Clearance of Hepatitis C Virus Prior to Lung Transplantation: A Case Report.

Hepatitis C virus (HCV) continues to be considered a relative contraindication to lung transplantation due to concerns of progression of liver disease with the introduction of immunosuppression. Since the recent introduction of effective antiviral therapy for HCV, new approaches in the management of the HCV-positive recipient are being utilized in liver transplantation to clear HCV pre- and post-transplant. Herein, we report use of ledipasvir/sofosbuvir for HCV clearance prior to lung transplantation in a patient with usual interstitial pneumonia. Listing for transplant was delayed until completion of HCV treatment, and he subsequently required extracorporeal membrane oxygenation as a bridge to transplantation due to progressive hypoxia. With antiviral cure rates exceeding 90%, HCV should no longer be considered a relative contraindication to lung transplant, and timing of antiviral treatment should consider the progressive nature of the recipient's lung disease.

Central mucoepidermoid carcinoma in a previously enucleated radiolucent lesion in the mandible. A case report.

Central muco epidermoid carcinomas (CMC) are rare tumours, representing about 2 to 3% of all mucoepidermoid carcinomas. Usually affecting the mandible, they appear as uni- or multilocular radiolucent lesions. We report a case of CMC in a 52-year-old Middle Eastern woman who presented with pain, limitation of jaw movement and tingling sensation of the tongue, related to a radiolucent lesion in the angle of the mandible. The lesion was first detected but not diagnosed in another hospital three years earlier. We describe the progression of the lesion over the past three years and describe the clinical, radiographic, histopathological, and surgical aspects of the case.

Flap design and mandibular third molar surgery: a split mouth randomized clinical study.

The aim of this study was to investigate the effects of two commonly used flap designs (envelope and triangular) used for the removal of mandibular third molars (M3) on postoperative morbidity. 19 patients with bilateral symmetrically impacted mandibular M3 were studied using a split mouth design. Swelling, pain and trismus measures were recorded on days 2, 7 and 14; periodontal indices were recorded on days 7 and 14, one final measure of probing depth on the distal aspect of the mandibular second molar (M2) was taken at the last follow up appointment. Data were analysed using the χ(2) test, the Mann-Whitney U-test and Pearson's correlations. The mean age of the patients was 21.4 ± 2.3 years (± SD). Facial swelling and the reduction in mouth opening were significantly greater in the early postoperative period (P<0.05) with pyramidal flap designs. There was no significant difference in pain scores, plaque accumulation and bleeding on probing indices between the two flap designs (P>0.05). Probing depth was significantly greater with envelope flaps in the early postoperative period (P<0.005). In conclusion, flap design in mandibular M3 surgery has an effect on postoperative recovery.

The effect of recipient hepatitis C virus infection on outcomes following heart transplantation.

BACKGROUND: Insufficient data exist on the clinical course of hepatitis C virus (HCV) infection in heart transplant (HT) recipients. Our study reports the outcomes of heart transplantation in pretransplantation HCV-positive (HCV+) recipients. METHODS: A retrospective analysis of the heart transplantation database at our institution was performed to identify HT recipients who were HCV+ prior to transplantation. Chart reviews yielded demographic features, liver function tests, graft function, incidence of posttransplantation acute hepatitis and transplant coronary artery disease, and patient survival data. RESULTS: Between 1995 and 2006, 10 HCV+ patients underwent cardiac transplantation. The recipient mean age was 47 years (range, 23-69). Seven recipients were males and 3 were females. At listing 9 patients had no cirrhosis. One patient with Child-B cirrhosis was listed for combined heart-liver transplantation. Two of 10 donors were known to be HCV carriers. Posttransplantation in-hospital survival rate was 100%. At a mean follow-up of 58 months (range, 1.6-145), 3 deaths occurred, yielding an overall survival rate of 70%. Only 1 death (10%) was linked to accelerated acute hepatitis. Transplant coronary artery disease was detected in 2 patients (20%). Echocardiograms of survivors at last follow-up revealed normal ejection fractions. In addition, there were no cases of hepatocellular carcinoma; all survivors were without evidence of hepatic dysfunction. CONCLUSIONS: Transplanting recipients known to have HCV did not seem to affect overall posttransplantation survival or to increase the risk of liver dysfunction or graft-related complications.

