[Atezolizumab therapy in Chinese patients with locally advanced or metastatic solid tumors: An open-label, phase â study].

OBJECTIVE: To evaluate pharmacokinetics (PK), efficacy, and safety of atezolizumab (anti-PD-L1) in high interest cancers in China, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), nasopharyngeal cancer (NPC), and non-small cell lung can-cer (NSCLC). METHODS: This phase I, open-label study was conducted at 6 Chinese sites from August 4, 2016 to April 15, 2019. The patients were ≥18 years old with a histologically documented incurable or metastatic solid tumor that was advanced or recurrent and had progressed since the last anti-tumor the-rapy. The PK phase characterized PK and safety of atezolizumab following multiple-dose administration when atezolizumab was administered as a single agent. The extension phase studied safety and efficacy of atezolizumab, as monotherapy (EC, GC, HCC, NPC) and with chemotherapy (NSCLC). RESULTS: This study enrolled 120 patients (PK phase: n=20; extension phase: n=20/cohort). Fourty-two patients (42.0%) were PD-L1 positive in atezolizumab monotherapy group (100 patients), of the 9 patients (9.0%) with microsatellite instability-high (MSI-H) tumors. Atezolizumab clearance was 0.219 L/d, and steady state was reached after 6 to 9 weeks (2-3 cycles) of repeated dosing. Objective response rates (ORRs) in EC, GC, HCC, NPC, and NSCLC were 10.0%, 15.0%, 10.0%, 5.0%, and 40.0%, respectively. In the patients with PD-L1 positive tumors, ORR was 11.9% with atezolizumab and 46.2% with atezolizumab plus gemcitabine and cisplatin. Two GC patients achieved durable response after pseudo-progression. The most common treatment-related adverse events in the atezolizumab monotherapy group were fatigue, anemia, fever, and decreased white blood cell count. The most common treatment-related adverse events in the combination group were anemia, decreased white blood cell count, and decreased appetite. No new safety signals were identified. CONCLUSION: Atezolizumab's PK, efficacy, and safety were similar in Chinese patients vs. global patients in previous studies.

Effects of direct-acting antiviral therapy for patients with advanced hepatocellular carcinoma and concomitant hepatitis C-A population-based cohort study.

OBJECTIVE: We analyzed real-world data to elucidate the effects of anti-Hepatitis C virus (HCV) direct-acting antiviral (DAA) therapy on survival in patients with advanced hepatocellular carcinoma (HCC) and concomitant HCV infection treated with sorafenib. MATERIALS AND METHODS: This population-based retrospective cohort study used the Taiwan National Health Insurance Research Database and the Registration System for Patients Treated with Oral Hepatitis C Antivirals to identify patients with advanced HCC and concomitant HCV infection who received initial targeted therapy (sorafenib) in 2018-2019. The overall survival (OS) of the DAA and non-DAA groups were compared using the Kaplan-Meier survival analysis. Propensity score matching was performed using a ratio of 1:4 to reduce confounding between the DAA and non-DAA groups. RESULTS: The study included 1,684 patients (122 DAA and 1,562 non-DAA users) with HCC and concomitant HCV infection who used sorafenib for the first time in 2018-2019. The Kaplan-Meier survival analysis indicated that advanced HCC patients who used DAAs had longer OS compared to non-DAA patients. The mean survival times were 20.7 months for DAA and 12.5 months for non-DAA. Results obtained after propensity matching indicated a significant difference in OS between the DAA and non-DAA groups. CONCLUSIONS: The analysis of big data from the Taiwan National Health Insurance Research Database revealed that advanced HCC patients on sorafenib benefited from DAAs as a treatment for HCV infection. Patients whose HCV infection was cured had better OS.

Dairy cattle with bovine leukaemia virus RNA show significantly increased leukocyte counts.

