Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration.

Cerebellar degeneration-related protein 2 (cdr2) is expressed in the central nervous system, and its ectopic expression in tumor cells of patients with gynecological malignancies elicits immune responses by cdr2-specific autoantibodies and T lymphocytes, leading to neurological symptoms. However, little is known about the regulation and function of cdr2 in neurodegenerative diseases. Because we found that cdr2 is highly expressed in the midbrain, we investigated the role of cdr2 in experimental models of Parkinson's disease (PD). We found that cdr2 levels were significantly reduced after stereotaxic injection of 1-methyl-4-phenylpyridinium (MPP(+)) into the striatum. cdr2 levels were also decreased in the brains of post-mortem PD patients. Using primary cultures of mesencephalic neurons and MN9D cells, we confirmed that MPP(+) reduces cdr2 in tyrosine hydroxylase-positive dopaminergic neuronal cells. The MPP(+)-induced decrease of cdr2 was primarily caused by calpain- and ubiquitin proteasome system-mediated degradation, and cotreatment with pharmacological inhibitors of these enzymes or overexpression of calcium-binding protein rendered cells less vulnerable to MPP(+)-mediated cytotoxicity. Consequently, overexpression of cdr2 rescued cells from MPP(+)-induced cytotoxicity, whereas knockdown of cdr2 accelerated toxicity. Collectively, our findings provide insights into the novel regulatory mechanism and potentially protective role of onconeural protein during dopaminergic neurodegeneration.

Angioplasty of communicating veins to the brachial vein in haemodialysis patients with obliterated superficial veins of the upper arm.

AIM: To evaluate the outcomes of angioplasty of the communicating veins when superficial veins of the upper arm were almost totally obliterated in haemodialysis patients. MATERIALS AND METHODS: Twenty-one angioplasties of the communicating veins that were performed for failing haemodialysis fistulas in patients with almost totally obliterated superficial veins of the upper arm from December 2006 to March 2011 were retrospectively reviewed. Fistulas were of the following types: native radiocephalic fistulas (n = 20) and radio-antecubital fistulas (n = 1). All angioplasties were performed using 5-8 mm conventional balloons. Cutting balloon angioplasty was additionally performed in five patients. The primary, secondary, and target lesion patency rate was calculated using Kaplan-Meier analysis. RESULTS: The communicating vein was located in the antecubital fossa. Technical and clinical success rates were 100% and 95.2%, respectively. Follow-up duration was 1-52 months (mean 20 months). The primary patency rates were 76%, 43%, and 29% at 3, 6, and 12 months, respectively, and target lesion patency rates were 81%, 62%, and 43% at 3, 6, and 12 months, respectively. The secondary patency rates were 81%, 76%, and 57% at 3, 6, and 12 months, respectively. There were no major or minor complications. CONCLUSION: Angioplasty of the communicating vein is effective in restoring function in failing haemodialysis fistula in patients with obliterated superficial veins of the upper arm.

Age matching improves graft survival after living donor kidney transplantation.

BACKGROUND: Donor and recipient age in kidney transplantation are known to affect graft and patient survival. To address the question of whether the age difference between donor and recipient impacts on graft survival and death-censored graft survival after transplantation, we examined the impact of age matching (less than 10-year age difference) on the survivals after living donor kidney transplantation. METHODS: Two hundred one cases of the primary living donor kidney transplantation were performed and were divided into two groups, age-matched (n = 123) versus age-discrepant (n = 78). Variables included in this study were age, gender, body weight, height, kidney disease, type and duration of dialysis before transplantation, degree of human leukocyte antigen mismatch, ischemic time, graft weight, episode of rejection, type of immunosuppression, recipient serum creatinine after transplantation, and causes of patient death and graft loss. RESULTS: We observed the disparities of graft survival (P = .008) and death-censored graft survival (P = .003) between the groups. One-, 3-, and 5-year death-censored graft survival was 100%, 100%, and 97% in the age-matched group, respectively; and 97%, 90%, and 88% in the age-discrepant group, respectively. By Cox regression multivariate analysis, the variable of age-matching was an independent predictor for both graft survival (ß = 1.325, P = .017) and death-censored graft survival (ß = 2.217, P = .021). CONCLUSION: During living donor and recipient matching, age difference between donor and recipient should be minimized.

Clinical significance of prophylactic antibiotics in renal transplantation.

