Comparative Genomics Identifies the Evolutionarily Conserved Gene TPM3 as a Target of eca-miR-1 Involved in the Skeletal Muscle Development of Donkeys.

Species within the genus Equus are valued for their draft ability. Skeletal muscle forms the foundation of the draft ability of Equus species; however, skeletal muscle development-related conserved genes and their target miRNAs are rarely reported for Equus. In this study, a comparative genomics analysis was performed among five species (horse, donkey, zebra, cattle, and goat), and the results showed that a total of 15,262 (47.43%) genes formed the core gene set of the five species. Only nine chromosomes (Chr01, Chr02, Chr03, Chr06, Chr10, Chr18, Chr22, Chr27, Chr29, and Chr30) exhibited a good collinearity relationship among Equus species. The micro-synteny analysis results showed that TPM3 was evolutionarily conserved in chromosome 1 in Equus. Furthermore, donkeys were used as the model species for Equus to investigate the genetic role of TPM3 in muscle development. Interestingly, the results of comparative transcriptomics showed that the TPM3 gene was differentially expressed in donkey skeletal muscle S1 (2 months old) and S2 (24 months old), as verified via RT-PCR. Dual-luciferase test analysis showed that the TPM3 gene was targeted by differentially expressed miRNA (eca-miR-1). Furthermore, a total of 17 TPM3 gene family members were identified in the whole genome of donkey, and a heatmap analysis showed that EaTPM3-5 was a key member of the TPM3 gene family, which is involved in skeletal muscle development. In conclusion, the TPM3 gene was conserved in Equus, and EaTPM3-5 was targeted by eca-miR-1, which is involved in skeletal muscle development in donkeys.

Bta-miR-127 inhibits secretion, proliferation and promotes apoptosis by targeting ITGA6 in bovine Sertoli cell.

Sertoli cell (SC) play a critical role in the spermatogenesis process involved in male fecundity and reproductive potential. SC development is regulated by microRNAs (miRNAs). However, the effect and molecular mechanism of miRNAs and target genes on bovine immature SC remains poorly understood. In this study, bta-miR-127 overexpression in SC inhibited cell secretion, proliferation, cell viability, and S-phase cells number. However, inhibition of bta-miR-127 had the opposite effect. An over-expression of bta-miR-127 significantly promotes SC apoptosis, and bta-miR-127 inhibition can significantly inhibit this process. These results reveal that bta-miR-127 is an inhibitor of SC proliferation and secretion. A combination of transcriptome sequencing, bioinformatics analysis, and dual-luciferase reporter assay showed that ITGA6 was targeted by bta-miR-127. The small interfering RNA of ITGA6 (si-ITGA6) inhibits SC proliferation and secretion, as well as promotes apoptosis. The SC proliferation and secretion marker genes, cell viability, and S phase cell number in co-transfected si-ITGA6 + miR-127 inhibitor was significantly lower than those of the bta-miR-127 inhibitor group. These results further confirmed that bta-miR-127 targeting ITGA6 inhibits the SC proliferation and secretion, and promotes SC apoptosis. These findings proposed a novel miRNA (bta-miR-127) that impeded bovine SC proliferation and promoted SC apoptosis through downregulation of ITGA6.

Nonionic surfactants enhanced enzymatic hydrolysis of cellulose by reducing cellulase deactivation caused by shear force and air-liquid interface.

Effects of nonionic surfactants on enzymatic hydrolysis of Avicel at different agitation rates and solid loadings and the mechanism were studied. Nonionic surfactants couldn't improve the enzymatic hydrolysis efficiency at 0 and 100rpm but could enhance the enzymatic hydrolysis significantly at high agitation rate (200 and 250rpm). Cellulase was easily deactivated at high agitation rate and the addition of nonionic surfactants can protect against the shear-induced deactivation, especially when the cellulase concentration was low. When 25mg protein/L of cellulase solution was incubated at 200rpm for 72h, the enzyme activity increased from 36.0% to 89.5% by adding PEG4600. Moreover nonionic surfactants can compete with enzyme in air-liquid interface and reduce the amount of enzyme exposed in the air-liquid interface. The mechanism was proposed that nonionic surfactants could enhance the enzymatic hydrolysis of Avicel by reducing the cellulase deactivation caused by shear force and air-liquid interface.

