Myoblast mechanotransduction and myotube morphology is dependent on BAG3 regulation of YAP and TAZ.

Skeletal muscle tissue is mechanically dynamic with changes in stiffness influencing function, maintenance, and regeneration. We modeled skeletal muscle mechanical changes in culture with dynamically stiffening hydrogels demonstrating that the chaperone protein BAG3 transduces matrix stiffness by redistributing YAP and TAZ subcellular localization in muscle progenitor cells. BAG3 depletion increases cytoplasmic retention of YAP and TAZ, desensitizing myoblasts to changes in hydrogel elastic moduli. Upon differentiation, muscle progenitors depleted of BAG3 formed enlarged, round myotubes lacking the typical cylindrical morphology. The aberrant morphology is dependent on YAP/TAZ signaling, which was sequestered in the cytoplasm in BAG3-depleted myotubes but predominately nuclear in cylindrical myotubes of control cells. Control progenitor cells induced to differentiate on soft (E' = 4 and 12 kPa) hydrogels formed circular myotubes similar to those observed in BAG3-depleted cells. Inhibition of the Hippo pathway partially restored myotube morphologies, permitting nuclear translocation of YAP and TAZ in BAG3-depleted myogenic progenitors. Thus, BAG3 is a critical mediator of dynamic stiffness changes in muscle tissue, coupling mechanical alterations to intracellular signals and inducing changes in gene expression that influence muscle progenitor cell morphology and differentiation.

Injury-mediated stiffening persistently activates muscle stem cells through YAP and TAZ mechanotransduction.

The skeletal muscle microenvironment transiently remodels and stiffens after exercise and injury, as muscle ages, and in myopathic muscle; however, how these changes in stiffness affect resident muscle stem cells (MuSCs) remains understudied. Following muscle injury, muscle stiffness remained elevated after morphological regeneration was complete, accompanied by activated and proliferative MuSCs. To isolate the role of stiffness on MuSC behavior and determine the underlying mechanotransduction pathways, we cultured MuSCs on strain-promoted azide-alkyne cycloaddition hydrogels capable of in situ stiffening by secondary photocrosslinking of excess cyclooctynes. Using pre- to post-injury stiffness hydrogels, we found that elevated stiffness enhances migration and MuSC proliferation by localizing yes-associated protein 1 (YAP) and WW domain-containing transcription regulator 1 (WWTR1; TAZ) to the nucleus. Ablating YAP and TAZ in vivo promotes MuSC quiescence in postinjury muscle and prevents myofiber hypertrophy, demonstrating that persistent exposure to elevated stiffness activates mechanotransduction signaling maintaining activated and proliferating MuSCs.

Endoscopic ligation for patients with active bleeding Mallory-Weiss tears.

BACKGROUND: Only a few patients with active nonesophageal variceal upper gastrointestinal bleeding have been treated with endoscopic ligation. To further address this issue, four patients with active bleeding Mallory-Weiss tears who underwent endoscopic band ligation are presented. PATIENTS AND METHODS: Endoscopic ligation was performed in four patients with a median age of 52 years (range, 40-93 years) after a diagnosis of active bleeding Mallory-Weiss tears (MWTs). A 45-year-old man with massive persistent upper gastrointestinal bleeding as a cause of a MWT underwent therapeutical endoscopic band ligation after an unsuccessful endoscopic injection trial. On the contrary, injection therapy should have been performed on a 93-year-old woman with multiple myeloma because of an actively bleeding MWT caused by the fibrotic tissue after an unsuccessful endoscopic ligation trial, although her other actively bleeding MWT lesion had been ligated successfully. RESULTS: After endoscopic ligation, all patients achieved complete hemostasis, and rebleeding did not occur. They were discharged without complications after a control endoscopy. CONCLUSIONS: Endoscopic ligation can be performed easily and without any complications such as perforation or delayed hemorrhage in patients with actively bleeding nonfibrotic MWTs.

Traumatic rupture of hydatid cysts: a 12-year experience from an endemic region.