Infection with bovine leukaemia virus (BLV), a retrovirus, causes dysfunction of the immune system and can have a marked economic impact on dairy industries due to decreased milk production and reduced lifespan in affected dairy cattle. The presence of proviral DNA has been the major diagnostic indicator of BLV infection. However in the course of BLV infection, the viral genome can be dormant, without detectable gene expression, resulting in limited impact on infected animals. At present, there is limited knowledge regarding haematological indices in dairy cattle that could indicate activation of the BLV genome and suggest reactivated BLV infection. In this study, BLV infection and BLV genome reactivation were evaluated based on the presence of BLV DNA and BLV env gene transcripts, respectively. BLV RNA transcription was confirmed. Among 93 whole blood samples obtained from asymptomatic dairy cattle, the prevalence of BLV proviral DNA and transcripts was 93.5% (n = 87/93) and 83.9% (n = 78/93), respectively. Between groups with and without BLV, the mean counts of white blood cells and lymphocytes in whole blood were significantly associated with the presence of BLV RNA (P < 0.05), but not with BLV proviral DNA. These results shed light on the activation status of the BLV genome and should be taken into account when evaluating the possible impact of BLV on cattle.

Effect of lower-energy, higher-fiber diets on pigs divergently selected for residual feed intake when fed higher-energy, lower-fiber diets.

Residual feed intake (RFI) is the difference between observed and predicted feed intake of an animal, based on growth and maintenance requirements. In Yorkshire pigs, divergent selection for increased (Low RFI) and decreased (High RFI) RFI was carried out over 10 generations (G) while feeding a corn- and soybean-meal-based, higher-energy, lower-fiber (HELF) diet. In G8 to G10, representing 4 replicates, barrows and gilts (n = 649) of the RFI lines were fed the HELF diet and a diet incorporating coproducts that were lower in energy and higher in dietary fiber (LEHF). The diets differed in ME, 3.32 vs. 2.87 Mcal/kg, and in neutral detergent fiber (NDF), 9.4% vs. 25.9%, respectively. The impact of the LEHF diet on 1) performance and growth, 2) diet digestibility, 3) genetic parameter estimates, and 4) responses to selection for RFI, when fed the HELF, was assessed. In general, the LEHF diet reduced the performance of both lines. When fed the HELF diet, the Low RFI pigs had lower (P < 0.05) ADFI (-12%), energy intake (-12%), ADG (-6%), and backfat depth (-12%); similar (P > 0.05) loin muscle area (LMA; +5%); and greater (P < 0.05) feed efficiency (i.e., 8% higher G:F and 7% lower RFI) than the High RFI line. These patterns of line differences were still present under the LEHF diet but differences for ADFI (-11%), energy intake (-10%), G:F (+2%), and RFI (-6%) were reduced compared to the HELF diet. Apparent total tract digestibility (ATTD) of the HELF and LEHF diets was assessed using 116 barrows and gilts from G8. When fed the HELF diet, ATTD of DM, GE, N, and NDF were similar between lines (P ≥ 0.27), but when fed the LEHF diet, the Low RFI pigs had greater digestibility (7%, 7%, 10%, and 32%) than the High RFI line (P ≤ 0.04). To measure responses to selection for RFI and estimate genetic parameters, data from all 10 generations were used (HELF; n = 2,310; LEHF, n = 317). Heritability estimates of performance traits ranged from 0.19 to 0.63, and genetic correlations of traits between diets were high and positive, ranging from 0.87 (RFI) to 0.99 (LMA). By G10, RFI in the Low RFI line was 3.86 and 1.50 genetic SD lower than in the High RFI line when fed the HELF and LEHF diets, respectively. Taken together, the results of this study demonstrate that responses to selection for RFI when fed a HELF diet are not fully realized when pigs are fed an extremely LEHF diet. Thus, feeding diets that differ from those used for selection may not maximize genetic potential for feed efficiency.

Prognostic impact of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in nasopharyngeal carcinoma: A retrospective study of 180 Taiwanese patients.