Addition of matrix metalloproteinase inhibition to conventional cytotoxic therapy reduces tumor implantation and prolongs survival in a murine model of human pancreatic cancer.

Matrix metalloproteinases (MMPs) participate in basement membrane degradation, a critical step in invasion of cancer cells. We have previously shown that MMP inhibition of pancreatic cancers improves survival and decreases MMP production in vivo. The purpose of this study was to determine whether BB-94 was better than cytotoxic therapy and would increase the efficacy of cytotoxic therapy (gemcitabine) in a murine model of human pancreatic cancer. A human pancreatic adenocarcinoma cell line (HPAC) was injected into the pancreata of BALB/c nu/nu mice. The mice were randomized 7 days after cancer cell injection to receive vehicle control, BB-94, gemcitabine, or gemcitabine and BB-94 until death or sacrifice at 84 days. At necropsy, tumors were harvested, and the relative enzyme activities of MMP-2 and MMP-9 were determined by gelatin zymography. Active MMP-2 levels in serum were determined using an ELISA technique. Combination treatment with gemcitabine and BB-94 significantly reduced implantation rates and improved survival in mice with documented orthotopic tumors compared with either therapy alone or control. Tumor levels of active and latent MMP-2 were higher than those of MMP-9 in both treated and control mice. There was a significant reduction of tumor MMP-2 activity in mice treated with BB-94, gemcitabine, or gemcitabine and BB-94. Serum levels of active MMP-2 were reduced in all treated groups, with the greatest reduction occurring in mice treated with gemcitabine and BB-94. Combination therapy with gemcitabine and BB-94 reduces cancer implantation and improves survival compared to treatment with BB-94, gemcitabine, or vehicle control alone. MMP production was reduced in all treated groups, reflecting reduced tumor progression, which was particularly seen with combination therapy with gemcitabine and BB-94. This study supports combining MMP inhibition with cytotoxic therapy (gemcitabine) for patients with pancreatic cancer.

Matrix metalloproteinase inhibition improves survival in an orthotopic model of human pancreatic cancer.

Matrix metalloproteinases (MMPs) have been implicated in the growth and invasiveness of primary and metastatic tumors. Hypothesizing that MMP inhibition would slow cancer growth, the MMP inhibitor BB-94 (batimistat) was evaluated in an orthotopic animal model of human pancreatic carcinoma. Ten million human pancreatic cancer cells were surgically implanted into the pancreata of 30 athymic nu/nu mice. Intraperitoneal administration of 30 mg/kg BB-94 or vehicle control began 7 days after tumor implantation (13 mice with confirmed implantations in each group) and continued daily for 21 days, and then three times weekly until death or sacrifice at day 70. Representative tumors harvested from mice in each group were analyzed for presence and activity of MMP-2 and MMP-9. Animal weights were significantly higher in the BB-94-treated group at sacrifice (mean 58.4 +/- 7.9 g vs. 39.8 +/- 6.2 g; P < 0.05, Student's t test). The likelihood of survival to 70 days was significantly higher in the treated group (4 of 13 vs. 0 of 13, P < 0.05, Z-test for end points) than in the control group as was overall survival (P = 0.03, Wilcoxon test). Nine mice in the control group developed metastases to the liver, peritoneum, abdominal wall, or local lymph nodes, whereas only two mice in the BB-94 group had evidence of metastatic disease (P < 0.02, Fisher's exact test), in both instances confined to the abdominal wall. Tumors from treated mice manifested lower MMP activity than those from control animals. These reports support the use of MMP inhibitors alone or as an adjunct in the treatment of pancreatic cancer.

Matrix metalloproteinase inhibition suppresses MMP-2 activity and activation of PANC-1 cells in vitro.

