How Much Are Upper or Lower Extremity Disabilities Associated with General Health Status in the Elderly?

Background  

Musculoskeletal complaints influence general health status, but the relative contribution of concurrent upper and lower extremity disabilities on patient perceptions of general health is unclear.     

Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats,Dogs, and Humans

Enterohepatic recirculation (EHC) can greatly enhance plasma drug exposures and therapeutic effects. This study aimed to develop a population pharmacokinetic model that can simultaneously characterize the extent and time-course of EHC in three species using fimasartan, a novel angiotensin II receptor blocker, as a model drug. All fimasartan plasma concentration profiles in 32 rats (intravenous doses, 0.3–3 mg/kg; oral doses, 1–10 mg/kg), 34 dogs (intravenous doses, 0.3–1 mg/kg; oral doses, 1–10 mg/kg), and 42 healthy volunteers (single or multiple oral doses, 20–480 mg) were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and simultaneously modeled in S-ADAPT. The proposed model quantitatively characterized EHC in three species after oral and intravenous dosing. The median (range) fraction of drug undergoing recirculation was 76.3% (64.9–88.7%) in rats, 33.3% (24.0–45.9%) in dogs, and 65.6% (56.5–72.0%) in humans. In the presence compared with the absence of EHC, the area under the curve in plasma was predicted to be 4.22-fold (2.85–8.85) as high in rats, 1.50-fold (1.32–1.85) in dogs, and 2.91-fold (2.30–3.57) in humans. The modeled oral bioavailability in rats (median (range), 38.7% (20.0–59.8%)) and dogs (median, 7.13% to 15.4%, depending on the formulation) matched the non-compartmental estimates well. In humans, the predicted oral bioavailability was 25.1% (15.1–43.9%) under fasting and 18.2% (12.2–31.0%) under fed conditions. The allometrically scaled area under the curve predicted from rats was 420 ng ⋅ h/mL for 60 mg fimasartan compared with 424 ± 63 ng ⋅ h/mL observed in humans. The developed population pharmacokinetic model can be utilized to characterize the impact of EHC on plasma drug exposure in animals and humans.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9764-2) contains supplementary material, which is available to authorized users.KEY WORDS: animal to human scaling, enterohepatic recirculation, fimasartan, population pharmacokinetics, S-ADAPT     

Inpatient Stroke Rehabilitation Outcomes in Korea Derived from the Korean Brain Rehabilitation Centers' Online Database System for the Years 2007 to 2011

The purpose of this report was to provide information for patients receiving inpatient rehabilitation after stroke and to identify the possible factors influencing functional outcome after inpatient rehabilitation. Stroke patients (n = 5,212) who were discharged from the Departments of Rehabilitation Medicine (RM) of university hospitals and rehabilitation hospitals from 2007 through 2011 were participants. Prevalence, age, transfer time after onset, length of stay (LOS), functional status at admission and discharge were analyzed. In all stroke subjects, cerebral infarctions (67%) were more common than hemorrhages. Cerebral infarctions in the middle cerebral artery territory were most common, while the basal ganglia and cerebral cortex were the most common areas for hemorrhagic stroke. The LOS decreased from 45 to 28 days. Transfer time after onset decreased from 44 to 30 days. Shorter transfer time after onset was correlated with better discharge functional status and shorter LOS. Initial functional status was correlated with discharge functional status. In ischemic stroke subtypes, cerebellar and brainstem strokes predicted better outcomes, while strokes with more than one territory predicted poorer outcomes with more disabilities. In hemorrhagic stroke subtypes, initial and discharge functional status was the lowest for cortical hemorrhages and highest for brainstem hemorrhages. This report shows that LOS and transfer time after onset has been decreased over time and initial functional status and shorter transfer after onset are predictors of better functional outcome at discharge.     