OBJECTIVES: Nasopharyngeal cancer (NPC) is an endemic disease in Taiwan. Prognostic factors the anatomical TNM stage are important for its prognostic stratification. An elevated neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with poor prognosis in various solid tumours. In this study, we analysed the prognostic impact of the NLR in NPC in Taiwan. DESIGN: Single-institution retrospective study. SETTING: Medical centre. PARTICIPANTS: One hundred and eighty patients with NPC treated at the Far Eastern Memorial Hospital, Taiwan, from January 2007 to December 2013. MAIN OUTCOME MEASURES: The association between the clinical or haematological presentations and the prognosis. RESULTS: The majority of the 180 patients included in this study were men (80%) and were <65 years old (91.7%). A neck mass (55.6%) was the most common clinical presentation, followed by nasal (39.4%) and aural (30.6%) symptoms. In addition, the majority (75.4%) of patients had advanced stage (III and IV) disease. Patients with a high NLR (≧3.6) had significantly lower progression-free survival, overall survival and disease-specific survival rates. The association between high NLR and poor prognosis was more pronounced in patients with advanced disease than in those with early-stage NPC. The results of a multivariate analysis revealed that advanced age, clinical symptoms including headache, diplopia and facial numbness, advanced disease stage, and high NLR were independent prognostic factors. CONCLUSION: A high NLR is an independent poor prognostic factor of NPC in Taiwan.

Neutrophil Gelatinase-Associated Lipocalin in Cats with Naturally Occurring Chronic Kidney Disease.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for the early prediction of renal damage and the progression of chronic kidney disease (CKD) in humans and dogs. HYPOTHESIS: Neutrophil gelatinase-associated lipocalin also may play a role in the progression of CKD in cats. ANIMALS: Eighty CKD and 18 control cats. METHODS: Cats were categorized into different stages according to the International Renal Interest Society (IRIS) staging system. Urine and plasma samples were collected and tested for NGAL concentrations using an in-house sandwich ELISA system and urinary NGAL (uNGAL)-to-creatinine ratio (UNCR) was determined. Cats in which serum creatinine concentration increased by >0.5 mg/dL from baseline within 30 days were defined as exhibiting progression. RESULTS: The urinary NGAL and UNCR of CKD cats were significantly higher than those of healthy cats (P < .05) and were highly correlated with serum creatinine concentration. The area under the receiver operating characteristic curve (AUROC) for uNGAL, when predicting the progression of CKD, was 0.71 and the best cutoff value was 2.06 ng/mL with a sensitivity of 76.9% and a specificity of 75%. The AUROC for UNCR when predicting the progression of CKD was 0.79 and the best cutoff value was 4.08 × 10-6 with a sensitivity of 76.9% and specificity of 79.2%. Cats with UNCR values higher than their cutoffs experienced significantly faster deterioration with a median of 19 days. CONCLUSIONS: Both urinary NGAL and UNCR are useful markers for the prediction of CKD progression in cats.

Detection of indoxyl sulfate levels in dogs and cats suffering from naturally occurring kidney diseases.

Indoxyl sulfate (IS), a protein-bound uraemic toxin, has been found to accumulate in the serum of people with renal diseases and is associated with free radical induction, nephrotoxicity cardiovascular toxicity, and osteoblast cytotoxicity. Although IS has been studied in humans and in experimental models, the role of IS in dogs and cats with kidney disease has not been investigated. A high performance liquid chromatography system was applied to detect plasma IS concentrations in non-azotaemic animals (63 dogs, 16 cats) and in animals with renal azotaemia (66 dogs, 69 cats). The IS levels of azotaemic animals were significantly higher (P <0.01) than those of non-azotaemic animals (median [IQR] 20.4 (9.5) mg/L vs. 7.2 (8.8) mg/L for dogs; median [IQR] 21 (18.9) mg/L vs. 14.8 (12.3) mg/L for cats). The IS level was significantly correlated with blood urea nitrogen, serum creatinine and phosphate concentrations. Dogs with acute kidney injury had significantly higher IS levels (P <0.01) than those with chronic kidney diseases (CKD) (median [IQR] 57.7 (40.8) mg/L vs. 17.7 (25.1) mg/L). When CKD was graded using the International Renal Interest Society (IRIS) staging system, IS levels were correlated with CKD severity in both dogs and cats. The IS concentration is directly related to loss of renal function. Further studies are necessary to determine whether measurement of IS provides any additional diagnostic or prognostic information in dogs and cats with kidney disease.