INTRODUCTION: The use of new selective immunosuppressants as well as the emergence of new antimicrobial resistances raise the use of prophylactic antibiotics as a matter of controversy. The purpose of this study was to retrospectively analyze the clinical significance of prophylactic antibiotics in kidney transplantation. METHODS: This retrospective study included 174 renal allograft recipients who were divided into two groups: group A including patients who received perioperative prophylactic antibiotics and group B, who did not receive them. We analyzed who the incidence of infectious complications as well as the causative micro-organisms and their antimicrobial resistance within 1 month after kidney transplantation. RESULTS: Overall bacterial infections were observed during the first postoperative month in 13 cases (7.4%): 6 (3.4%) surgical site 4 (2.3%) urinary tract, 2 (1.1%) bacteremic, and 1 (0.6%) central catheter infections. There was no respiratory infection. The incidence of bacterial infection was not significantly different between the two groups. The major micro-organisms isolated after kidney transplantation, were Staphylococcus aureus and Escherichia coli; both of which had already shown multidrug resistance at the initial time of infection. CONCLUSION: Not only did use of prophylactic antibiotics have little impact to prevent bacterial infections after kidney transplantation, but also it may induce antimicrobial resistance against the antibiotics used for prophylaxis. Moreover, the increased antibiotic resistance prior to kidney transplantation hampers the effectiveness of prophylactic antimicrobial agents. Guidelines for perioperative antibiotic prophylaxis should be therefore revised.

Endovascular treatment for immature autogenous arteriovenous fistula.

AIM: To evaluate the anatomical causes of maturation failure and to assess clinical outcomes after the causative lesions of immature arteriovenous fistula (AVF) have been corrected by endovascular treatment. MATERIALS AND METHODS: The medical records and radiological data from 141 patients who underwent endovascular treatment for immature AVF were retrospectively reviewed. Clinical outcomes, such as the success rates and the patency rates following the procedure, were included. The variables, including patients' age, gender, co-morbidities, fistula age, fistula type, numbers of lesions, degree of stenosis, presence of accessory veins, were analysed as the potential predictors of primary and secondary patency. RESULTS: Technical and clinical success rates were 95.7% (135 of 141 AVFs) and 86.5% (122 of 141 AVFs), respectively. The primary and secondary patency rates were 71.9% and 82.8% at 1 year, 60.1% and 82.0% at 2 years, and 54.5% and 82.0% at 3 years, respectively. By multivariate analysis using Cox proportional hazards model, stenosis of >90% was the only independent predictor for both the primary and secondary patency rates [hazard ratio (HR) 5.026, 95% confidence interval (CI) 2.47-10.24, p < 0.0001 for primary patency and HR 11.076, CI 1.49-82.58, p = 0.019 for secondary patency, respectively]. CONCLUSION: All immature AVFs had significant anatomical causes of failure to mature, which could be safely and effectively salvaged with endovascular treatment. A degree of stenosis >90% was an independent predictor for both the primary and secondary patency after the treatment.

Clinical significance of upper-arm cephalic vein patency in autogenous radial-cephalic wrist fistulas for hemodialysis.

OBJECTIVES: To investigate the significance of upper-arm cephalic veins (UACVs) in radial-cephalic arteriovenous fistulas (RCAVFs), the medical records of 183 patients who had undergone RCAVF creation were reviewed retrospectively. METHODS: The patients were divided into two groups according to the status of the UACV upon preoperative venography: group A of 153 cases (83.6%) with a patent UACV and group B of 30 cases (16.3%) with a stenosed or occluded UACV. The clinical outcomes were compared. RESULT: RCAVFs in group B had a significantly higher maturation failure rate (26.7% vs. 9.8%, p = 0.009) and lower primary/secondary patency rates (log-rank test, p < 0.0001) than those in the group A. The patients in group B required more frequent endovascular intervention to maintain access function (p = 0.002). The most common stenosis site was a draining vein in group B, in comparison to juxta-anastomosis in group A. In the multivariate analyses, the status of the UACV was an independent predictor of the primary and secondary patency rates of RCAVFs (p < 0.005). CONCLUSION: UACV patency has a significant impact on clinical outcome for RCAVFs. When planning an RCAVF placement, venous status including the UACV should be considered.

Cytokine gene expression in peripheral blood mononuclear cells during acute renal allograft rejection.

