinogen levels decreased significantly after radical surgery. Adjusting for TNM factors, multivariate analysis indicated that hyperfibrinogenemia was an independent prognostic factor for poor survival (hazard ratio = 2.607, 95 % confidence interval = 1.180-5.761, P = 0.018). CONCLUSION: Preoperative hyperfibrinogenemia was associated with tumor progression, inflammatory mediators, and poor overall survival in patients with gastric cancer.

[Total parenteral nutrition and the usefulness of CV ports].

Management of nutrition in cancer patients plays an important role in supporting anti-cancer treatment. Parenteral nutrition is considered to assist with nutrition in cancer patients. Central venous catheters(CVC)are useful for intravenous infusion of not only nutrients with high osmotic pressure but also chemotherapeutic drugs and other substances. Central venous access through CV ports reduces patient's burden and complications, and it contributes to maintaining a patient's quality of life(QOL).

[Two cases of long-term home parenteral nutrition in which increased doses of intravenous selenium were administered and the serum and hair selenium concentration was measured].

Care should be taken regarding the intravenous administration of selenium (Se), an essential element, which is known to be associated with toxemia. The concentration of Se in the serum and hair of 2 patients (patient A and B) with short bowel syndrome, undergoing long-term home parenteral nutrition (HPN), was measured. As nutritional management, commercial total parenteral nutrition infusion was used without restricting oral intake. The patients received sodium selenite (Na2O3Se x 5H2O), a hospital preparation, at the Toho University Omori Medical Center. The dosage was gradually increased from 40 microg/ week to 120 micog/week over 17 months, and the Se concentration in serum and hair was measured bimonthly using inductively coupled plasma mass spectrometry (ICP-MS). The serum concentration of Se increased from 2.0 to 5.3 microg/dL and from 9.0 to 9.7 microg/dL in the case of patient A and B, respectively; however, it did not reach the average value that was observed in healthy volunteers (11.8 microg/dL). In contrast, the concentration of Se in hair gradually approached the reference value (reference range, 405-784 ppb at color correction criteria range 217-520 ppb) in the case of patient A (change from 189 to 278 ppb) and B (change from 291 to 200 ppb). Therefore, we were able to safely manage these cases without any deficiency and poisoning symptoms, by gradually increasing the administration doses.

Evaluation of remnant liver function using 13C-breath tests in a rat model of 70% partial hepatectomy.

BACKGROUND/AIMS: A 13C breath test was applied to evaluate the early stage of postoperative liver function after hepatectomy. It was examined in comparison with functional and morphological recovery. METHODOLOGY: Rats were subjected to 70% partial hepatectomy (H group) and control group (S group). Expired air, blood and remnant liver tissue were collected at 12, 24, 48 and 72h, and 7 and 14 days postoperatively. Phenylalanine and leucine were used as the 13C-labeled substrates. The 13CO2 was collected until 120min. The mean values of the H and S groups were compared using the highest mean level of 13CO2 excreted in breath (Cmax). The liver regenerative ability was evaluated by Ki-67. RESULTS: In the 13C-phenylalanine breath test, the Cmax value tended to be lower for the H group 12h postoperatively (p=0.06). Cmax was significantly lower for the H group 24h postoperatively (p<0.05). Both groups showed equal recovery at 48h postoperatively. In the 13C-leucine breath test, both groups had no significant difference after hepatectomy. The peak of Ki-67 positive rate is estimated to be at 52.8h postoperatively, meaning that the time difference was only approximately 5h between the peak time of Ki-67 positive rate and the 13C-phenylalanine breath test. CONCLUSIONS: These results strongly support that the 13C-phenylalanine breath test can become a non-invasive indicator to evaluate the early stage of postoperative liver function after hepatectomy.

[A case of home parenteral nutrition therapy associated with some problems in exchanging of a popular TPN one bag solution to a new type one bag TPN solution containing all elements of essential nutritionals].