Expression of matrix metalloproteinases (MMP-2, MMP-9) and their inhibitors (TIMP-1, TIMP-2) in canine testis, epididymis and semen.

This study aims to investigate the role of matrix metalloproteinases (MMPs) in determining semen quality and to evaluate the expression and cellular localization of MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 in the testes, epididymis and ejaculated spermatozoa. Gelatinase activities between normal (n = 21) and abnormal (n = 25) semen samples showed a significant, sixfold increase in proMMP-2 and MMP-2 activity in high than low sperm concentration samples (p < 0.001). ProMMP-9 and MMP-9 levels were significantly elevated in samples with low sperm counts compared to those with high sperm density (p < 0.001). High levels of proMMP-2 and MMP-2 were associated with high sperm motility (≥70%, p < 0.001). Sperm-rich fraction showed significantly (eight-fold) higher proMMP-9 enzymatic activity compared with prostatic fraction. The mRNA expressions of MMP-2, MMP-9, TIMP-1 and TIMP-2 were confirmed in testicular and epididymal tissues. Immunohistochemical staining illustrated the MMP-2-specific strong immunoreactivity in the head of mature spermatids during spermatogenesis, whereas MMP-9, TIMP-1 and TIMP-2 were absent in these cells. Matrix metalloproteinase-9 immunoreactivity was observed in the spermatocyte and round spermatid, whereas TIMP-1 was only exhibited in the residual bodies. Immunolabeling of epididymal and ejaculated sperm demonstrated MMP-2 localization along acrosomal region of sperm, while MMP-9, TIMP-1 and TIMP-2 localization was merely limited to the flagella. In conclusion, spermatozoa initially acquire MMP-2 during their formation at testicular level, and the presence of this protein persists through the epididymal transit and up to ejaculate. The enzymatic activity of MMP-2 and MMP-9 may serve as an alternative biomarker in determining semen quality.

Analysis of 28 generations of selection for reproduction, growth, and carcass traits in swine.

Selection (28 generations, G) in a Large White-Landrace composite population for traits aimed at increasing live pigs born per litter (BA), with additional selection for increased 180-d weight (WT180) and longissimus muscle area (LMA) and decreased back fat (BF10) in the last 8 generations, was practiced. Objectives herein were to estimate genetic and phenotypic responses and genetic parameters (n = 1,883 to 54,174) and to investigate whether a plateau in response for BA occurred. Line 2 (L2) was selected for an index of ovulation rate and embryo survival (G0 to G11), fully formed pigs (FF) per litter (G12 to 14), and BA and pig birth weight (PBW, G15 to G19), and its control line (LC1) was selected randomly (G0 to G21). Line 4 (L4), derived from L2, and line 5 (L5), derived from LC1, at G8 were selected in 2 stages for ovulation rate and FF (G9 to G16) and BA and PBW (G17 to G19), and their control (LC6) was selected randomly. At G20, L4 and L5 were crossed to form L45, and L4 and L2 were crossed to continue L2; L2 and L45 were subsequently selected for BA, WT180, LMA, and BF10 (G21 to G28). At G21, LC1 and LC6 were reciprocally crossed to form LC16, control for L2, and LC61, control for L45. Selection in L2 and L45 was first for BA and then for other traits among pigs selected for BA. Line sizes were 40 to 60 litters by 15 to 20 sires/G. Cumulative selection differentials (CSD) were calculated. MTDFREML was used to estimate variance components, EBV, and responses. Genetic changes at G28 in L2 were 4.63 FF and 3.66 BA, with 72% (FF) and 86% (BA) of the change occurring after G11. Two-stage selection produced similar responses (P < 0.01) in FF in L4 and L5 (0.27 and 0.29 pigs/G) but a greater response in BA in L5 (0.19 vs. 0.28 pigs/G). Genetic change in L45 from G20 to G28 was 0.17 pigs/G for both FF and BA (P < 0.01). Genetic changes at G28 in L45 were 4.16 FF and 3.68 BA. Genetic correlations of reproductive and growth traits were near zero, ranging from -0.43 (stillborn pigs/litter with BF10) to 0.21 (mummies/litter with LMA). Selection for growth traits along with litter size selection during G19 to G28 resulted in responses consistent with the selection applied and the heritability of the trait. No evidence for a selection plateau existed; selection differentials and variances of FF and BA in selection lines during G20 to G28 were similar to those in earlier generations. Over all generations, heritability of BA was 0.20 ± 0.03 and remained at approximately 0.17 in selection lines in later generations.

