Serum xylosyltransferase 1 level increases during early posttraumatic osteoarthritis in mice with high bone forming potential

Increased proteoglycan (PG) synthesis is essential for the stimulation of cartilage repair processes that take place during the reversible phase of osteoarthritis (OA). In articular cartilage, xylosyltransferase 1 (Xylt1) is the key enzyme that initiates glycosaminoglycan (GAG) chain synthesis by transferring the first sugar residue to the PG core protein. Biological activity of PGs is closely linked to GAG biosynthesis since their polyanionic nature directly contributes to the proper hydration and elastic properties of the cartilage tissue present at the articular interface. The aim of this study was to investigate whether variations in the level of Xylt1 present in serum can be used to predict OA disease progression. The influence of bone forming activity on the systemic release of this enzyme was addressed by experimentally-inducing OA in mice of two different genetic backgrounds that were previously characterized for their distinct bone metabolism: C57BL/6J (B6, high bone remodelers) or C3H/HeJ (C3H, high bone formers). Serum was collected after medial meniscectomy or sham surgeries in young adult mice of these two strains over a period of 3.5months at which point knee histopathology was assessed. A significant increase in serum Xylt1 levels observed shortly after meniscectomy positively correlated with severe cartilage damage evaluated by histological assessment at later time points in mice of the C3H background. In contrast, no temporal regulation of Xylt1 level was found between meniscectomies and control surgeries in B6 mice, which developed OA at a slower rate. Additionally, longitudinal evaluation of the serum levels of other markers of cartilage/bone metabolism (C1,2C, osteocalcin) did not reveal any association with late knee damages. Our results strongly support the idea that serum Xylt1 has a clinical value for monitoring risk of OA progression in young adults with high bone forming potential. Ultimately, the understanding of posttraumatic mechanisms regulating PG synthesis and their modification by GAG will be essential so that interventions that stimulate cartilage regrowth can be undertaken prior to irreversible destruction of the joint tissue. This article is part of a Special Issue entitled "Osteoarthritis".     

Renal cell carcinoma with metastases to the gallbladder: four cases from the National Cancer Institute (NCI) and review of the literature

ObjectiveWe evaluate presentation and outcome of patients with metastatic RCC to the gallbladder from our institution and published literature.MethodsPatients with a history of gallbladder metastasis from RCC were selected from our institution's prospective database. A systematic PubMed search was performed to identify articles describing patients with metastatic RCC to the gallbladder. The final cohort included 33 patients: 4 from our institution and 29 from 28 previously published cases. Survival analysis was conducted using log-rank Kaplan-Meier analysis.ResultsMedian patient age was 63 years and the majority of patients were male. Most patients were asymptomatic and diagnosed with gallbladder metastasis on imaging performed for surveillance or staging. The median time to gallbladder metastasis following nephrectomy was 4 years. Metastasis to the gallbladder occurred both synchronously (33%) and metachronously (67%). Of the patients with available histology, all had clear cell RCC (n = 28). Of all patients, 13 (39%) had metastasis only to the gallbladder, while 20 (61%) had additional sites of metastasis. The most common sites of additional metastasis were contralateral kidney (30%), pancreas (21%), lung (18%), adrenal (18%), and lymph nodes (9%). All patients underwent cholecystectomy. At a median follow up time of 1.5 years after cholecystectomy, 54% of patients had no evidence of disease, 14% were alive with metastasis, 23% had died from metastatic RCC, and 9% died from causes unrelated to their cancer.ConclusionGallbladder metastasis from RCC is a rare event that may occur synchronously or metachronously with most patients being asymptomatic. Clear cell carcinoma appears to be the primary pathology associated with gallbladder metastasis. High rates of bilateral RCC and pancreatic metastasis suggest novel associations in patients with RCC and gallbladder metastasis.     

