Functional STAT3 deficiency compromises the generation of human T follicular helper cells

T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.     

Abnormal intracellular calcium homeostasis in sympathetic neurons from young prehypertensive rats

Hypertension is associated with cardiac noradrenergic hyperactivity, although it is not clear whether this precedes or follows the development of hypertension itself. We hypothesized that Ca(2+) homeostasis in postganglionic sympathetic neurons is impaired in spontaneously hypertensive rats (SHRs) and may occur before the development of hypertension. The depolarization-induced rise in intracellular free calcium concentration ([Ca(2+)](i); measured using fura-2-acetoxymethyl ester) was significantly larger in cultured sympathetic neurons from prehypertensive SHRs than in age matched normotensive Wistar-Kyoto rats. The decay of the [Ca(2+)](i) transient was also faster in SHRs. The endoplasmic reticulum Ca(2+) content and caffeine-induced [Ca(2+)](i) amplitude were significantly greater in the young SHRs. Lower protein levels of phospholamban and more copies of ryanodine receptor mRNA were also observed in the young SHRs. Depleting the endoplasmic reticulum Ca(2+) store did not alter the difference of the evoked [Ca(2+)](i) transient and decay time between young SHRs and Wistar-Kyoto rats. However, removing mitochondrial Ca(2+) buffering abolished these differences. A lower mitochondrial membrane potential was also observed in young SHR sympathetic neurons. This resulted in impaired mitochondrial Ca(2+) uptake and release, which might partly be responsible for the increased [Ca(2+)](i) transient and faster decay in SHR sympathetic neurons. This Ca(2+) phenotype seen in early development in cardiac stellate and superior cervical ganglion neurons may contribute to the sympathetic hyperresponsiveness that precedes the onset of hypertension.     

Intrahepatic cholangiojejunostomy (Longmire procedure) for recurrent bilioenteric anastomotic stricture with hepatolithiasis

Interventional procedure via percutaneous transhepatic route is often performed, as an initial treatment, in patients with benign bilioenteric anastomotic stricture. However, surgical management is required in most cases in which radiological intervention is unsuccessful. In this report, we describe a case of a 67-year-old woman with recurrent bilioenteric anastomotic stricture, accompanying bilateral hepatolitiasis after several times of transhepatic interventions. The patient underwent intrahepatic cholangiojejunostomy (Longmire procedure) and cholangioscopic lithotomy after resection of an atrophic left lateral segment resulting from hepatolithiasis. Although the damaged hilar bile duct had to be isolated and divided from the corresponding vasculature for re-anastomosis, it was quite impossible due to severe inflammatory change at the hepatic hilus. We, therefore, anastomosed the intact biliary stump on the cut surface of the left lateral segment to the jejunal loop with a stent tube. The patient's postoperative course was uneventful and she exhibited no evidence of cholangitis during follow-up period of 1 year after surgery. At present, the indications for intrahepatic cholangiojejunostomy for biliary obstruction, are quite limited, but biliary surgeons should keep this procedure in mind at the time of biliary reconstruction for benign proximal bile duct stricture, particularly in cases of multiply operated hilum.     

The Effect of Cell Cycle and Expression of Cyclin B1 and Cyclin C Protein in Hepatocellular Carcinoma Cell Line HepG2 and SMMC-7721 after of Silencing β-Catenin Gene

Background/Aims: Abnormalities in cell cycle regulation are reported to be strongly associated with tumorigenesis and progression of tumors. Wnt/β-catenin signaling pathway and cell cycle play key roles during the genesis and development of hepatocellular carcinoma (HCC). Current studies indicated that expressions of cyclin A, E and D1 were affected after silencing of β-catenin gene in HCC, but it is unclear if other cyclins are affected. Methodology: To determine the relation, small interference RNA (siRNA) against β-catenin was transfected into HCC cell lines HepG2 and SMMC-7721, and cell cycle and cyclin B1 and cyclin C protein expression were detected. Results: Cell cycle was arrested in G0/G1 at 72h after transfection and the cell cycle began to transfer from G0/G1 to G2/M through S and had a trend to revert at 96h. In addition, β-catenin protein expression was decreased at both 72 and 96h, although the level was slightly higher at 96h than that at 72h. However, cyclin B1 expression decreased at 72h and increased at 96h, cyclin C expression increased at 72h and decreased at 96h. Conclusions: These findings suggest that silencing β-catenin gene may induce the changes of cell cycle and cyclin B1 and cyclin C protein expression. Wnt/β-catenin signaling pathway probably takes part in the genesis and development of HCC through regulating cell cycle and the expression of cyclin B1 and cyclin C.     

Stenting for colorectal cancer obstruction compared to surgery—a study of consecutive patients in a single institution

Background  

Colonic obstruction is a common complication to colorectal cancer and surgical treatment is associated with high morbidity and mortality. Stenting has emerged as an alternative to surgery. The aim of this study was to compare short-term morbidity, mortality and hospital stay between treatment with self-expandable metallic stent and emergency surgery performed at our department during a 5-year period in a non-randomized setting.     

Rectocele—does the size matter?

Objectives

Large rectoceles (>2?cm) are believed to be associated with difficulty in evacuation, constipation, rectal pain, and rectal bleeding. The aim of our study was to determine whether rectocele size is related to patient’s symptoms or defecatory parameters.

Methods

We conducted a retrospective study on data collected on patients referred to our clinic for the evaluation of evacuation disorders. All patients were questioned for constipation, fecal incontinence, and irritable bowel syndrome and were assessed with dynamic perineal ultrasonography and conventional anorectal manometry.

Results

Four hundred eighty-seven women were included in our study. Rectocele was diagnosed in 106 (22%) women, and rectocele diameter >2?cm in 93 (87%) women. Rectocele size was not significantly related to demographic data, parity, or patient’s symptoms. The severity of the symptoms was not correlated to the size or to the position of the rectocele. The diagnosis of irritable bowel syndrome was neither related to the size of the rectocele. Rectocele location, occurrence of enterocele, and intussusception were not related to the size of the rectocele. Full evacuation of rectoceles was more common in small rectoceles (79% vs. 24%, p?=?0.0001), and no evacuation was more common in large rectoceles (37% vs. 0, p?=?0.01). Rectal hyposensitivity and anismus were not related to the size of the rectocele.

Conclusion

In conclusion, only the evacuation of rectoceles was correlated to the size of the rectoceles, but had no clinical significance. Other clinical, anatomical factors were also not associated to the size of the rectoceles. Rectoceles’ size alone may not be an indication for surgery.