Neutrophil gelatinase-associated lipocalin in dogs with naturally occurring renal diseases.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is released from renal tubular cells after injury and serves in humans as a real-time indicator of active kidney damage, including acute kidney injury (AKI) and chronic kidney disease (CKD). However, NGAL concentrations in dogs with naturally occurring AKI or CKD rarely have been explored in detail. HYPOTHESIS/OBJECTIVES: The goal of this study was to evaluate whether NGAL can serve as a useful biomarker in dogs with naturally occurring renal disease. ANIMALS: Client-owned dogs with renal disease (57) and control dogs without any disease (12) were examined. METHODS: Serum NGAL (sNGAL) and urine NGAL (uNGAL) concentrations were measured in each animal by a newly developed ELISA system. Demographic, hematologic, and serum biochemical data were recorded. Survival attributable to AKI and CKD was evaluated at 30 days and 90 days, respectively. RESULTS: Serum and urine NGAL concentrations in azotemic dogs were significantly higher than in nonazotemic dogs and were highly correlated with serum creatinine concentration (P < .05). Among CKD dogs, death was associated with significantly higher sNGAL and uNGAL concentrations compared with survivors. Receiver-operating characteristic curve (ROC) analysis showed that sNGAL was better than serum creatinine concentration when predicting clinical outcomes for CKD dogs (P < .05). The best cutoff point for sNGAL was 50.6 ng/mL, which gave a sensitivity and a specificity of 76.9 and 100%, respectively. Furthermore, dogs that had higher concentrations of sNGAL survived for a significantly shorter time. CONCLUSION: sNGAL is a useful prognostic marker when evaluating dogs with CKD.

The use of pseudo-dynamic magnetic resonance imaging for evaluating the relationship between temporomandibular joint anterior disc displacement and joint pain.

The relationship between temporomandibular joint (TMJ) pain and the magnetic resonance imaging (MRI) finding of articular disc displacement is debated. The purpose of this study is to investigate the correlation between TMJ pain and anterior disc displacement (ADD) using pseudo-dynamic MRI. A retrospective review of MRI studies was carried out on 130 TMJs in 65 patients presenting unilateral TMJ pain. The contralateral asymptomatic joints served as the control group. Bilateral oblique sagittal and coronal MRIs as well as pseudo-dynamic studies in the oblique sagittal plane were obtained. The disc-condyle relationship was divided into three subtypes (normal disc position, ADD with reduction, and ADD without reduction), based on the pseudo-dynamic MRI findings. Fisher's exact test was used to determine whether the TMJ pain was linked to ADD. The results showed that TMJ pain was significantly related to ADD (with and without reduction) compared to the group with a normal disc position (P=.0001). A significant correlation was found between TMJ pain and the ADD subtype without reduction, as compared to the ADD subtype with reduction (P=.0156). These data suggest that a displaced disc, particularly in the subtype without reduction, is an important source of pain.

