Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.Essential tremor is one of the most frequent movement disorders in humans (1). It is characterized primarily by postural or kinetic tremor of the arms and hands, but head, legs, voice, and other regions of the body may also be affected (2). The worldwide prevalence is 0.9%, increasing to more than 4% in elderly populations (1). Familial essential tremor is genetically heterogeneous. Genetic linkage studies of multiply affected families revealed three genomic regions segregating with the condition, on chromosomes 3q13 [ETM1; Online Mendelian Inheritance in Man (OMIM) 190300], 2p22-24 (ETM2; OMIM 602134), and 6p23 (ETM3; OMIM 611456) (3–5). No clearly causal mutations have been identified in these regions, although the common variant DRD3 p.S9G in the ETM1 region has been proposed as a risk factor and HS1BP3 p.A265G in the ETM2 region appeared in two multiply affected families (6, 7). Genomewide association studies of essential tremor reported associations with common variants in an intron of LINGO1 and in an intron of SLC1A2 (8–10). Recently, DNAJC13 p.N855S, which had been identified in Parkinson disease patients, was also found in two unrelated patients with essential tremor (11). Nonsense mutation p.Q290X in the RNA-binding protein FUS was identified by whole exome sequencing in a large family with essential tremor (ETM4; OMIM 614782) (12). Screening other subjects with essential tremor for FUS revealed two rare missense variants, suggesting that mutations in FUS explain a subset of cases with the condition (13, 14).In this study, we examined a six-generation family segregating essential tremor, and in multiple relatives, essential tremor as a feature of Parkinson disease. We carried out whole exome sequencing of genomic DNA from three severely affected family members and subsequent pedigree analysis to identify the genetic basis of essential tremor and Parkinson disease in the family.     

Flexural properties of rectangular nickel-titanium orthodontic wires when used as ribbon archwires

Objective:To compare the flexural properties of rectangular nickel-titanium (Ni-Ti) orthodontic wires in occlusoapical and faciolingual orientations using a standardized test method.Materials and Methods:Twenty-two rectangular Ni-Ti wire groups were tested in occlusoapical (ribbon) orientation: eight conventional Ni-Ti products, five superelastic Ni-Ti products, and nine thermal Ni-Ti products (n = 10 per group). Six products of thermal Ni-Ti wire were tested in faciolingual (edgewise) orientation. A three-point bending test was performed to measure deactivation force at 3.0-, 2.0-, 1.0-, and 0.5-mm deflections of each rectangular wire at 37.0 ± 0.5°C. Analysis of variance and post hoc Student-Newman-Keuls tests were used to compare the mean values of the different groups (α = .05).Results:The ranges of deactivation forces varied greatly with different kinds, sizes, products, and deflections of Ni-Ti wires. One product of conventional and superelastic Ni-Ti wires had steeper force-deflection curves. Four products had similarly shaped flat force-deflection curves, whereas the sixth product had a moderately steep force-deflection curve. Thermal Ni-Ti wires had smaller deactivation forces ranging from 0.773 N (78.8 g) to 2.475 N (252.4 g) between deflections of 1.0 and 0.5 mm, whereas wider ranges of force from 3.371 N (343.7 g) to 9.343 N (952.7 g) were predominantly found among conventional Ni-Ti wires between deflections of 3.0 and 2.0 mm.Conclusions:Clinicians should critically select archwires for use in the occlusoapical orientation not only based on Ni-Ti wire type, size (0.022 × 0.016-in or 0.025 × 0.017-in), and product but also with deactivation deflections from 0.5 and 1.0 mm to obtain light forces in the occlusoapical orientation.     

Evaluation of the Relation Between Hepatic Fibrosis and Basic Laboratory Parameters in Patients With Chronic Hepatitis B Fibrosis and Basic Laboratory Parameters

Background:

The hepatitis B virus is an important healthcare problem. According to current clinical practice, a liver biopsy is required for the diagnosis and treatment of chronic liver disease. However, a liver biopsy is an invasive, inconvenient procedure, which requires an expert pathologist opinion. Therefore requirement of biochemical tests, which are considered to indicate hepatic fibrosis and may be repeated easily, increases gradually today.

Objectives:

This study evaluated the correlation between hepatic fibrosis and routine laboratory values in patients with chronic hepatitis B.

Patients and Methods:

The files of 456 patients with CHB (chronic hepatitis B) who were referred to the infectious diseases and clinical microbiology clinic between January 2009 and March 2012 were screened retrospectively. Liver biopsy samples were examined according to Ishak scoring. Laboratory parameters and histopathology reports were recorded, and correlations between the fibrosis grade and laboratory parameters were analyzed.

Results:

There were 320 male and 136 female patients, with a mean age 36.7 ± 12.1 years. According to liver biopsy results, a low fibrosis score (stage 0-2) was detected in 281 patients (61.6%), and a high fibrosis score (stage 3-5) was detected in 175 patients (38.4%). Patients with a high fibrosis score had significantly higher ALT (alanine amino transferase), AST (aspartate aminotransferase), and HBV-DNA values and a significantly lower platelet count compared with those with a low fibrosis score (P = 0.001, 0.001, 0.025, and 0.001, respectively). A positive correlation was detected between the fibrosis score and age, BMI, HAI, ALT, and AST values, and a negative correlation was detected between the fibrosis score and albumin and platelet counts. In the regression analysis performed to evaluate the factors associated with high-stage fibrosis, fibrosis was determined to be associated with thrombosis, ALT, and gender. The results of the regression analysis demonstrated that the risk of fibrosis was 4.6 fold higher in men.