A randomized, 4-week double-blind placebo control study on the efficacy of donepezil augmentation of lithium for treatment of acute mania.

INTRODUCTION: A significant number of mania patients fail to respond to current pharmacotherapy, thereby there is need for novel augmentation strategies. The results of some early studies showed the effectiveness of cholinomimetics in the treatment of mania. One open case series suggested the efficacy of donepezil in the treatment of bipolar disorder. Our aim was to explore whether an oral cholinesterase inhibitor, donepezil, administered during a 4-week treatment period, would benefit patients with acute mania. METHODS: We conducted a 4-week double-blind, placebo-controlled trial of donepezil as an adjunctive treatment to lithium in patients with acute mania. Eligible subjects were randomly assigned to receive donepezil or placebo in addition to lithium. Donepezil was started at 5 mg/day, and increased to 10 mg/day in the first week. Patients were rated with the Young Mania Rating Scale (YMRS) and Brief Psychiatric Rating Scale (BPRS) at baseline, day 1, week 1, week 2, and week 4. RESULTS: Out of the 30 patients who were enrolled, 15 were on donepezil and 15 were on placebo. All patients completed the 4-week trial. On the first day, there was a difference of 1.97 units on the psychomotor symptoms scale of the YMRS in the donepezil group as compared to the placebo group (t = 2.39, P = 0.02). There was a difference of 0.57 units (t = 2.09, P = 0.04) in the speech item and a difference of 0.29 units in the sexual interest item (t = 2.11, P = 0.04) in the donepezil group as compared to the placebo group. The total YMRS difference on the first day approached the conventional significance level (1.97 units, t = 1.84, P = 0.07). Over the course of 4 weeks, we failed to find that donepezil produced any significant difference in the YMRS (6.71 units difference, t = -1.44, P = 0.16) or the BPRS scale (1.29 units difference, t = -0.33, P = 0.75) as compared to placebo. Ten subjects (66.67%) in both groups met the criteria for clinical response (Fisher's exact P = 1.00). Five subjects (33.33%) in the donepezil group met the criteria for clinical remission while nine subjects (60.00%) in the placebo group met the remission criteria (Fisher's exact P = 0.27). CONCLUSION: Use of the oral anticholinergic donepezil had some benefit in the augmentation of lithium treatment on the first day, but did not provide any significant benefits in the long-term.

Genetic sequence variants are associated with severity of lower urinary tract symptoms and prostate cancer susceptibility.

PURPOSE: While a clear heritable component underlies lower urinary tract symptoms and benign prostatic hyperplasia, few studies have identified specific genetic factors. In contrast, recent genome-wide association studies identified single nucleotide polymorphisms that increase prostate cancer risk. Some of these single nucleotide polymorphisms may also predispose to surgical intervention for benign prostatic hyperplasia. We determined whether these single nucleotide polymorphisms are also associated with lower urinary tract symptom severity and benign prostatic hyperplasia medication use. MATERIALS AND METHODS: The genotypes of 38 single nucleotide polymorphisms previously associated with prostate cancer risk were determined for 1,168 healthy white male volunteers. American Urological Association symptom index score and medication for benign prostatic hyperplasia were documented prospectively. Statistical analyses were done to compare the frequency of the single nucleotide polymorphisms with American Urological Association symptom index and benign prostatic hyperplasia medication use. RESULTS: Several single nucleotide polymorphisms, including rs2736098 on chromosome 5p15, showed a significant relationship with benign prostatic hyperplasia medication. After adjusting for the other genetic variants, patient age and medication use, rs1571801 on chromosome 9q33.2 (OR 1.31, 95% CI 1.0-1.74) and rs5945572 on chromosome Xp11 (OR 1.28, 95% CI 1.04-1.59) were significantly associated with increased urinary symptoms. In contrast, rs445114 on chromosome 8q24 was marginally associated with decreased urinary symptoms (OR 0.83, 95% CI 0.66-1.01). CONCLUSIONS: Of 38 single nucleotide polymorphisms that predispose to prostate cancer we identified 3 that are also associated with a well characterized lower urinary tract symptom phenotype. These single nucleotide polymorphisms may aid in the improved characterization of men with lower urinary tract symptoms/benign prostatic hyperplasia.

