Accelerated cell turnover 48 h after intestinal ischemia is NOTCH independent.

AIM OF THE STUDY: Notch signaling plays important roles in maintaining intestinal epithelial homeostasis. When Notch signaling is blocked, proliferation ceases and epithelial cells become secretory. The purpose of the present study was to evaluate the role of Notch signaling pathway following intestinal ischemia-reperfusion (IR) injury in a rat model. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly divided into four experimental groups: Sham-24 and Sham-48 rats underwent laparotomy and were killed 24 or 48 h later, respectively; IR-24 and IR-48 rats underwent occlusion of SMA and portal vein for 30 min followed by 24 or 48 h of reperfusion, respectively. Enterocyte proliferation and enterocyte apoptosis were determined at killing. Notch-related gene and protein expression were determined using Real Time PCR, Western blotting and immunohistochemistry 48 h followed IR. MAIN RESULTS: IR-48 rats demonstrated significantly increased rates of cell proliferation and increased cell apoptosis in both jejunum and ileum compared to Sham rats. IR-48 rats exhibited a significant decrease in Notch-1 protein expression (Western blot) that was coincided with a significant decrease in the number of Notch-1 positive cells (immunohistochemistry) in jejunum (35% decrease, p < 0.05) and ileum (twofold decrease, p < 0.05) as well as Hes-1 positive cells in jejunum (28% decrease, p < 0.05) and ileum (31% decrease, p < 0.05) compared to Sham-48 rats. CONCLUSIONS: Forty-eight hours following intestinal IR in rats, accelerated cell turnover was associated by inhibited Notch signaling pathway. Intestinal stem cells differentiation toward secretory progenitors rather than differentiation toward absorptive cells is important at this phase of intestinal recovery.

An Open-Label Pilot Study to Evaluate the Efficacy of Tofacitinib in Moderate to Severe Patch-Type Alopecia Areata, Totalis, and Universalis.

Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of ∼2%. In AA, the immune system targets the hair follicle, resulting in clinical hair loss. The prognosis of AA is unpredictable, and currently there is no definitive treatment. Our previous whole genome expression studies identified active immune circuits in AA lesions, including common γ-chain cytokine and IFN pathways. Because these pathways are mediated through JAK kinases, we prioritized clinical exploration of small molecule JAK inhibitors. In preclinical trials in mice, tofacitinib successfully prevented AA development and reversed established disease. In our tofacitinib trial in 12 patients with moderate to severe AA, 11 patients completed a full course of treatment with minimal adverse events. Following limited response to the initial dose (5 mg b.i.d.), the dose was escalated (10 mg b.i.d.) for nonresponding subjects. Eight of 12 patients demonstrated ≥50% hair regrowth, while three patients demonstrated <50% hair regrowth, as measured by Severity in Alopecia Tool scoring. One patient demonstrated no regrowth. Gene expression profiles and Alopecia Areata Disease Activity Index scores correlated with clinical response. Our open-label studies of ruxolitinib and tofacitinib have shown dramatic clinical responses in moderate to severe AA, providing strong rationale for larger clinical trials using JAK inhibitors in AA. ClinicalTrials.gov ID NCT02299297.

Fenofibrate reduces intestinal damage and improves intestinal recovery following intestinal ischemia-reperfusion injury in a rat.

PURPOSE: Fenofibrate (FEN) is known as a nuclear receptor activator which regulates many pathophysiological processes, such as oxidative stress, inflammation, and leukocyte endothelium interactions. Recent studies have demonstrated an anti-oxidant, anti-inflammatory, and anti-ischemic role of FEN in the attenuation of ischemia-reperfusion (IR) injury in the kidney, liver, brain, and heart. The purpose of the present study was to examine the effect of FEN on intestinal recovery and enterocyte turnover after intestinal IR injury in rats. METHODS: Male Sprague-Dawley rats were divided into four experimental groups: (1) sham rats underwent laparotomy, (2) sham-FEN rats underwent laparotomy and were treated with intraperitoneal (IP) FEN (20 mg/kg); (3) IR rats underwent occlusion of both the superior mesenteric artery and the portal vein for 30 min followed by 24 h of reperfusion, and (4) IR-FEN rats underwent IR and were treated with IP FEN immediately before abdominal closure. Intestinal structural changes, Park's injury score, enterocyte proliferation, and enterocyte apoptosis were determined 24 h following IR. The expression of Bax, Bcl-2, p-ERK, and caspase-3 in the intestinal mucosa was determined using real-time PCR, Western blot, and immunohistochemistry. RESULTS: Treatment with FEN resulted in a significant decrease in Park's injury score in jejunum (32 %) and ileum (33 %) compared to IR animals. IR-FEN rats also demonstrated a significant increase in mucosal weight in jejunum (23 %) and ileum (22 %), mucosal DNA (38 %) and protein (65 %) in jejunum, villus height in jejunum (17 %) and ileum (21 %), and crypt depth in ileum (14 %) compared to IR animals. IR-FEN rats also experienced significant proliferation rates as well as lower apoptotic indices in jejunum and ileum which was accompanied with higher Bcl-2 levels compared to IR animals. CONCLUSIONS: Treatment with fenofibrate prevents intestinal mucosal damage and stimulates intestinal epithelial cell turnover following intestinal IR in a rat model.