Outcome of Orthotopic Liver Transplantation in Patients with Hepatitis C

Recurrence of chronic hepatitis C (HCV) after orthotopic liver transplantation (OLT) is universal. The published studies suggest that the short-term outcome is good in these patients, but the long-term prognosis remains unclear. The purpose of this study was to evaluate the outcome of patients with HCV undergoing OLT in a single center and to analyze the risk factors associated with poor outcome. In this retrospective study, we evaluated the outcome of 58 OLT patients with proven HCV who underwent OLT between February 1990 and April 1997 at our institution. The median follow-up time was 36.9 months. Recurrent posttransplant HCV hepatitis was confirmed by liver biochemistry, histology, and persistent HCV RNA in the serum. The patient and graft survival of patients with HCV was compared to that of 42 primary biliary cirrhosis (PBC) and 41 primary sclerosing cholangitis (PSC) patients transplanted during the same period. Following OLT, biochemical evidence of recurrent HCV hepatitis was absent in 46%. Forty percent of patients had recurrent HCV hepatitis and 14% had clinical evidence of recurrent HCV. Thirty-one patients were on cyclosporine, 22 patients on tacrolimus, and 5 patients had cyclosporine switched to tacrolimus or vice versa. The recurrence rate of HCV chronic hepatitis was similar in patients who had cyclosporine (35.5%) or tacrolimus (45.5%) based immunosuppression. Eleven patients (19%) died and five patients (8.6%) were retransplanted for chronic rejection (two), mismatch (one), or primary graft nonfunction (two). The cumulative patient survival rates of one, three, and five years were 94.8%, 84.1%, and 62.2%, respectively. The severity of liver disease progressed with time; 8% of patients developed cirrhosis within two years. The survival rate did not show any relation between HCV recurrence and the type of immunosuppression. In conclusion, although the survival of patients with HCV was not statistically significant compared to those with PBC or PSC, there was a trend towards a lower five-year survival in HCV.     

Bone scintigraphy of skeletal metastasis in hepatoma patients treated by TAE

BACKGROUND/AIMS: Skeletal metastasis in hepatocellular carcinoma patients has become clinically important as a result of advances in treatment modalities. However, the diagnostic accuracy of bone scintigraphy in hepatocellular carcinoma has been questioned. METHODOLOGY: 99mTc-MDP bone scintigraphy was performed in 63 unresectable hepatocellular carcinoma patients treated by transcatheter arterial embolization who either developed musculoskeletal pain (n = 43) or elevated serum alpha-fetoprotein levels (n = 20) during follow-up. Results were categorized as positive or negative for metastases, and their accuracy was evaluated by radiological studies, biopsy, and clinical follow-up. RESULTS: Bone scintigraphy was positive in 22/43 (51.2%) subjects with pain and 2/20 with alpha-feto-protein elevation. Among 24 bone scintigraphy(+) patients, metastasis was confirmed in 17 and excluded in 6. Frequent sites for metastatic bone scintigraphy lesions were the spine, pelvic bone and ribs. Although 8 metastatic lesions had low or mixed uptake, most had increased uptake on bone scintigraphy. Among 39 bone scintigraphy(-) patients, metastasis was excluded in 32 and confirmed in 1. The sensitivity and specificity of bone scintigraphy in this subset of patients was 94.4% and 84.2%, respectively. CONCLUSIONS: Transcatheter arterial embolization treated hepatocellular carcinoma patients with musculoskeletal pain have a high likelihood of bone metastasis, and bone scintigraphy is a highly reliable method for its detection.     

Clinical significance of intrahepatic biliary stricture in efficacy of hepatic resection for intrahepatic stones