BACKGROUND: We have shown previously that the metalloproteinase inhibitor, BB-94, prolongs survival and attenuates MMP-2 activity in a murine model of pancreatic cancer. The purpose of this study was to determine the effect of BB-94 on the activity and activation of MMP-2 by PANC-1 cells in vitro. MATERIALS AND METHODS: The poorly differentiated pancreatic cancer cell line PANC-1 was stimulated in vitro with the phorbol ester PMA (20 nM) and grown in the presence of increasing doses of BB-94 (0, 40, 200, and 400 ng/ml) for 24 h. Activation of MMP-2 was determined by gel zymography. In a separate experiment detailing the effects of BB-94 on MMP-2 activity, PANC cells were stimulated for 24 h with PMA and run out on four separate zymograms, each incubated in the previously noted concentrations of BB-94. Using densitometry, band intensity on all gels was determined and compared for each concentration of BB-94. The Matrigel assay was used to determine BB-94's effect on the invasive potential of PANC cells at the previously studied concentrations. The presence of MT-MMP (a putative component of MMP-2 activation) was confirmed using Western blot in each group. RESULTS: BB-94 inhibited the conversion of latent to active MMP-2 in a dose-dependent fashion. BB-94 also inhibited the activity of MMP-2 when run out on gel zymograms incubated with increasing concentrations of BB-94. Decreased activity and activation of MMP-2 by BB-94 were manifested by a significant reduction in the invasive potential of PANC as determined by the Matrigel assay. MT-MMP was universally present in each study group. CONCLUSIONS: The previously described salutary effects of MMP blockade in mice implanted with pancreatic cancer can be explained in vitro by a dose-dependent diminution of MMP-2 activity and activation in PANC cells exposed to BB-94.

Induction of tolerance to hemorrhagic or endotoxic shock involves activation of NF-kappaB.

BACKGROUND: Tolerance to hemorrhagic or endotoxic shock can be induced by prior sublethal hemorrhage (SLH). The purpose of this study was to explore whether alterations in signal transduction pathways involving NF-kappaB occur in macrophages (Mphi) following induction of tolerance by SLH. METHODS: Using a model of SLH previously shown in our lab to impart a survival benefit to subsequent hemorrhagic or endotoxic shock, rats (n = 30) were conditioned by SLH. Peritoneal Mphi were harvested 24 h after conditioning and stimulated with lipopolysaccharide (LPS) (10 microg/mL). Nuclear and cytosolic proteins were isolated 1 h later for determination of NF-kappaB activation by gel-shift assay and IkappaB-alpha by Western blot. TNF mRNA gene expression was measured 4 h after LPS stimulation by reverse transcription/polymerase chain reaction (RT/PCR). TNF protein levels were measured in cellular supernatants by enzyme-linked immunosorbent assay (ELISA) 18 h after LPS. RESULTS. LPS stimulation of sham Mphi increased NF-kappaB activation with corresponding loss of its inhibitor IkappaB-alpha. In contrast, IkappaB-alpha was not detectable following conditioning, and conditioned Mphi had NF-kappaB activation at baseline which increased minimally with LPS stimulation. LPS increased TNF gene expression and significantly increased protein production by both sham and conditioned Mphi, but this increase was greater in the sham-conditioned group. CONCLUSIONS: The ability of Mphi from animals made tolerant by SLH to produce TNF in vitro is conserved. Nevertheless, these same Mphi exhibit alterations in TNF gene induction and expression as well as signal transduction, specifically, changes in IkappaB-alpha and NF-kappaB activation. This suggests a role for activation of NF-kappaB in the induction of tolerance.

Matrix metalloproteinase (MMP) inhibition selectively decreases type II MMP activity in a murine model of pancreatic cancer.