Effect of taurine on intestinal recovery following intestinal ischemia-reperfusion injury in a rat.

PURPOSE: Taurine (TAU) is a sulfur-containing amino acid that is involved in a diverse array of biological and physiological functions, including bile salt conjugation, osmoregulation, membrane stabilization, calcium modulation, anti-oxidation, and immunomodulation. Several studies have established that treatment with TAU significantly protects cerebral, cardiac and testicular injury from ischemia-reperfusion (IR). The purpose of the present study was to examine the effect of TAU on intestinal recovery and enterocyte turnover after intestinal IR injury in rats. METHODS: Male Sprague-Dawley rats were divided into four experimental groups: (1) Sham rats that underwent laparotomy, (2) Sham-TAU rats that underwent laparotomy and were treated with intraperitoneal (IP) TAU (250 mg/kg); (3) IR-rats that underwent occlusion of both superior mesenteric artery and portal vein for 30 min followed by 48 h of reperfusion, and (4) IR-TAU rats that underwent IR and were treated with IP TAU (250 mg/kg) immediately before abdominal closure. Intestinal structural changes, Park's injury score, enterocyte proliferation and enterocyte apoptosis were determined 24 h following IR. The expression of Bax, Bcl-2, p-ERK and caspase-3 in the intestinal mucosa was determined using Western blot and immunohistochemistry. RESULTS: Treatment with TAU resulted in a significant decrease in Park's injury score compared to IR animals. IR-TAU rats also demonstrated a significant increase in mucosal weight in jejunum and ileum, villus height in jejunum and ileum and crypt depth in ileum compared to IR animals. IR-TAU rats also experienced significantly lower apoptotic indices in jejunum and ileum which was accompanied by a higher Bcl-2/Bax ratio compared to IR animals. CONCLUSIONS: Treatment with taurine prevents gut mucosal damage and inhibits intestinal epithelial cell apoptosis following intestinal IR in a rat.

The role of the BMP signaling cascade in regulation of stem cell activity following massive small bowel resection in a rat.

PURPOSE: Bone morphogenetic proteins (BMPs) are a group of growth factors that are implicated in intestinal growth, morphogenesis, differentiation, and homeostasis. The role of the BMP signaling cascade in stimulation of cell proliferation after massive small bowel resection is unknown. The purpose of this study was to evaluate the role of BMP signaling during intestinal adaptation in a rat model of short bowel syndrome (SBS). METHODS: Male rats were divided into two groups: Sham rats underwent bowel transection and SBS rats underwent a 75 % bowel resection. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined 2 weeks after operation. Illumina's Digital Gene Expression analysis was used to determine the BMP signaling gene expression profiling. BMP-related genes and protein expression were determined using real-time PCR, Western blotting and immunohistochemistry. RESULTS: From the total number of 20,000 probes, 8 genes related to BMP signaling were investigated. From these genes, five genes were found to be up-regulated in jejunum (BMP1-10 %, BMP2-twofold increase, BMP3-10 %, BMP2R-12 % and STAT3-28 %) and four genes to be up-regulated in ileum (BMP1-16 %, BMP2-27 %, BMP3-10 %, and STAT3-20 %) in SBS vs sham animals with a relative change in gene expression level of 10 % or more. SBS rats also demonstrated a significant increase in BMP2 and STAT3 mRNA and protein levels (determined by real-time PCR and Western blot) compared to control animals. CONCLUSION: Two weeks following massive bowel resection in rats, the BMP signaling pathway is stimulated. BMP signaling may serve as an important mediator of reciprocal interactions between the epithelium and the underlying mesenchymal stroma during intestinal adaptation following massive bowel resection in a rat.

Conservative management for an entero-adnexal fistula at initial presentation of advanced ovarian carcinoma.