BACKGROUND: Trauma as a cause of hydatid cyst rupture leads to various clinical sequelae. However, extensive data in the current literature regarding clinical presentation and management of such patients are lacking. METHODS: This article is a retrospective review of 16 patients with traumatic rupture of hydatid cysts treated at a university hospital in an endemic area. RESULTS: Falls (44%) were the most common cause of trauma. The ruptured cysts were located in the liver in 13 patients (81%), in the spleen in 2 patients, and in the lung in 1 patient. Computerized tomography had a sensitivity of 100% in demonstrating cyst rupture; whereas, ultrasonography had a sensitivity of 85%. Ten patients (62%) had rupture into the peritoneal cavity and 5 patients (31%) into the biliary tree. Five (31%) of the cysts were infected. Surgical procedures included introflexion (five patients), pericystectomy-choledochoduodenostomy (three patients), external drainage-choledochoduodenostomy (two patients), unroofing-external drainage (two patients), splenectomy (two patients), unroofing (one patient), and right hepatectomy (one patient). Mean length of hospitalization was 15.9 days (range, 5-61 days). One patient (6%) died, and eight patients (50%) developed complications. Nine patients (56%) were followed-up for an average of 30 months (range, 3-72 months), and there was no recurrence. CONCLUSION: Computed tomography is currently the most sensitive diagnostic tool for demonstrating hydatid cyst rupture. The surgical options vary depending on intraoperative findings. Allergic reactions and recurrence as a result of intraperitoneal spillage are not as common as once believed. Biliary rupture is associated with an increased rate of wound infection.

Abdominal stab wounds: the role of selective management.

OBJECTIVE: To investigate the role of a selective approach to the operative treatment of abdominal stab wounds. DESIGN: Retrospective study. SETTING: University hospital, Turkey. SUBJECTS: 387 patients with stab wounds of the abdomen, who presented between January 1992 and January 1995. INTERVENTIONS: After local exploration of the wound, 200 patients in whom the wound had penetrated the peritoneum, underwent diagnostic peritoneal lavage. The lavage fluid was examined for white cells, red cells, and amylase and alkaline phosphatase activity. The severity of the injury was evaluated with the penetrating abdominal trauma index (PATI). MAIN OUTCOME MEASURES: Morbidity and mortality. RESULTS: The main complications were wound infection (n=15), wound dehiscence (n=5), pneumonia (n=3) and renal failure (n=1). Five patients died. The median hospital stay was 6.1 days when patients were operated on, and 1.5 days when they were not. CONCLUSIONS: We managed to minimise the number of negative and unnecessary laparotomies. We emphasise that the selective approach may easily be applied in teaching hospitals.

The use of laparoscopy as a primary diagnostic and therapeutic method in penetrating wounds of lower thoracal region.

Diagnostic laparoscopy (DL) was found to be a sensitive and specific method that reduced the incidence of negative or nontherapeutic laparotomy in patients having penetrating abdominal trauma. Twenty-two patients with penetrating trauma of the lower thoracal region were evaluated by DL at the Emergency Department of the Istanbul Medical Faculty to decide on either laparotomy or conservative treatment. There were 7 (31.8%) female and 15 (68.2%) male patients. Mean age was 26.5 (2146) years. Three (13.6%) patients had gunshot wounds and 19 (86.4%) stab injuries. No peritoneal penetration was detected by DL in 11 (50%) patients, and none of these patients later required laparotomy. Of the remaining 11 patients who had peritoneal penetration, diaphragmatic laceration was detected in 9 (81.8%). Nineteen patients (86.4%) avoided nontherapeutic laparotomy. The specificity and sensitivity of DL were 100% in lower thoracal penetrating trauma. The positive diagnostic value and negative predictive value for peritoneal penetration were found to be 100%. The positive predictive value for therapeutic laparotomy and negative predictive value for nontherapeutic laparotomy were 100% as well. All patients who underwent only DL was discharged within 24 hours. There were no mortality or morbidity. Mean follow-up period was 13 months, and no associated complication was encountered during this time.

[The role of diagnostic laparoscopy in treatment of penetrating injuries of the lower thoracic wall and anterior abdominal wall]. / Die Rolle der diagnostischen Laparoskopie bei der Behandlung von penetrierenden Verletzungen des unteren Brustkorbs und der vorderen Bauchwand.

Penetrating injuries of the lower thoracic wall and anterior abdominal wall cause difficulties in the decision for laparotomy. For gunshot wounds laparotomy without further investigations is in most cases justified, but in other penetrating traumata one should use every diagnostic modality to prevent unacceptably high negative laparotomy rates. We performed diagnostic laparoscopy (DL) on 39 patients with penetrating injuries of the anterior abdominal wall and/or lower thoracic wall. Of these 39 patients, 25 had negative and 14 positive results. We had only one false-negative finding. No false-positive result occurred. We think that DL is a very reliable diagnostic tool which requires a relatively high technology.