Differential effects of arsenic on calcium signaling in primary keratinocytes and malignant (HSC-1) cells.

Arsenic is highly toxic to living cells, especially skin, and skin cancer is induced by drinking water containing arsenic. The molecular mechanisms of arsenic-induced cancer, however, are not well understood. To examine the initial processes in the development of arsenic-induced cancer, we analyzed calcium signaling at an early stage of arsenic treatment of human primary cells and compared the effects with those observed with arsenic treatment in carcinoma-derived cells. We found that arsenic inhibited inositol trisphosphate receptor (IP3R) function in the endoplasmic reticulum by inducing phosphorylation, which led to decreased intracellular calcium levels. Blockade of IP3R phosphorylation by the serine/threonine protein kinase Akt inhibitor wortmannin rescued calcium signaling. In contrast, arsenic treatment of cells derived from a carcinoma (human squamous carcinoma; HSC-1) for 1h had no obvious effect. Taken together, these results suggest that arsenic-induced reduction in calcium signaling is one of the initial mechanisms underlying the malignant transformation in the development of skin cancer.

Prognostic factors and a prognostic index for cats with acute kidney injury.

BACKGROUND: The clinical manifestations of acute kidney injury (AKI) range from mild to fatal in cats; however, prognosis factors have been rarely studied. HYPOTHESIS/OBJECTIVES: To find the clinical factors significantly correlated with the outcome among cats with AKI and to develop a simple prognostic index. ANIMALS: Seventy cats with AKI were recruited. METHODS: Demographic and clinicopathological data obtained from 70 cats with AKI were retrospectively collected. Student's t-test or Mann-Whitney U-test and Pearson chi-square test or Fisher's exact were applied to determine the factors associated with survival in cats with AKI. Using logistic regression, the statistically significant factors associated with prognosis were identified and a new prediction model was generated. RESULTS: The overall case fatality rate was 64% (45/70). The results showed that nonsurviving cats had significantly lower levels of PCV, WBC, RBC, LDH and albumin, a lower albumin/globulin ratio, lower blood glucose, and a reduced body temperature, as well as being older. Serum urea and creatinine concentrations were not statistically significant as prognostic factors, but a decrease in these 2 variables in 3 days was significantly related to a reduction in death. A summary prognostic index including body temperature and LDH and albumin concentrations had area under the receiver-operating characteristic curve (AUROC) for predicting death of 0.86 (P < .05) and a cut-off value of 0.82, a sensitivity of 77% and a specificity of 90%. CONCLUSIONS: The prognosis in cats with AKI is quite different from that found for human and dogs.

Correlates of anti-EBV EBNA1 IgA positivity among unaffected relatives from nasopharyngeal carcinoma multiplex families.

BACKGROUND: To determine whether non-viral nasopharyngeal carcinoma (NPC) risk factors might be associated with (and mediated through) Epstein-Barr virus (EBV) serological responses linked to NPC risk, we evaluated predictors of risk of anti-EBNA1 IgA seropositivity and other markers among unaffected relatives from a large NPC family study in Taiwan. METHODS: Multivariate logistic regression conditioned on family was used to examine the associations between sociodemographic, dietary, lifestyle, and occupational variables and risk of anti-EBV EBNA1 IgA positivity, anti-VCA IgA, and anti-DNase positivity. RESULTS: Among 2393 unaffected relatives from 319 multiplex families, 1180 (49.3%) were anti-EBV EBNA1 IgA seropositive. None of the associations with anti-EBNA1 IgA were statistically significant, except for being 31-50 years of age (vs <30, adjusted ORs 0.51-0.57). For one or more EBV serological markers, there were suggestive associations for older age, GuangDong firm salted fish, betel use, current alcohol use, and male gender. CONCLUSION: Overall, we found little evidence to suggest that non-viral NPC risk factors significantly alter EBV serological patterns, suggesting that non-viral NPC risk factors act through pathways independent of EBV serological responses.