Effects of pioglitazone on metabolic abnormalities, psychopathology, and cognitive function in schizophrenic patients treated with antipsychotic medication: a randomized double-blind study.

BACKGROUND: Schizophrenic patients treated with antipsychotic drugs (AP) have an increased frequency of glucose-lipid metabolic abnormalities and diabetes. Pioglitazone has been shown to be effective in the treatment of glucose and lipid abnormalities in diabetes and decreasing longer-term conversion of impaired glucose tolerance to frank diabetes. Some studies also suggest possible pro-cognitive and antidepressant effects of pioglitazone. We studied the effects of pioglitazone on potential metabolic, symptomatic and cognitive benefits in schizophrenic patients treated with AP. METHODS: 54 schizophrenic patients with at least both a)impaired glucose and b) triglycerides≥120mg/dL and/or low HDL levels, participated in a double-blind placebo controlled study of 3month treatment with Pioglitazone (30-45mg/day) or matched placebo, at 5 sites (4 U.S., 1 China). Fasting glucose and lipid parameters, and psychopathology (PANSS scale) were assessed monthly, and patients had a glucose tolerance test and cognitive testing (RBANS and CPT) at baseline and at the end of study. Statistical analysis used mixed model repeated measures analysis, supplemented by completer and LOCF analysis. RESULTS: In the total sample there was an overall effect (P's<.05 to <.01) of pioglitazone on preventing deterioration in fasting glucose and improving HDL and PANSS depression scores; in the pioglitazone group comparison of baseline vs 3month values also showed significant (P<.05) decreases in fasting insulin, 2h glucose in GTT and insulin resistance (HOMA-IR). However there were marked differences between the responses of patients in the U.S. sites vs the China site. In the U.S. sample, patients treated with pioglitazone, when compared to placebo treated patents, had significantly lower fasting glucose (F=3.99, P=0.02), improved insulin sensitivity (lower H0MA-IR, F=6.24, P=.002), lower triglycerides (F=2.68, P=.06) and increased HDL (F=6.50, P=.001). By the end of the study 52% of the pioglitazone treated patients compared to 15% of the placebo patients had fasting glucose in the normal range (Fisher's exact test P=.02). Pioglitazone also significantly improved PANSS depression factor scores (F=2.82, P=0.05). It did not improve cognitive performance on the RBANS or CPT tasks. Pioglitazone did not increase weight or produce any other significant side-effects. In the small mainland China site sample, pioglitazone treatment, as compared to placebo, did not show greater improvement in metabolic parameters or psychopathology ratings. CONCLUSIONS: In the sample of patients from the U.S., pioglitazone was an efficacious and safe treatment for glucose and lipid metabolic abnormalities in schizophrenic patients treated with AP, and it may also have beneficial effects on depressive symptoms. It may be particularly useful in patients whose weight gain effects from antipsychotics have plateaued and where weight loss is not the primary goal. The risk vs. benefits of longer term treatment with pioglitazone has to be carefully evaluated for individual patients.

Personalized prostate specific antigen testing using genetic variants may reduce unnecessary prostate biopsies.