This case was a 62-year-old female patient who had received a home parenteral nutrition therapy for the past 15 years.In order to simplify a management of home parenteral nutritional therapy, she tried to exchange a current use of popular TPN one bag solution to a new type one bag solution containing all elements of essential nutritionals, which could reduce a number of mixing procedures.However, she unfortunately encountered a new problem increasing a number of solution contained boxes(from 7 popular solution bags per box to 5 bags per box)to be brought into her house.Consequently, her living space was limited with more new boxes in the house.Moreover, a new solution bag was not easy to mix all elements of nutritionals, and a 1, 500 mL bag was too heavy for her to lift.In conclusion, there are many different problems associated with each patient, so that we ought to consider each patient's living environment as one of the important issues.

Survival of geriatric patients after percutaneous endoscopic gastrostomy in Japan.

AIM: To examine the long term survival of geriatric patients treated with percutaneous endoscopic gastrostomy (PEG) in Japan. METHODS: We retrospectively included 46 Japanese community and tertiary hospitals to investigate 931 consecutive geriatric patients (≥ 65 years old) with swallowing difficulty and newly performed PEG between Jan 1st 2005 and Dec 31st 2008. We set death as an outcome and explored the associations among patient's characteristics at PEG using log-rank tests and Cox proportional hazard models. RESULTS: Nine hundred and thirty one patients were followed up for a median of 468 d. A total of 502 deaths were observed (mortality 53%). However, 99%, 95%, 88%, 75% and 66% of 931 patients survived more than 7, 30, 60 d, a half year and one year, respectively. In addition, 50% and 25% of the patients survived 753 and 1647 d, respectively. Eight deaths were considered as PEG-related, and were associated with lower serum albumin levels (P = 0.002). On the other hand, among 28 surviving patients (6.5%), PEG was removed. In a multivariate hazard model, older age [hazard ratio (HR), 1.02; 95% confidence interval (CI), 1.00-1.03; P = 0.009], higher C-reactive protein (HR, 1.04; 95% CI: 1.01-1.07; P = 0.005), and higher blood urea nitrogen (HR, 1.01; 95% CI: 1.00-1.02; P = 0.003) were significant poor prognostic factors, whereas higher albumin (HR, 0.67; 95% CI: 0.52-0.85; P = 0.001), female gender (HR, 0.60; 95% CI: 0.48-0.75; P < 0.001) and no previous history of ischemic heart disease (HR, 0.69; 95% CI: 0.54-0.88, P = 0.003) were markedly better prognostic factors. CONCLUSION: These results suggest that more than half of geriatric patients with PEG may survive longer than 2 years. The analysis elucidated prognostic factors.

[Themes of nutrition-related cooperation pass candidates made by medical association].

Hospitals in Shinagawa-ku and Ota-ku, the secondary medical sphere of Tokyo, have been working on various medical care tasks in order to provide a seamless transition from hospital to home medical care. In the area of nutritional medical therapy, the Shinagawa and Ota nutrition workshop was founded in 2006 to share the information, which contains thoroughly from a special nutrition therapy to a general therapy. In September 2007, a nutrition questionnaire survey was conducted for the members of Ebara-, Shinagawa-, Omori-, Kamata- and Denen-Chofu-medical association to make themes of nutrition related cooperation pass candidates. Then, we debated on the theme of priorities based on the result of the survey. In the scientific meeting held in May 2010, we examined the candidates, and decided to enrich the present diabetes passes and to a new establishment of PEG management.

[Patterns causing hepatic arterial inner wall injury by catheter insertion-from a case in which catheter probe patency was confirmed 65 months after implant].

We experienced a case in which the hepatic artery catheter system could be used long term. Even after 5 years and five months, there was no damage to the hepatic artery, and we could still use this system. For insertion of the catheter, a fine catheter with the tip tapered at 2.7 F was selected. This catheter was inserted into the hepatic artery peripheral branch in the liver, after a side hole was created 11 cm from the tip, and the side hole was adjusted to stay in the common hepatic artery. We speculated that the reason for little injury to the hepatic artery was use of a fine catheter despite possible damage to the hepatic artery wall like saw cutting in this case. We classified the patterns according to which a catheter damaged the inner wall of the hepatic artery into 5: "straight punch type", "hook punch type", "whiplash type", "elbow blow type", "and saw type".