BACKGROUND: Basement membrane degradation is a critical component of tumor invasion and metastasis that is facilitated by the family of enzymes known as matrix metalloproteinases (MMPs). MMP-2 and MMP-9 are two subtypes that have specifically been identified in tumors of gastrointestinal origin. We have previously shown that broad inhibition of these enzymes with the MMP inhibitor BB-94 improves survival in a murine model of pancreatic cancer. The purpose of this study was to determine MMP-2 and MMP-9 activity in orthotopic tumors from mice treated with and without BB-94. METHODS: Ten million cells of a moderately differentiated pancreatic cancer cell line (HPAC) were implanted orthotopically into Balb/c nu/nu mice. The mice were treated with BB-94 or vehicle control for 70 days or until death. At necropsy, tumors were harvested, total protein was extracted, and MMPs were purified from 400 microgram of crude protein extract by gelatin-Sepharose affinity chromatography. Relative enzyme levels and activity of MMP-2 and MMP-9 were determined by Western blot and gelatin zymography. RESULTS: Tumors from treated animals were significantly smaller than those from nontreated animals. MMP-2 was present in greater amounts in both treated and nontreated animals than MMP-9. Active MMP-2 was present in both groups but significantly decreased in animals treated with BB-94. Active MMP-9 was absent in both groups, whereas levels of latent MMP-9 appeared lower than those of MMP-2 in all samples. CONCLUSIONS: Activated MMP-2 and not MMP-9 in HPAC cells grown in nude mice suggests that this MMP subtype is more critical in the phenotypic behavior of such tumors. Furthermore, attenuated levels of active MMP-2 in animals treated with the enzyme inhibitor BB-94 suggest that previously observed improvements in survival correlate with the level of MMP-2 activity.

Absorption, enterohepatic circulation, and excretion of 5-aminosalicylic acid in rats.

After oral administration of sulfasalazine, the majority of the administered dose reaches the colon, where it is split into 5-aminosalicylic acid (5-ASA) and sulfapyridine. 5-ASA is believed to be the effective component in the treatment of inflammatory bowel disease. After intraduodenal administration of 5-ASA (20 mg) in rats, 91% of the drug was absorbed in the proximal small intestine. Peak serum 5-ASA concentration (55 micrograms/ml) was reached in 1 h. Approximately 61 and 6% of the administered dose were excreted in the urine and bile, respectively, in 24 h, almost exclusively in the acetylated form. When sulfapyridine (20 mg) was administered in addition to 5-ASA, 70% of the sulfapyridine was absorbed in the small intestine, peak serum concentration (50 micrograms/ml) was reached in 1 h, and 30% of the administered dose was excreted in the urine in 24 h. The results indicate that after oral administration of 5-ASA, a therapeutically significant concentration of the drug is not expected in the terminal ileum which is a common site of involvement in Crohn's disease. The therapeutic implications of these findings are discussed herein.

An antibody against revertant forms of cell-wall deficient bacterial variant in sera from patients with Crohn's disease.

Sera from patients with Crohn's disease or ulcerative colitis, and from controls were examined by indirect immunofluorescence for antibody against two strains of pseudomonas-like cell-wall-defective bacterial variants. Serum samples from 22 of 25 patients with Crohn's disease produced fluorescence of both revertant cell-wall-defective bacterial strains. Intensity of fluorescence correlated positively with the degree of disease activity. Sera from 23 patients with ulcerative colitis and from 15 control subjects did not produce any significant staining of either of the two revertant cell-wall-defective bacterial strains. Absorption of sera with Escherichia coli, Bacteroides thetaiotaomicron, and Pseudomonas aeruginosa did not alter the intensity of fluorescence in patients with Crohn's disease, whereas similar absorption of sera from patients with ulcerative colitis and controls abolished the slight staining of cell-wall-defective strains produced by 29% of unabsorbed serum samples.

An unusual form of measles meningoencephalitis. A report of two cases.

Two patients are reported with a chronic progressive illness characterized by dementia, ataxia and spasticity. There were no myoclonic jerks and both had normal electroencephalograms (EEG). Pathological findings in three brain biopsies were those of viral meningoencephalitis with perivenous demyelination. Serological data in both patients indicated the presence of measles virus infection. Intracytoplasmic structures resembling measles virus nucleocapsids were found in the brain biopsy of one patient. Immunofluorescent staining showed antibody in the temporal lobe biopsy of both patients. It is suggested that these patients are examples of a chronic form of measles meningoencephalitis hitherto undescribed.

Subacute sclerosing panencephalitis. Immunological findings in saliva and salivary glands.

Antimeasles antibody was detected in the saliva of 14 patients with subacute sclerosing panencephalitis. Immunofluorescent staining showed antibody in salvary gland biopsy of 7 patients.