Immunosuppression withdrawal after auxiliary liver transplantation for acute liver failure

BACKGROUND: The potential for immunosuppression withdrawal is the rationale for auxiliary liver transplantation (AUX) in patients with acute liver failure (ALF). PATIENTS AND METHODS: Forty-four AUX were performed in 28 adults and 16 children with ALF secondary to seronegative hepatitis (n = 20; 45%), paracetamol hepatotoxicity (n = 14; 32%), acute viral hepatitis (hepatitis B virus [HBV] n = 3, Epstein-Barr virus n = 1; 9%), drug-induced hepatitis (n = 3; 7%), autoimmune hepatitis (n = 2; 5%), and mushroom poisoning (n = 1; 2%). All patients fulfilled the King's College Hospital transplant criteria for ALF. After partial hepatectomy, 38 patients received a segmental auxiliary graft and six, a whole auxiliary graft. Immunosuppression was based on calcineurin inhibitors and steroids. RESULTS: Thirty-four patients (77%) are alive after a median follow-up of 30 months (range 4 to 124). Eight adults and two children died of sepsis (n = 6; 14%) at a median interval of 30 days (range 2 to 66), intraoperative cardiac failure (n = 1), brain edema on postoperative day 8 (n = 1), sudden death on day 35 (n = 1), and multiple organ failure associated with HBV recurrence 4 years after transplantation (n = 1). Three patients underwent retransplantation for small-for-size graft syndrome with sepsis on postoperative day 15 (n = 1) and for ductopenic rejection 4 and 15 months after AUX (n = 2). In 10/31 (32%) survivors (6/18 adults and 4/13 children) immunosuppression was completely withdrawn after a median of 19 months. CONCLUSION: Complete immunosuppression withdrawal can be achieved in a significant proportion of patients after AUX for ALF.     

Inhibition of tyrosine-kinase-mediated cellular signaling by tyrphostins AG 126 and AG556 modulates murine experimental acute pancreatitis

BACKGROUND: The effects of the tyrosine kinase inhibitors, tyrphostin AG126 and AG556 in a murine model of acute pancreatitis are investigated. METHODS: Intraperitoneal injection of cerulein in mice resulted in a severe, acute pancreatitis, which was characterized by edema, neutrophil infiltration, tissue hemorrhage, and cell necrosis as well as elevation in the serum activities of amylase or lipase. RESULTS: Infiltration of the pancreatic tissue of these animals with neutrophils (measured as increase in myeloperoxidase activity) was associated with signs of enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination showed a marked increase in immunoreactivity for nitrotyrosine and poly (ADP-ribose) polymerase (PARP) in the pancreas of cerulein-treated mice. Pretreatment or posttreatment with tyrphostin AG126 and AG556, 2 different tyrosine kinase inhibitors, significantly reduced the degree of pancreatic inflammation and tissue injury (histologic score). In particular, the treatment with the 2 tyrosine kinase inhibitors reduced the cerulein-induced nitrotyrosine formation and PARP activation in the pancreas as well as the systemic release of tumor necrosis factor alpha. CONCLUSIONS: This study provides the first evidence that (1) prevention of the activation of protein tyrosine kinases reduces the development of acute pancreatitis, and (2) inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of acute pancreatitis.     

Structural and functional analysis of the semitendinosus tendon after harvest for soft tissue reconstructive procedures: a dynamic ultrasonographic study

Purpose

To assess the potential for regeneration of the hamstring tendons after harvesting for various soft tissue reconstructive procedures, this study uses dynamic, high-resolution ultrasound to evaluate the presence of any tissue in the harvest gap and to characterize tissue functionality.

Methods

Patients who underwent ACL reconstruction using ipsilateral hamstring autograft were identified in the database of a single surgeon. Dynamic 12-MHz sonographic imaging was used to evaluate the ipsilateral and contralateral (control) semitendinosus tendons from their insertion sites to proximal muscle bellies. The presence or absence and echogenicity of tissue in the harvest defect, tissue appearance, degree of retraction of the proximal tendon stump, thickness of gap tissue, and motion of the proximal tendon stump were recorded. Data were analysed with Wilcoxon–Mann–Whitney, sign or binomial tests, with significance of P < 0.05.