PURPOSE: Recent studies have identified genetic variants associated with increased serum prostate specific antigen concentrations and prostate cancer risk, raising the possibility of diagnostic bias. By correcting for the effects of these variants on prostate specific antigen, it may be possible to create a personalized prostate specific antigen cutoff to more accurately identify individuals for whom biopsy is recommended. Therefore, we determined how many men would continue to meet common biopsy criteria after genetic correction of their measured prostate specific antigen concentrations. MATERIALS AND METHODS: The genotypes of 4 single nucleotide polymorphisms previously associated with serum prostate specific antigen levels (rs2736098, rs10788160, rs11067228 and rs17632542) were determined in 964 healthy Caucasian volunteers without prostate cancer. Genetic correction of prostate specific antigen was performed by dividing an individual's prostate specific antigen value by his combined genetic risk. Analyses were used to compare the percentage of men who would meet commonly used biopsy thresholds (2.5 ng/ml or greater, or 4.0 ng/ml or greater) before and after genetic correction. RESULTS: Genetic correction of serum prostate specific antigen results was associated with a significantly decreased percentage of men meeting biopsy thresholds. Genetic correction could lead to a 15% or 20% relative reduction in the total number of biopsies using a biopsy threshold of 2.5 ng/ml or greater, or 4.0 ng/ml or greater, respectively. In addition, genetic correction could result in an 18% to 22% reduction in the number of potentially unnecessary biopsies and a 3% decrease in potentially delayed diagnoses. CONCLUSIONS: Our results suggest that 4 single nucleotide polymorphisms can be used to adjust a man's measured prostate specific antigen concentration and potentially delay or prevent unnecessary prostate biopsies in Caucasian men.

A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer.

In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

Outcomes in patients with Gleason score 8-10 prostate cancer: relation to preoperative PSA level.

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High-grade prostate cancers are associated with poor disease-specific outcomes. A proportion of these tumours produce little PSA. This study demonstrates that among Gleason 8-10 prostate cancers, some of the worst survival outcomes are associated with the lowest PSA levels. OBJECTIVE: • To assess outcomes of patients with Gleason score 8-10 prostate cancer (CaP) with a low (≤ 2.5 ng/mL) vs higher preoperative serum PSA levels. PATIENTS AND METHODS: • From 1983 to 2003, 5544 patients underwent open radical prostatectomy, of whom 354 had a Gleason 8-10 tumour in the prostatectomy specimen. • Patients were stratified according to preoperative PSA level into four strata: ≤ 2.5 ng/mL (n= 31), 2.6-4 ng/mL (n= 31), 4.1-10 ng/mL (n= 174), and >10 ng/mL (n= 118). • We compared biochemical progression-free survival (PFS), metastasis-free survival (MFS), and cancer-specific survival (CSS) as a function of preoperative PSA level. RESULTS: • Patients with PSA level ≤ 2.5 ng/mL were more likely to have seminal vesicle invasion (P= 0.003). • On Kaplan-Meier survival analysis, patients with a PSA level ≤ 2.5 ng/mL had proportionately worse outcomes than their counterparts with higher PSA levels. • The 7-year PFS in the PSA ≤ 2.5 ng/mL stratum was lower than those of the PSA 2.6-4 ng/mL and 4-10 ng/mL strata (36% vs 50 and 42%, respectively); however, the lowest 7-year PFS was found in those with a PSA level >10 ng/mL (32%, P= 0.02). • Gleason score 8-10 tumours with a PSA level ≤ 2.5 ng/mL also tended to have the lowest 7-year MFS (75, 93, 89 and 92% for PSA level ≤ 2.5, 2.6-4, 4.1-10 and >10 ng/mL, respectively, P= 0.2) and CSS (81, 100, 94 and 90% for PSA level ≤ 2.5, 2.6-4, 4.1-10 and >10 ng/mL, respectively, P= 0.3), although these differences were not statistically significant. • In the subset with palpable disease, Gleason grade 8-10 disease with PSA level ≤ 2.5 ng/mL also was associated with a worse prognosis. CONCLUSIONS: • In patients with Gleason grade 8-10 disease, a proportion of these tumours are so poorly differentiated that they produce relatively little PSA. • Patients with high-grade, low-PSA tumours had less favourable outcomes than many of those with higher PSA levels.

Association of prostate cancer risk alleles with unfavourable pathological characteristics in potential candidates for active surveillance.