Prognosis of acute kidney injury in dogs using RIFLE (Risk, Injury, Failure, Loss and End-stage renal failure)-like criteria.

A retrospective case-series study evaluated the prognosis of 853 dogs with acute kidney injury (AKI) based on the RIFLE (Risk, Injury, Failure, Loss and End-stage renal failure) criteria, derived from human medicine. The 30-day mortality of dogs with AKI in each class was found to be 23.8 per cent (40 of 168) dogs for Risk, 41.0 per cent (107 of 261) dogs for Injury and 78.5 per cent (333 of 424) dogs for Failure. Using the dogs in the Risk class as the reference, the mortality of dogs in either the Injury or Failure class was significantly higher than that of dogs in the Risk class (P<0.05). The longest median survival time was observed in the Risk class (nine days) and the shortest median survival time was observed in the Failure class (three days). Using a multiple logistic regression model, a new score that simultaneously considered RIFLE class, diarrhoea status and serum phosphorus level was calculated to predict prognosis. Evaluation using the area under the receiver-operating characteristic curve (AUROC) indicated that the new scoring method (AUROC 0.80) was a better prognostic indicator than using RIFLE criteria alone (AUROC 0.73).

Diagnosis of feline polycystic kidney disease by a combination of ultrasonographic examination and PKD1 gene analysis.

Persian-related and non-Persian-related cats were examined by ultrasonography and/or molecular testing to determine the prevalence of feline polycystic kidney disease (PKD) and the presence of a PKD1 gene mutation. PCR was used to amplify exon 29 of the PKD1 gene using genomic DNA extracted from blood samples, and the PCR products were analysed by direct DNA sequencing. Among the 111 cats included in the study, 54 were examined by both ultrasonography and gene testing for a point mutation in exon 29 of the PKD1 gene. The prevalence of PKD diagnosed by ultrasonography was 25.9 per cent in all the cats and 24.2 per cent in Persian-related cats. The prevalence of the transversion mutation in exon 29 of the PKD1 gene was 13.5 per cent in all cats and 15.7 per cent in Persian-related cats. Three cats that were diagnosed with PKD by ultrasonography did not have the mutation within exon 29. Nucleotide analysis of exon 29 indicated that male cats had a higher point mutation rate than female cats.

Effect of pen mates on growth, backfat depth, and longissimus muscle area of swine.

Records on final BW (kg), backfat depth (cm), and LM area (cm(2)) of pigs from a University of Nebraska Large White/Landrace composite population were analyzed to estimate the effects of pen mates. Measurements were at approximately 180 d of age for 3,524 pigs in 351 pens (9 to 11 pigs per pen) farrowed from 1999 to 2005. The area of each pen was 8.13 m(2). The full model (M1) included the fixed effects of contemporary group, sex, line, and the covariates of age and inbreeding coefficient, and included random direct genetic, genetic pen-mate, permanent environmental, pen, litter, and residual effects. A derivative-free algorithm was used to obtain REML estimates of variance components for final BW adjusted to 180 d of age with M1 and 7 reduced models, and with 4 reduced models for the carcass traits. For final BW, likelihood ratio tests showed that M1 did not fit the data better than model 2 (permanent environmental effect omitted from M1) or model 3 (pen omitted from M1). Model 2 was not significantly (P > 0.05) better than model 3, which shows that variance attributable to pen effects and permanent environmental effects cannot be separated. Large sampling variances of estimates of the pen component of variance for models with pen-mate effects also indicate an inability to separate pen effects from the effects of pen mates. When pen-mate genetic effects were not in the model, estimates of components of variance and the fit of the data were the same for models 4 (included both permanent environmental and pen effects), 6 (included pen effects), and 7 (included permanent environmental effects), which shows that including both pen and permanent environmental effects was no better than including one or the other. Models 4, 6, and 7 were significantly better than model 8, which did not include pen-mate effects and pen effects, implying that pen effects are important. The estimate of pen variance with model 2 was approximately (number of pen mates - 1) times the estimate of variance of pen-mate permanent environmental effects with model 3. Patterns of estimates of variance components with models 2, 5, 6, and 8 for backfat depth and LM area were similar to those for final BW. Estimates of direct genetic variance and phenotypic variance were similar for all models. Estimates of heritability for direct genetic effects were approximately 0.40 for final BW, 0.45 for backfat depth, and 0.27 for LM area. Estimates of heritability for pen-mate genetic effects were 0.001 for the 3 traits for models including either pen or permanent environmental effects. Under the management conditions for this experiment, the conclusion is that the model for genetic evaluation should include litter effects and either pen effects or pen-mate permanent environmental effects and possibly genetic pen-mate effects, in general agreement with the results of studies of different populations at other locations.