In the Far East, hepatic resection is the definitive treatment for complicated intrahepatic stones (IHS). However, many investigators have reported that the associated intrahepatic biliary stricture is the main cause of treatment failure. A retrospective comparative study was undertaken to clarify the long-term efficacy of hepatic resection for treatment of IHS and to investigate the clinical significance of intrahepatic biliary stricture in treatment failure after hepatic resection performed in 44 patients with symptomatic IHS. The patients were divided into two study groups: group A, with intrahepatic biliary stricture (n = 28) and group B, without stricture (n = 16). Residual or recurrent stones, recurrence of intrahepatic biliary stricture, late cholangitis, and final outcomes were analyzed and compared statistically between the two groups. The patients were followed up for a median duration of 65 months after hepatectomy. The overall incidence of residual or recurrent stones was 36% and 11%, respectively, in groups A and B. The initial treatment failure rate was 50% in group A and 31% in group B. Intrahepatic biliary stricture recurred in 46% of patients in group A, while none of the group B patients had biliary stricture recurrence (P = 0.001). More than two-thirds of the restrictures in group A were identified at the primary site. The incidence of late cholangitis was higher in group A (54%) than in group B (6%) (P = 0.002). Three-quarters of the patients with cholangitis in group A had severe cholangitis, that was recurrent, and related to stones and strictures (n = 11). They and 2 asymptomatic patients in group B required secondary procedures done at a median of 12 months after hepatectomy. Final outcomes after hepatectomy with or without secondary management were good in 80%, fair in 16%, and poor in 4% of our 44 patients. Most recurrent cholangitis after hepatectomy in patients with IHS was related to recurrent intrahepatic ductal strictures. Therefore, to be effective, hepatic resection should include the strictured duct. However, with hepatectomy alone it is difficult to clear the IHS or relieve the ductal strictures completely, particularly in patients with bilateral IHS, so perioperative team approaches that include both radiologic and cholangioscopic interventions should be combined for the effective management of IHS.     

Expression of cyclooxygenase-2 in cholangiocarcinoma: correlation with clinicopathological features and prognosis

BACKGROUND AND AIMS: No information is available on the nature of the correlation between cyclooxygenase-2 (COX-2) expression and the clinicopathological features and prognosis of cholangiocarcinoma (CC). The goal of the present study was to determine the possible roles and clinical significance of COX-2 expression in CC. METHODS: We investigated the immunohistochemical expression of COX-2 in 102 patients with CC with respect to clinicopathological characteristics, namely evidence of Clonorchis sinensis infection, proliferation index (PI, assessed by Ki-67 expression), apoptotic index (AI, assessed by TUNEL stain), and microvessel density (MVD, assessed by CD34 expression). Evidence of C. sinensis infection was assessed by the microscopic examination of stools for C. sinensis ova, serological testing (ELISA), and the detection of peripheral bile duct dilations by imaging studies. RESULTS: An immunohistochemical investigation demonstrated the immunolabeling of tumor cells, mainly in the cytoplasmic and perinuclear regions, in 53 (52%) of the 102 patients with CC. No significant differences were found in terms of age, sex, tumor differentiation, involvement of the resection margin, presence of lymph nodes or liver metastases, or in pTNM stage between COX-2 positive and COX-2 negative patients. However, evidence of C. sinensis infection was more common in COX-2 positive patients (P < 0.05). No significant differences were found for PI, AI, MVD, or cumulative survival between COX-2 positive and COX-2 negative patients. CONCLUSION: Clonorchis sinensis infection is related to aberrant COX-2 expression in patients with CC. However, COX-2 expression is not related to clinical outcome in CC patients.     

Nitrite-Induced Cross-Linking Alters Remodeling and Mechanical Properties of Collagenous Engineered Tissues

Cumulative damage to long-lived connective tissue proteins play a key role in the development of age-related human diseases such as cardiovascular stiffening and age-related macular degeneration. The processes that result in the accumulation of increasingly insoluble, undigestible damaged collagen are only partially known. Nonenzymatic glycation (NEG) is one such process and has been linked to the development of diabetic-related complications and aging. An additional novel mechanism particularly relevant to smoking- and inflammation-related diseases involves the nonenzymatic nitrite (NEN) modification of connective tissue proteins. The present study was undertaken to examine the effects of NEN of fibrillar type I collagen on cell-mediated remodeling and mechanical properties of collagenous tissues. Using a modification of an in vitro fibroblast-populated collagen gel model system developed in our laboratory, we tested two hypotheses: NEN reduces the ability of primary adult cardiac fibroblasts to remodel type I collagen gels; NEN reduces the deformability of type I collagen gels subjected to mechanical testing. The results show that NEN impairs both cell-mediated remodeling and mechanical deformability in collagenous engineered tissues. Furthermore, these mechanical changes correlate with the degree of cross-linking as determined by SDS-PAGE. Thus, we concluded that NEN reactions may contribute to alterations in the biomechanical properties of collagen-containing tissues consistent with the age-related functional decline observed in human disease.