OBJECTIVE: • To assess whether the carrier status of 35 risk alleles for prostate cancer (CaP) is associated with having unfavourable pathological features in the radical prostatectomy specimen in men with clinically low risk CaP who fulfil commonly accepted criteria as candidates for active surveillance. PATIENTS AND METHODS: • We studied men of European ancestry with CaP who fulfilled the commonly accepted clinical criteria for active surveillance (T1c, prostate-specific antigen <10 ng/mL, biopsy Gleason ≤6, three or fewer positive cores, ≤50% tumour involvement/core) but instead underwent early radical prostatectomy. • We genotyped these men for 35 CaP risk alleles. We defined 'unfavourable' pathological characteristics to be Gleason ≥7 and/or ≥ pT2b in their radical prostatectomy specimen. RESULTS: • In all, 263 men (median age 60 [46-72] years) fulfilled our selection criteria for active surveillance, and 58 of 263 (22.1%) were found to have 'unfavourable' pathological characteristics. • The frequencies of three CaP risk alleles (rs1447295 [8q24], P= 0.004; rs1571801 [9q33.2], P= 0.03; rs11228565 [11q13], P= 0.02) were significantly higher in men with 'unfavourable' pathological characteristics. • Two other risk alleles were proportionately more frequent (rs10934853 [3q21], P= 0.06; rs1859962 [17q24], P= 0.07) but did not achieve nominal statistical significance. • Carriers of any one of the significantly over-represented risk alleles had twice the likelihood of unfavourable tumour features (P= 0.03), and carriers of any two had a sevenfold increased likelihood (P= 0.001). • Receiver-operator curve analysis demonstrated an area under the curve of 0.66, suggesting that the number of single nucleotide polymorphisms carried provided discrimination between men with 'favourable' and 'unfavourable' tumour features in their prostatectomy specimen. CONCLUSION: • In potential candidates for active surveillance, certain CaP risk alleles are more prevalent in patients with 'unfavourable' pathological characteristics in their radical prostatectomy specimen.

Lithium-induced renal insufficiency: a longitudinal study of creatinine increases in intellectually disabled adults.

BACKGROUND: Lithium has been shown to increase serum creatinine levels in a subgroup of patients. However, lithium-induced increases in serum creatinine have not been well studied with regard to timing, trajectory, or predictability. METHODS: The medical records of 16 intellectually disabled individuals treated with lithium between 1980 and 2010 in whom serum creatinine levels peaked at 1.5 mg/100 mL or higher (ie, who developed renal insufficiency) were reviewed. These individuals were compared with a group of 36 similar lithium-treated individuals in whom serum creatinine did not reach 1.5 mg/100 mL. RESULTS: The 16 lithium-treated individuals who developed renal insufficiency had a mean peak serum creatinine level of 1.8 ± 0.3 mg/100 mL while on lithium. The mean time from institution of lithium until the 1.5 mg/100 mL serum creatinine level was first reached was 7.9 years. After lithium was discontinued, overall mean serum creatinine levels did not significantly change. Reaching a serum creatinine level of 1.3 or 1.4 mg/100 mL predicted reaching a 1.5 mg/100 mL level or higher. No significant differences in the age lithium was started, baseline serum creatinine levels, years receiving lithium, sex, or race differentiated those who developed renal insufficiency. CONCLUSIONS: Prescribing lithium led to elevated serum creatinine levels in some individuals. A serum creatinine level of 1.3 and/or 1.4 mg/100 mL predicted renal insufficiency. Clinical implications of this study are that if 1 serum creatinine result reaches 1.3 mg/100 mL or more, intensive monitoring for further increases is indicated.

Prostate cancer risk alleles and their associations with other malignancies.

OBJECTIVE: To determine whether certain risk alleles are responsible for the relationship between prostate cancer (CaP) and other malignancies. CaP has been associated with other common malignancies. Recently, numerous single nucleotide polymorphisms (SNPs) have been associated with CaP susceptibility. METHODS: We genotyped 1121 patients with CaP for 36 risk alleles known to be significantly associated with CaP susceptibility and determined their relationships to other malignancies in CaP probands and their first-degree relatives. RESULTS: The most common other malignancies in the CaP probands were nonmelanoma skin cancer (13.6%), leukemia (7.3%), melanoma (3.9%), non-Hodgkin's lymphoma (0.7%), colorectal cancer (0.6%), and multiple myeloma (0.3%). Among the probands, a significantly increased frequency of leukemia was found in the carriers of SNP rs2736098 (5p15, P = .03) and melanoma in the carriers of either SNP rs1512268 (8p21, P = .006) or SNP rs5759167 (22q13, P = .02). Multiple myeloma was more common in carriers of SNP rs9364554 (6q25, P = .02). The probands who were carriers of SNP rs16901979 (8q24) were significantly more likely to report a family history of melanoma (P = .03), and the probands with a family history of multiple myeloma and non-Hodgkin's disease were significantly more likely to be carriers of SNP rs12621278 (2q31, P = .04) and rs6465657 (7q21, P = .02), respectively. CONCLUSION: Certain alleles associated with CaP susceptibility might be associated with an increased or a decreased risk of other malignancies in CaP probands and their first-degree relatives. Additional studies are warranted to examine the underlying mechanisms of these SNPs in CaP and other malignancies.