A novel defense mechanism that is activated on amyloid-beta insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling.

Amyloid-beta (Abeta) is known to induce apoptotic cell death and its underlying mechanism has been studied extensively, but the endogenous protection mechanism that results from Abeta insult is less known. In this study, we have found that Abeta(1-42) produced a dose-dependent decrease in cell viability and dose-dependent increase in apoptotic cell death in PC12 cells. Meanwhile, Abeta(1-42) (0.1 muM) increased the phosphorylation of serum- and glucocorticoid-inducible kinase1 (SGK1) at Ser-78 specifically. A parallel increase in ERK1/2, STAT1 and STAT2 phosphorylation and the anti-apoptotic gene Mcl-1 expression was also observed. Transfection of rat siRNAs against ERK1/2, SGK1, STAT1 and STAT2 abolished these effects of Abeta. Transfection of sgkS78D, the constitutively active SGK1, dose-dependently protected against Abeta-induced apoptosis and dose-dependently increased the expression of Mcl-1. SGK1 activation further phosphorylates STAT1 at Tyr-701 and Ser-727 directly, and activates STAT2 at Tyr-690 indirectly. Phosphorylation of STAT1/STAT2 upregulated Mcl-1 expression which in turn protected against Abeta-induced apoptosis. But Mcl-1 siRNA transfection enhanced Abeta-induced apoptosis. Mutation of SGK1 at Ser-78 blocked the effect of Abeta on STAT1/STAT2 phosphorylation and Mcl-1 expression. Further, mutation of STAT1/STAT2 prevented the effect of both Abeta and SGK1 on Mcl-1 expression. These results together showed a novel endogenous protection mechanism that is activated on Abeta insult to mediate cell survival.

Prediction of conversion from clinically isolated syndrome to clinically definite multiple sclerosis according to baseline MRI findings: comparison of revised McDonald criteria and Swanton modified criteria.

BACKGROUND: The International Panel on the Diagnosis of Multiple Sclerosis first incorporated abnormalities demonstrated by brain and spinal cord MRI into the diagnostic criteria (McDonald criteria) for multiple sclerosis (MS), which were later revised in 2005. In 2006, Swanton and colleagues modified the MRI criteria to simplify and speed the diagnosis. OBJECTIVE: The purpose of this study was to compare the ability of two sets of criteria (the revised McDonald MRI criteria and Swanton's modified criteria) to predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) from baseline MRI findings. METHODS: Sixty-four patients presenting with CIS suggestive of multiple sclerosis were recruited from 2001 to 2006 and followed up for at least 2 years. Their baseline brain and spinal cord MRI studies were retrospectively evaluated. The patients who developed CDMS during follow-up were treated as positive cases. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of the two MRI dissemination-in-space criteria were calculated. RESULTS: Thirty patients (46.9%) converted to CDMS. The sensitivity specificity, PPV, NPV and accuracy (%) of the revised McDonald criteria were 53, 100, 100, 71 and 78, respectively, while those for Swanton's modified criteria were 60, 100, 100, 74 and 81. CONCLUSIONS: In conclusion, Swanton's modified criteria are more sensitive and accurate (but not significantly so). However, Swanton's criteria are simpler to use and have equally high specificity and PPV.