Many studies have explored the participation of cytokines and their genes in renal allograft rejection by using biopsy tissues. To screen for rejection, a biopsy is too invasive to perform without a clinical clue. Therefore, we studied the expression of cytokines that contribute to the early phase of allograft rejection by analyzing mRNA transcripts in sequential blood samples of peripheral blood mononuclear cells (PBMCs) 120 of 6 among patients transplanted before diagnosis of rejection. for comparison with 6 control recipients. The relative expression amount of cytokine genes encoding interleukin (IL) 2, IL-4, IL-10, IL-15, and interferon-γ were assessed using real-time reverse-transcription polymerase chain reactions. IL-2, IL-4, and IL-15 mRNA expressions in clinically stable prerejection phase of the rejection group were significantly higher than those of the control group. In the prerejection samples, the expression of mRNA encoding IL-10 negatively correlated with the expressions of IL-2, IL-4, and IL-15 mRNAs, which were not different from the positive correlations in the postoperative samples from the control group. The expression patterns of IL-2, IL-4, IL-10, and IL-15 genes in PBMCs after transplantation may help to identify acute rejection episodes before clinical deterioration to monitor the efficacy of immunosuppressive treatment.

Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma.

Asthma is a complex, persistent, inflammatory disease characterised by airway hyperresponsiveness in association with airway inflammation. Studies suggest that regular use of high-dose inhaled corticosteroids and long-acting bronchodilators or omalizumab (a humanised monoclonal antibody that binds to immunoglobulin E and is often used as next-step therapy) may not be sufficient to provide asthma control in all patients, highlighting an important unmet need. Interleukin-4, interleukin-13, and the signal transducer and activator of transcription factor-6 are key components in the development of airway inflammation, mucus production, and airway hyperresponsiveness in asthma. Biological compounds targeting these molecules may provide a new therapeutic modality for patients with uncontrolled severe asthma. The purpose of this review is to summarise current studies of compounds targeting the interleukin-4/interleukin-13 pathway and to provide a rationale for the development of such compounds for this use.

An adenylyl cyclase signaling pathway predicts direct dopaminergic input to vestibular hair cells.

Adenylyl cyclase (AC) signaling pathways have been identified in a model hair cell preparation from the trout saccule, for which the hair cell is the only intact cell type. The use of degenerate primers targeting cDNA sequence conserved across AC isoforms, and reverse transcription-polymerase chain reaction (RT-PCR), coupled with cloning of amplification products, indicated expression of AC9, AC7 and AC5/6, with cloning efficiencies of 11:5:2. AC9 and AC5/6 are inhibited by Ca(2+), the former in conjunction with calcineurin, and message for calcineurin has also been identified in the trout saccular hair cell layer. AC7 is independent of Ca(2+). Given the lack of detection of calcium/calmodulin-activated isoforms previously suggested to mediate AC activation in the absence of Gαs in mammalian cochlear hair cells, the issue of hair-cell Gαs mRNA expression was re-examined in the teleost vestibular hair cell model. Two full-length coding sequences were obtained for Gαs/olf in the vestibular type II-like hair cells of the trout saccule. Two messages for Gαi have also been detected in the hair cell layer, one with homology to Gαi1 and the second with homology to Gαi3 of higher vertebrates. Both Gαs/olf protein and Gαi1/Gαi3 protein were immunolocalized to stereocilia and to the base of the hair cell, the latter consistent with sites of efferent input. Although a signaling event coupling to Gαs/olf and Gαi1/Gαi3 in the stereocilia is currently unknown, signaling with Gαs/olf, Gαi3, and AC5/6 at the base of the hair cell would be consistent with transduction pathways activated by dopaminergic efferent input. mRNA for dopamine receptors D1A4 and five forms of dopamine D2 were found to be expressed in the teleost saccular hair cell layer, representing information on vestibular hair cell expression not directly available for higher vertebrates. Dopamine D1A receptor would couple to Gαolf and activation of AC5/6. Co-expression with dopamine D2 receptor, which itself couples to Gαi3 and AC5/6, will down-modulate levels of cAMP, thus fine-tuning and gradating the hair-cell response to dopamine D1A. As predicted by the trout saccular hair cell model, evidence has been obtained for the first time that hair cells of mammalian otolithic vestibular end organs (rat/mouse saccule/utricle) express dopamine D1A and D2L receptors, and each receptor co-localizes with AC5/6, with a marked presence of all three proteins in subcuticular regions of type I vestibular hair cells. A putative efferent, presynaptic source of dopamine was identified in tyrosine hydroxylase-positive nerve fibers which passed from underlying connective tissue to the sensory epithelia, ending on type I and type II vestibular hair cells and on afferent calyces.

Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulation.

Plasminogen activator inhibitor (PAI)-1 is a major inhibitor of the fibrinolytic system. PAI-1 levels are markedly increased in asthmatic airways, and mast cells (MCs), a pivotal cell type in the pathogenesis of asthma, are one of the main sources of PAI-1 production. Recent studies suggest that PAI-1 may promote the development of asthma by regulating airway remodelling, airway hyperresponsiveness (AHR), and allergic inflammation. The single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at -675 bp of the PAI-1 gene is the major genetic determinant of PAI-1 expression. Plasma PAI-1 level is higher in people with the 4G/4G genotype than in those with the 5G/5G genotype. A strong association between the 4G/5G polymorphism and the risk and the severity of asthma has been suggested. Levels of plasma IgE and PAI-1 and severity of AHR are greater in asthmatic patients with the 4G/4G genotype than in those with the 5G/5G genotype. The PAI-1 promoter with the 4G allele renders higher transcription activity than the PAI-1 promoter with the 5G allele in stimulated MCs. The molecular mechanism for the 4G allele-mediated higher PAI-1 expression is associated with greater binding of upstream stimulatory factor-1 to the E-box adjacent to the 4G site (E-4G) than to the E-5G. In summary, PAI-1 may play an important role in the pathogenesis of asthma. Further studies evaluating the mechanisms of PAI-1 action and regulation may lead to the development of a novel prognostic factor and therapeutic target for the treatment and prevention of asthma and other PAI-1-associated diseases.

Prospective, open-label, comparative study of clindamycin 1%/benzoyl peroxide 5% gel with adapalene 0.1% gel in Asian acne patients: efficacy and tolerability.

BACKGROUND: Used as individual agents, topical antibiotics and benzoyl peroxide are known to be effective in treatment of acne. Clindamycin phosphate 1% with benzoyl peroxide 5% (CDP/BPO) is a new combination gel, made by rationale, in that combination drug is more effective than either ingredients used alone. Adapalene 0.1% (ADA) is the third-generation retinoid, shown to be as effective as other topical retinoid with well tolerability. OBJECTIVES: To compare the efficacy and tolerability in combination of CDP/BPO in comparison with ADA in Asian patients with mild to moderate acne vulgaris. METHODS: Total of 69 patients, including 31 patients for CDP/BPO group and 38 for ADA group, with mild to moderate acne vulgaris were enrolled for a 12-week prospective, randomized, open-label comparative study of topical agents. Efficacy was assessed by lesion counts, acne grading system, and global improvement. Adverse events were also evaluated in scale of 0 (none) to 3 (severe). RESULTS: Both CDP/BPO and ADA were effective in reducing lesion counts and acne severity scale and showed significant global improvement. However, CDP/BPO offered greater efficacy against inflammatory lesions than ADA. Both drugs were well tolerated with minimal adverse drug reactions. CONCLUSION: Combination formulation of CDP/BPO and ADA were shown to be both effective in decreasing total, inflammatory, and non-inflammatory lesion counts along with well tolerability in Asian patients with mild to moderate acne vulgaris.

Predicting the ideal serum creatinine of kidney transplant recipients by a simple formula based on the balance between metabolic demands of recipients and renal mass supply from donors.

Serum creatinine (Scr) is the most frequently used test to estimate graft function after kidney transplantation. Our previous study demonstrated that the independent predictors of recipient posttransplantation Scr included the ratio of graft weight to recipient body weight, the ratio of graft weight to recipient body surface area (BSA), and the ratio of graft weight to recipient body mass index (BMI). A prospective analysis about the impact of the balance between metabolic demands and renal supply on posttransplantation Scr of recipients was previously reported. We plotted the scatter graph using the X-axis as the independent predictors of Scr by linear regression and the Y-axis as the recipient Scr. To generate the predictive formula of Scr, we calculated a fit of the line of plotted cases using a linear regression method with 2 regression lines for prediction of the upper and lower 95% confidence intervals. Each line was converted into a predictive formula: Scr = -0.0033* (Graft weight(g)/Recipient BSA(m2))+1.75. Under 95% confidence, the Scr ranges from -0.0033* (Graft weight(g)/Recipient BSA(m2))+1.07 to -0.0033* (Graft weight(g)/Recipient BSA (m2))+2.44. Scr = -0.1049* (Graft weight(g)/Recipient body weight(kg))+1.72, which ranges from -0.1049* (Graft weight(g)/Recipient body weight(kg))+1.06 to -0.1049* (Graft weight(g)/Recipient body weight(kg))+2.37. Scr = -0.0158* (Graft weight(g)/Recipient BMI(kg/m2))+1.56, which ranges from -0.0158* (Graft weight(g)/Recipient BMI(kg/m2))+0.75 to -0.0158* (Graft weight(g)/Recipient BMI(kg/m2))+2.26. Prediction of posttransplantation Scr may be achieved by measuring graft weight as well as recipient weight and height. When recipient Scr is significantly higher than that predicted by the formula, a clinician should suspect an underlying graft injury.