Conclusions:

According to the results obtained in our study, advanced age, higher BMI, AST, ALT, and HBV-DNA levels, and low albumin and platelet levels are correlated with advanced fibrosis in patients with CHB.     

Hospital acquired infections (HAI) in the elderly: comparison with the younger patients

The aim of this retrospective study is to determine the frequency, type, microbiological characteristics and outcome of HAIs in the elderly (age ≥ 65) and to compare the data with younger patients in a Turkish Training and Research Hospital. From January 2008 to December 2009, the infection control team analyzed HAIs among 60,585 hospitalized patients (20,109 aged ≥ 65 and 40,747 aged between 18 and 64 years) with a total number of 419,017 patient days. A total of 825 HAIs episodes were detected in 607 patients, of which 395 episodes were in 301 elderly patients. The incidence of HAIs per 1000 patient days was 2.49 in the elderly and 1.64 in the younger patients’ group (p < 0.001). The most common site of infection in the elderly patients was the urinary tract, whereas in non-elderly group this was the lower respiratory tract. The incidence density of urinary tract infections, respiratory tract infections, surgical site, skin and soft tissue infections, primary bacteremia, and prosthesis infections were significantly higher in the elderly group (p < 0.05). Gram-negative species were the most frequently isolated agents in both groups. There were no significant differences between the groups in the frequency of isolated pathogens or antibiotic susceptibility patterns. Overall, the fatality rate was found 16.8%. The elderly patients were more likely to have crude mortality rates (22% vs. 12%; p < 0.01). The death was most often related to pneumonia, primary bacteremia or intravascular catheter infections in both groups.     

Two-suture fish-mouth end-to-side microvascular anastomosis with fibrin glue

The most decisive step during free tissue transfers and replantation surgery may be respected as microvascular anastomosis. The conventional end-to-side anastomosis technique with simple interrupted sutures is well established and proven to be successful. On the other hand, conventional technique can be time consuming and can cause vascular thrombosis, vessel narrowing, and foreign-body reactions. Search for a more rapid and secure alternative to conventional technique is carried on. In this study, we defined a new technique for end-to-side anastomosis with fish-mouth incisions and application of fibrin glue and compared our results with those we obtained with conventional end-to-side anastomosis. We evaluated end-to-side anastomosis of carotid arteries of a total number of 64 Wistar-Albino rats. In control group (n = 32), conventional anastomoses with 8 to 10 sutures were performed. In experimental group (n = 32), fish-mouth incisions were applied first on the recipient artery, followed by performing anastomosis with only 2 corner sutures and applying commercially available fibrin glue. Time taken to perform the anastomosis was significantly shorter with the experimental group (P = 0.001), whereas early and late patency and aneurysm rates were comparable to those achieved with control group. Histological evaluation did not point out any significant differences between the groups. We have defined a rapid and safe alternative technique of end-to-side anastomosis with the use of fibrin glue. This method may be an alternative especially where multiple anastomoses are required or where it is difficult to approach anastomotic line, as it is easily performed, rapid, safe, and not involving any complex equipments.     

Recipient splenic artery utilization for arterial re-anastomosis in living donor liver transplantation: single-center experience

Thrombosis of recipient hepatic artery is a life threatening complication for liver transplantation. The etiology of hepatic arterial thrombosis is multi-factorial and can be caused by intimal dissection, poor surgical technique and coagulopathies. The patency of hepatic arterial flow is very important for both graft survival and patient survival. Intraoperative diagnosis of inadequate hepatic arterial flow found with Doppler ultrasonography is essential in order to achieve good results after liver transplantation. Urgent re-anastomosis is necessary when the arterial blood flow is insufficient. We performed 317 living donor liver transplantations from July 2004 to July 2011. We used recipient splenic artery for hepatic artery reconstruction in six patients. These six patients were included in this study. Using the recipient splenic artery is a simple, safe and practical alternative for hepatic artery re-anastomosis in living donor liver transplantations.     

Carbohydrate antigen-125 and N-terminal pro-brain natriuretic peptide levels: compared in heart-failure prognostication

Carbohydrate antigen-125 (CA-125) is emerging as a prognostic biomarker of risk in heart failure. In a prospective study, we compared the prognostic values of CA-125 and amino-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with stable heart failure.We enrolled 102 consecutive chronic, stable, systolic-heart-failure patients (68 men and 34 women; median age, 71 yr) from November 2008 through February 2010. We measured baseline NT-proBNP and CA-125 levels and compared their prognostic values. The primary endpoint was all-cause death and other major adverse events, defined as hospitalization for decompensated heart failure or acute coronary syndrome.During a mean follow-up period of 14 ± 2 months, 12 patients died and 35 others sustained major adverse events. We found that CA-125 level significantly correlated with New York Heart Association functional class, pulmonary artery pressure, microalbuminuria, creatine kinase-MB fraction, and hemoglobin, albumin, and NT-proBNP levels. Upon receiver operating characteristic curve analysis, CA-125 and NT-proBNP had similar accuracy in predicting major adverse events and death: for major adverse events, area under the curve (AUC) was 0.699 for CA-125 (P=0.002) and 0.696 for NT-proBNP (P=0.002); for death, AUC was 0.784 for CA-125 (P=0.003) and 0.824 for NT-proBNP (P=0.001). Multivariate Cox regression analysis showed that CA-125 levels greater than 32 U/mL and NT-proBNP levels greater than 5,300 pg/mL had independent prognostic value for major adverse events and death.We conclude that baseline CA-125 and NT-proBNP levels are comparably reliable as heart-failure markers, and that CA-125 can be used for prognosis prediction in heart failure.