Results

Eighteen knees in 15 patients (aged 17–51 years) were studied. The proximal amputated stump was retracted an average of 9.0 ± 7.6 cm (range, 0–18 cm; P = 0.0063). With dynamic testing, 9 of 15 knees demonstrated decreased excursion of the proximal tendon stump when compared to the native, contralateral muscle–tendon unit (P = 0.0039). Tissue was detected in the harvest gap in nine knees, five of which had harvest gap tissue with a disorganized appearance compared to the native tendon (P < 0.0001). Six of these nine knees had tissue in the gap demonstrating either less or no excursion with active knee flexion when compared to the native, contralateral side (P = 0.0313).

Conclusions

The presence of tissue in the harvest gap after ACL reconstruction is variable. When tissue is present, there is proximal retraction of the musculotendinous junction and disorganized appearance of the tissue that does not demonstrate normal excursion or physiological function similar to the native muscle-tendon unit.

Level of evidence

Case series, Level IV.     

Role of F-18 FDG PET/CT in assessing bone marrow involvement in pediatric Hodgkin’s lymphoma

Objectives

The aim of the current study was to assess the utility of F-18-fluoro-2-deoxy-d-glucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) in assessing bone marrow involvement (BMI) compared to bone marrow biopsy (BMB) in initial staging of Hodgkin’s lymphoma (HL) in pediatric patients.

Methods

Data of 38 pediatric patients (mean age 9.8 years, range 3–18 years) with HL were analyzed for the involvement of bone marrow. All patients underwent non-contrast F-18 FDG PET/CT study. BMB was done in 31 patients from the bilateral iliac crests. Scans were interpreted by two nuclear medicine physicians blinded to the details of BMB.

Results

Of the 31 patients who underwent BMB, 5 patients had lymphomatous involvement on BMB. PET/CT was positive in four of these five patients. In 26 patients negative on BMB, PET was negative in 23 patients and positive in 3 patients for BMI. The sensitivity and negative predictive value of F-18 FDG PET/CT was 87.5 and 96 %, respectively, for BMI.

Conclusions

F-18 FDG PET/CT can predict BMB results with high accuracy. F-18 FDG PET/CT may be used at initial staging of pediatric Hodgkin’s lymphoma as it uncovers unsuspected BMI and BMB may be omitted in patients with PET-positive BMI.     

Inhibition of Na(+)/H(+) isoform-1 exchange protects hearts perfused after 6-hour cardioplegic cold storage.

OBJECTIVES: Cardiac ischemia-reperfusion activates Na(+)/H(+) exchange; excess Na(+) and the resulting Ca(2+) overload, through reverse Na(+)/Ca(2+) exchange, cause cellular injury and cardiac dysfunction. We postulated that inhibiting the Na(+)/H(+) isoform-1 exchanger would add to the protection of hearts after long-term cold storage in acidic cardioplegic solution. METHODS: Guinea pig hearts were isolated and perfused at 37 degrees C with Krebs-Ringer's solution (KRS) and then switched to an acidic St. Thomas solution (STS) at 25 degrees C. Perfusion was stopped at 10 degrees C, and hearts were stored for 6 hours in STS at 3.4 degrees C. On reperfusion to 25 degrees C, hearts were perfused with KRS for 60 minutes. Hearts were divided into 4 groups: sham control (SHAM); eniporide (EPR, EMD96785) IV, 1 mg/kg given IV over 15 minutes before heart isolation; EPR intracoronary, 1 micromol/liter in STS given intracoronary after heart isolation; and EPR IV and intracoronary. RESULTS: Values at 60 minutes reperfusion (the percentage of control [100%] before cold storage) are given, respectively, for EPR IV, EPR intracoronary, and EPR IV and intracoronary vs drug-free SHAM (SEM, *p < 0.05 vs SHAM): 72% +/- 3%*, 65% +/- 3%*, and 81% +/- 2%* vs 55% +/- 3% for left ventricular pressure; 94% +/- 3%*, 96% +/- 5%*, and 102% +/- 2%* vs 81% +/- 3% for coronary flow; 60% +/- 2%, 58% +/- 3%, and 74%* +/- 3% vs 58% +/- 4% for cardiac efficiency; 106% +/- 2%*, 108% +/- 3%*, and 107% +/- 2%* vs 116% +/- 4% for percentage of O(2) extraction. Infarct size as percentage of ventricular weight was 20% +/- 3%*, 31% +/- 3%, and 6% +/- 2%* vs 35% +/- 3% (SHAM) after 60 minutes of reperfusion. CONCLUSIONS: Na(+)/H(+) isoform-1 exchanger inhibition, particularly if given IV before storage and intracoronary during cooling and rewarming, adds to the protection of cardioplegic solutions.     

Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer

PURPOSE: Hereditary leiomyomatosis and renal cell cancer is a recently described hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and kidney cancer. Our initial experience revealed the aggressive behavior of these renal tumors, often with early metastasis, despite small primary tumor size. We report the clinical characteristics and urological treatment of patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors. MATERIALS AND METHODS: A total of 19 patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors were evaluated. The 11 women and 8 men had a median age at diagnosis of 39 years (range 22 to 67), and a median clinical and radiological followup of 34 months (range 6 to 141). Hereditary leiomyomatosis and renal cell cancer manifestations in patients with renal tumors included cutaneous leiomyomas in 11 of 17 evaluable patients (65%) and uterine leiomyomas in 7 of 7 evaluable females (100%). RESULTS: Median pathological tumor size was 7.8 cm (range 1.5 to 20). Histological subtypes were consistent with hereditary leiomyomatosis and renal cell cancer renal carcinoma. Four of 7 patients with 2.0 to 6.7 cm T1 tumors had spread to regional lymph nodes or metastases at nephrectomy. Overall 9 of 19 patients (47%) presented with nodal or distant metastases. CONCLUSIONS: Renal tumors in patients with hereditary leiomyomatosis and renal cell cancer syndrome are significantly more aggressive than those in patients with other hereditary renal tumor syndromes. In contrast to other familial renal cancer syndromes, the observation of 3 cm or less renal tumors associated with hereditary leiomyomatosis and renal cell cancer is not recommended. Careful followup of affected and at risk individuals in families is necessary.     

Bariatric Surgery in Patients with Cirrhosis and Portal Hypertension

Introduction

Studies on bariatric patients with cirrhosis and portal hypertension are limited. The aim of this study was to review our experience in cirrhotic patients with portal hypertension who had bariatric surgery.

Method

All cirrhotic patients with portal hypertension who underwent laparoscopic bariatric surgery, from 2007 to 2017, were retrospectively reviewed.

Results

Thirteen patients were included; eight (62%) were female. The median age was 54 years (interquartile range, IQR 49–60) and median BMI was 48 kg/m² (IQR 43–55). Portal hypertension was diagnosed based on endoscopy (n?=?5), imaging studies (n?=?3), intraoperative increased collateral circulation (n?=?2), and endoscopy and imaging studies (n?=?3). The bariatric procedures included sleeve gastrectomy (n?=?10, 77%) and Roux-en-Y gastric bypass (n?=?3, 23%). The median length of hospital stay was 3 days (IQR 2–4). Three 30-day complications occurred including wound infection (n?=?1), intra-abdominal hematoma (n?=?1), and subcutaneous hematoma (n?=?1). No intraoperative or 30-day mortalities. There were 11 patients (85%) at 1-year follow-up and 9 patients (69%) at 2-year follow-up. At 2 years, the median percentage of excess weight loss (EWL) and total weight loss (TWL) were 49 and 25%, respectively. There was significant improvement in diabetes (100%), dyslipidemia (100%), and hypertension (50%) at 2 years after surgery.

Conclusion

Bariatric surgery in selected cirrhotic patients with portal hypertension is relatively safe and effective.