Gastrointestinal fistulae can occur in ovarian cancer patients, usually in the setting of advanced relapsed disease. Treatment typically involves immediate surgery.Here, we describe a case of an abscess resulting from an intestinal fistula as the first manifestation of advanced epithelial ovarian cancer, and we review the current literature on this subject. The patient was successfully treated with a combination of chemotherapy, antibiotics, and delayed surgery. Optimal debulking was achieved without a need for bowel resection.This report is the first of conservative management of a fistula in an ovarian cancer patient in the chemotherapy-naïve setting.

[Ductal carcinoma in situ].

Ductal carcinoma in situ (DCIS) is now found far more frequently because of mammograms, appearing with microcalcifications. Actually, it is probably very common. Premalignant lesions such as ductal carcinoma in situ are demonstrating the truth of a major concept: that there are lesions within the breast that may be locally removed and controlled before the development of metastatic disease. This article, presents the current management of ductal carcinoma in situ.

Noninfectious gas accumulation in an infarcted spleen.

BACKGROUND: Intentional selective occlusion of the arterial blood supply to tumors of abdominal organs is a well established therapeutic procedure. Several reports described gas accumulation at the infarcted sites. These gas collections are usually nonsuppurative; however, the differential diagnosis should include abscess formation. CASE REPORT: We present a 59-year-old patient in whom the splenic artery was accidentally ligated during gastrectomy surgery, with resultant splenic infarction. Gas accumulation was diagnosed by sonography and CT studies. To the best of our knowledge this is the first report ever published in the English medical literature describing nonsuppurative gas formation within an abdominal organ, caused by accidental ligation of its main arterial supply during surgery. SUMMARY: Possible theories regarding this noninfectious gas accumulation are discussed and the differential diagnosis between abscess formation and noninfectious gas accumulation is emphasized. Establishing the correct diagnosis is of big clinical importance as the treatment of choice is completely different in each one of these entities although the imaging features, in ultrasound as well as in CT, are somewhat similar.

[The fate of gallstones dropped during laparoscopic cholecystectomy].

Laparoscopic cholecystectomy is considered the procedure of choice for removing symptomatic, stone-containing gallbladders. It is estimated that in 30-40% of these operations stone(s) spill into the peritoneal cavity. It was assumed that these "dropped stones" are harmless and are dissolved and absorbed spontaneously. We present a 70-year-old woman in whom such a stone, dropped during laparoscopy, led to formation of an intraperitoneal abscess.

Increasing examiner involvement in an objective structured clinical examination by integrating a structured oral examination.

INTRODUCTION: The role of physician examiners in an objective structured clinical examination (OSCE) is relatively passive. In our institution examiners criticized the passive nature of their role. This study evaluates the reliability and viability of adding a structured oral examination to an OSCE. METHOD: Ten 24-minute stations consisted of three parts. Part I: 12 minutes-patient encounter. Part II: 6 minutes-oral presentation covering findings, differential diagnosis, and management plan. Part III: 6 minutes-structural oral examination (SOE), containing 5 predetermined questions. RESULTS: Over 6 consecutive days, 72 graduates were assessed. Overall average score: 72.02 (SD 5.05); reliability 0.84. Part I of the OSCE average score: 69.2 (SD 7.4); reliability 0.69. Part II oral presentation average score 64 (SD 5.8) reliability 0.87. SOE average score 77.7 (SD 6.3); reliability 0.64. Eighty-nine percent of the examiners indicated satisfaction with the new format. CONCLUSIONS: The SOE was a reliable component of an OSCE and contributed to the overall reliability. Examiners reported a higher degree of satisfaction with the examination.

[Laparoscopic unroofing of a giant renal cyst].

Simple cysts of the kidney represent a common abnormality. They may be single or multiple and usually are asymptomatic. However, occasionally they may cause pain and hematuria. Open surgical unroofing eliminates the cyst but may incur postoperative complications and prolonged hospitalization. Laparoscopic unroofing of symptomatic renal cysts has recently been described, but only a few cases have been reported. We present a 24-year-old man with a giant, painful, renal cyst successfully unroofed via transperitoneal laparoscopy.

[Treatment of well-differentiated thyroid cancer].

Well-differentiated thyroid cancer is the most common malignancy of the thyroid gland, yet its optimal management remains controversial. 269 patients with such lesions were operated on, with or without supplementary treatment. It was concluded that young patients with stage I disease can be safely treated by subtotal thyroidectomy. Total thyroidectomy combined with radioactive ablation is indicated in patients with more advanced systemic disease.