Is the metabolism of toast alcohol beverages influenced by a meal taken five minutes later?

Alcohol is commonly consumed with, or soon after, a meal that affects gastric emptying and thus, absorption and metabolism of alcohol. The aim of this study is to evaluate the effect of liquid test meal ingested soon after, alcohol ingestion on alcohol metabolism, as is common in the social setting. First, a 100 mL of water containing of 80 mg of 13C-ethanol was administrated orally in 7 healthy subjects, and 200 mL of liquid meal (200 kcal) was administrated 5 min after alcohol ingestion. Breath samples were taken at baseline and at 10-min interval for 150 min. Next, 13C-ethanol breath test was performed without ingestion of liquid meal. Cmax was decreased after ingestion of liquid meal, whereas Tmax was unchanged. The descending gradient of 13CO2 excretion curves after ingestion of liquid meal is parallel to that without liquid meal, while the ascending gradient of 13CO2 excretion curves in the first 10 min had a tendency to be greater after ingestion of liquid meal than without ingestion of liquid meal. A significant delay in breath 13CO2 excretion after ingestion of liquid meal was found and the AUC values were lower after ingestion of liquid meal in each time point, indicating that liquid meal ingested soon after alcohol ingestion may not affect elimination but absorption and/or metabolism of a small amount of alcohol.

Removal of ovarian hormones affects the ageing process of acetate metabolism.

BACKGROUND: Despite a close association between gastrointestinal motility and sex hormones, it has been unknown whether ovarian hormones affect absorption and metabolism of nutrients. The aim of this study is, therefore, to evaluate metabolism of acetate in rats with age and the influence of ovariectomy on its change. METHODS: Fourteen female rats of the F344 strain were used, and 13C-acetate breath test was performed at 2, 7 and 13 months of age. Seven rats were ovariectomized at three weeks of age (ovariectomy group) and the remaining seven rats were studied as control group. After 24-hr fasting, rats are orally administrated 1ml of water containing sodium (13)C-acetate (100mg/kg) and housed in an animal chamber. The expired air in the chamber is collected in a breath-sampling bag using a aspiration pump. The (13)CO(2) concentration is measured using an infrared spectrometer for 120 min and expressed as delta per mil. RESULTS: The breath (13)CO(2) excretion increased with time and peaked 30 min in control rats. In ovariectomized rats, thee peak time of (13)CO(2) excretion was prolonged to 40 min at 7 and 13 months of age. Cmax was significantly higher at 2 months of age but lower at 4 months of age in ovariectomized rats than in control rats. Those of two groups became equal at 7 months of age. CONCLUSIONS: From the viewpoint of acetate metabolism, removal of ovarian hormones might make rats to be precocious ones and accelerate ageing.

Influence of chronic ethanol consumption on extra-pancreatic secretory function in rat.

BACKGROUND: The usefulness of the typical direct methods involving duodenal intubation, such as the secretin and secretin-cholecystokinin tests, in the diagnosis of exocrine pancreatic dysfunction is widely accepted. However, these diagnostic tests tend to be avoided because of their technical complexity and the burden on patients. Recently, a simple breath test was developed for assessment of exocrine pancreatic function employing 13C-dipeptide [i.e., benzoyl-L-tyrosyl-[1-13C] alanine (Bz-Tyr-Ala)]. Although alcohol abuse causes pancreatic damage in humans, this has been unclear in rats. AIMS: The aim of the study is to evaluate the effect of ethanol exposure beginning at an early age on extra-pancreatic secretory function in rats. MATERIALS AND METHODS: Twelve female rats of the F344 strain aged 12 months were used. Seven rats were fed on a commercial mash food with 16% ethanol solution (Japanese Sake) as drinking-fluid since at 29 days of age (ethanol group). The remaining five rats were fed on a nutrient-matched isocaloric diet with water as drinking-fluid (control group). After 24-hr fasting, rats are orally administrated 1cc of water containing sodium 13C-dipeptide (5 mg/kg) and housed in an animal chamber. The expired air in the chamber is collected in a breath-sampling bag using a tube and aspiration pump. The 13CO2 concentration is measured using an infrared spectrometer at 10-min interval for 120 min and expressed as delta per mil. RESULTS: The breath 13CO2 level increased and peaked at 20 min in both two groups. In general, 13CO2 excretion peaked rapidly and also decreased sooner in ethanol rats than in control rats. The mean value of the maximal 13CO2 excretion is 34.7 per mil in ethanol rats, greater than in control rats (31.4 per mil), but the difference did not reach the statistically significance. CONCLUSION: Chronic ethanol feeding beginning at an early age does not affect extra-pancreatic secretory function in rats.