Effects of olanzapine and risperidone on lipid metabolism in chronic schizophrenic patients with long-term antipsychotic treatment: a randomized five month study.

OBJECTIVE: Metabolic syndrome and elevated lipids, related to cardiovascular risk factors, are more prevalent in schizophrenia and there has been much debate about the extent to which specific antipsychotics contribute more to the increased risk of developing hyperlipidemia and metabolic syndrome. Most studies have concentrated on fasting levels in patients recently started on medication. Randomized prospective studies of metabolic effects of 2nd generation antipsychotics using both fasting measures and provocative tests may provide results that are more informative. We present results of a randomized prospective study of lipid metabolism and metabolic syndrome in chronic schizophrenic patients using both fasting and post-prandial lipid measures. METHOD: Hospitalized patients with chronic schizophrenia, most of whom had been treated with multiple antipsychotics in the past, were randomly assigned to treatment with a single antipsychotic, olanzapine or risperidone, for a period of 5 months. At baseline and every treatment month thereafter, fasting levels of lipids, free fatty acid (FFA) and leptin were assessed. At baseline and end of month 2 of treatment patients had a fatty meal test (FMT) in which postprandial lipids were measured at several time points before and after meal ingestion. Weight was assessed monthly and waist measures were taken at baseline and month 5. Data was analyzed on 23 patients randomized to risperidone and 23 patients randomized to olanzapine. RESULTS: Overall, there were no differential drug effects on any fasting lipid measure and fasting triglycerides did not increase in olanzapine treated patients after 5 months of treatment. However, at 2 months of drug treatment the FMT revealed a significantly greater increase in triglycerides, and very low density (VLDL) cholesterol and triglycerides, in olanzapine compared to risperidone patients (Ps=.05-.01). There was no difference between treatments with olanzapine vs. risperidone on development of metabolic syndrome during the 5 month treatment period. CONCLUSIONS: Chronic schizophrenic patients treated for years with first and second generation antipsychotics may have developed tolerance to the effects of olanzapine on increasing fasting triglycerides and other lipids, but some underlying metabolic abnormalities may be revealed in postprandial tests of lipid metabolism. These findings suggest that the development of standardized tests and criteria for measurement of postprandial triglycerides and related lipid levels, in addition to fasting levels, may be helpful in identifying metabolic effects of olanzapine and other second generation antipsychotics in chronically treated schizophrenics. In some reports postprandial increases in triglycerides have been identified as important risk factors for cardiovascular disease, but the actual differential consequences of these lipid metabolic differences for development of atherosclerosis and cardiovascular disease in patients treated with different antipsychotics need more objective outcome measures to determine and quantify cardiovascular risk outcomes.

Lower number of cerebellar Purkinje neurons in psychosis is associated with reduced reelin expression.

Reelin is an extracellular matrix protein synthesized in cerebellar granule cells that plays an important role in Purkinje cell positioning during cerebellar development and in modulating adult synaptic function. In the cerebellum of schizophrenia (SZ) and bipolar (BP) disorder patients, there is a marked decrease ( approximately 50%) of reelin expression. In this study we measured Purkinje neuron density in the Purkinje cell layer of cerebella of 13 SZ and 17 BP disorder patients from the McLean 66 Cohort Collection, Harvard Brain Tissue Resource Center. The mean number of Purkinje neurons (linear density, neurons per millimeter) was 20% lower in SZ and BP disorder patients compared with nonpsychiatric subjects (NPS; n = 24). This decrease of Purkinje neuron linear density was unrelated to postmortem interval, pH, drugs of abuse, or to the presence, dose, or duration of antipsychotic medications. A comparative study in the cerebella of heterozygous reeler mice (HRM), in which reelin expression is down-regulated by approximately 50%, showed a significant loss in the number of Purkinje cells in HRM (10-15%) compared with age-matched (3-9 months) wild-type mice. This finding suggests that lack of reelin impairs GABAergic Purkinje neuron expression and/or positioning during cerebellar development.