Beneficial effects on the renal function of both recipients and donors in living donor kidney transplantation.

In living donor kidney transplantation, initial function of the donor kidneys is split into the remnant kidney and the recipient's implanted kidney. We addressed the questions whether the donor's remnant kidney function increases or decreases after donation and whether the donor's donated kidney is greater or less than that of the recipient's implanted kidney after transplantation. We measured and calculated the functional ratio of each kidney using technetium-99m diethylenetriaminepentaacetic acid (99mTcDTPA) as well as serum creatinine (Scr; mg/dL) and creatinine clearance (Ccr; mL/min/1.73 m2) using 24-hour urines from 100 donors. The Ccr was also calculated using the Cockcroft-Gault formula (Ccr-CG; mL/min/1.73 m2). Within 7 days postnephrectomy, we measured Scr, Ccr, and Ccr-CG of the remnant kidney. For recipients, the Scr, Ccr, and Ccr-CG of the implanted kidney with 24-hour urine were obtained within 7 days posttransplantation. The average Scr, Ccr, and Ccr-CG of the donors were 0.85 +/- 0.17 mg/dL, 110.4 +/- 20.8 mL/min/1.73 m2, and 82.8 +/- 17.3 mL/min/1.73 m2, respectively. After donation, the Ccr and Ccr-CG of remnant kidney increased from 54.5 +/- 11.4 and 40.8 +/- 9.3 mL/min/1.73 m2 to 68.0 +/- 14.3 and 53.6 +/- 11.6 mL/min/1.73 m2, respectively. The recipient Ccr and Ccr-CG of donated kidney also increased from 55.9 +/- 11.8 and 42.0 +/- 9.9 mL/min/1.73 m2 to 78.4 +/- 18.0 and 53.4 +/- 16.4 mL/min/1.73 m2, respectively. Kidney transplantation from a living donor should be encouraged with total functional benefit for both donors and recipients.

Tumescent superficial liposuction with curettage for treatment of axillary bromhidrosis.

BACKGROUND: Axillary bromhidrosis is a common but unpleasant and distressing problem faced by many societies, particularly in Asia, where malodour is reflected as a social handicap. Currently, local surgery is the treatment of choice among various non-surgical and surgical treatment. OBJECTIVES: To evaluate the clinical efficacy and safety of tumescent superficial liposuction and curettage in treating axillary bromhidrosis. METHODS: Forty-three patients (25 females and 18 males, average age 24.5 years) have undergone tumescent superficial liposuction and curettage. Local anaesthesia, tumescent solution, was injected into the hair-bearing area of the axilla. Two tiny incisions were made for Fatemi cannule, and subcutaneous tissue was removed by stroke movement under negative pressure. Subsequently, additional curettage was done around the incision sites. We evaluated the clinical efficacy (excellent, good, fair and poor) and complications. In addition, preoperative and postoperative histologic findings were reviewed in 15 patients. RESULTS: The follow-up evaluation started 3 months after the surgery, and mean follow-up period was 15.8 months, ranging from 3 to 54 months. Among 43 patients, 31 patients (72.1%) showed excellent to good results. The most common postoperative complication was transient ecchymosis which spontaneously regressed in 1 to 2 weeks. Focal skin necrosis, induration, and haematoma or seroma were each noted in four, three, and one patients, respectively, but resolved after proper dressing. The preoperative histological findings included increase in size and number of apocrine glands in cross-section view, and the postoperative specimen evidently showed removal of subcutaneous tissue, including apocrine and eccrine glands, and remnant sweat glands were severely destructed. CONCLUSION: Tumescent superficial liposuction with curettage for axillary bromhidrosis is an effective and safe treatment method for axillary bromhidrosis.