Reduced risk of peristomal infection of direct percutaneous endoscopic gastrostomy in cancer patients: comparison with the pull percutaneous endoscopic gastrostomy procedure.

BACKGROUND: Although pull percutaneous endoscopic gastrostomy (Pull-PEG) is a commonly used procedure, peristomal infection and tumor implantation are considered unavoidable complications of this procedure as the instrument passes through the oral cavity. A novel extracorporeal PEG technique, Direct-PEG, has been developed to reduce the risk of peristomal infection and implantation. STUDY DESIGN: The Direct-PEG procedure was performed on 87 patients from April 2006 to April 2007 in a single, high-volume cancer center in Japan. To compare the surgical outcomes of Direct-PEG and Pull-PEG, the clinical outcomes of Direct-PEG, such as peristomal infection, were retrospectively collected and compared with those of 64 patients having Pull-PEG procedures from April 2005 to March 2006. RESULTS: The mean operation time for the Direct-PEG group (13+/-1 minutes) was comparable to that for the Pull-PEG group (12+/-1 minutes), and the mean visual analogue pain score during surgery was lower for the Direct-PEG group (3.5+/-1.7) than for the Pull-PEG group (24.6+/-3.6; p < 0.001). The incidence of peristomal infection was lower in the Direct-PEG group (1%) than in the Pull-PEG group (9%; p=0.001). Although the most common major underlying disease in the groups was oropharyngeal or esophageal tumor, tumor implantation was not observed in either group. CONCLUSIONS: Direct-PEG may be superior to the Pull-PEG method for a high-volume cancer center because of reduced risks of infection.

Local glutathione redox status does not regulate ileal mucosal growth after massive small bowel resection in rats.

Glutathione (GSH) concentration affects cell proliferation and apoptosis in intestinal and other cell lines in vitro. However, in vivo data on gut mucosal GSH redox status and cell turnover are limited. We investigated the effect of altered GSH redox status on the ileal mucosa in a rat model of short bowel syndrome following massive small bowel resection (SBR). Rats underwent 80% mid-jejunoileal resection (RX) or small bowel transection (TX; as operative controls), with administration of either saline or D, L-buthionine-sulfoximine (BSO), a specific inhibitor of cellular GSH synthesis. Ileal mucosal redox, morphology, and indices of cell proliferation and apoptosis were determined at different days after surgery. Ileal GSH redox status was assessed by GSH and GSH disulfide (GSSG) concentrations and the redox potential of GSH/GSSG (Eh). Ileal lipid peroxidation [free malondialdehyde (MDA)] was measured as an index of lipid peroxidation. BSO markedly decreased ileal mucosal GSH, oxidized GSH/GSSG Eh, and increased MDA content without inducing morphological damage as assessed by light or electron microscopy. As expected, SBR stimulated adaptive growth of ileal villus height and total mucosal height at 7 d after surgery, but this response was unaffected by BSO treatment despite a modest increase in crypt cell apoptosis. Ileal cell proliferation (crypt cell bromodeoxyuridine incorporation) increased at 2 d after SBR but was unaffected by BSO. Collectively, our in vivo data show that marked depletion of ileal GSH and oxidation of the GSH redox pool does not alter indices of ileal epithelial proliferation or SBR-induced ileal mucosal adaptive growth.