The Decrease of n-3 Fatty Acid Energy Percentage in an Equicaloric Diet Fed to B6C3Fe Mice for Three Generations Elicits Obesity.

Feeding mice, over 3 generations, an equicaloric diet in which alpha-linolenic acid, the dietary precursor of n-3 polyunsaturated fatty acids, was substituted by linoleic acid, the dietary precursor of n-6 polyunsaturated fatty acids, significantly increased body weight throughout life when compared with standard diet-fed mice. Adipogenesis observed in the low n-3 fatty acid mice was accompanied by a 6-fold upregulation of stearyl-coenzyme A desaturase 1 (Scd1), whose activity is correlated to plasma triglyceride levels. In total liver lipid and phospholipid extracts, the sum of n-3 fatty acids and the individual longer carbon chain acids, eicosapentaenoic acid (20:5n3), docosapentaenoic acid (22:5n3), and docosahexaenoic acid (22:6n3) were significantly decreased whereas arachidonic acid (20:4n6) was significantly increased. In addition, low n-3 fatty acid-fed mice had liver steatosis, heart, and kidney hypertrophy. Hence, reducing dietary alpha-linolenic acid, from 1.02 energy % to 0.16 energy % combined with raising linoleic acid intake resulted in obesity and had detrimental consequences on organ function.

Effects of olanzapine and risperidone on glucose metabolism and insulin sensitivity in chronic schizophrenic patients with long-term antipsychotic treatment: a randomized 5-month study.

BACKGROUND: Comparisons of diabetic potential, glucose related metabolic levels, and insulin resistance between olanzapine and risperidone have produced variable results in cross-sectional and epidemiologic studies. Randomized prospective studies of metabolic effects during treatment with these drugs may provide results that are more informative. METHOD: Hospitalized patients with chronic schizophrenia (DSM-IV), most of whom had been treated with multiple antipsychotics in the past, were randomly assigned to treatment with a single antipsychotic, olanzapine or risperidone, for a period of 5 months. At baseline and every treatment month thereafter, fasting glucose, insulin, insulin-related metabolic measures, and prolactin were assessed, and an oral glucose tolerance test (OGTT) was performed during baseline and months 1, 2, and 5 of treatment. Weight was assessed monthly, and waist and hip measures were taken at baseline and month 5. Data were analyzed on 23 patients randomly assigned to risperidone and 23 patients randomly assigned to olanzapine. The study was conducted from February 2003 to August 2007. RESULTS: Most patients were overweight or obese at baseline (mean body mass index [BMI] = 29.4), but there were no differential drug effects on weight change and no differences between drug groups at the 5-month time point. There were no overall drug treatment differences in fasting glucose or glycohemoglobin or 2-hour glucose levels in OGTT and no differences between the two drug groups at the 5-month time point. There were no consistent drug treatment differences in the number of patients who developed borderline or diabetic glucose levels. Olanzapine-treated patients showed a significantly greater increase than risperidone-treated patients in a fasting measure of insulin resistance (P = .041), and olanzapine patients showed greater decreases in insulin sensitivity during OGTT (P = .023) compared to risperidone-treated patients. Olanzapine-treated patients had a significantly greater increase in 1-hour glucose and insulin levels during OGTT in subsequent months compared to baseline and greater increase in glucose and insulin area under the curve over time than the risperdone-treated patients. Prolactin levels decreased in olanzapine patients and increased in risperidone patients (P values approximately .02). There were no significant drug treatment differences in C-peptide levels or 2 indices proposed as measures of insulin secretion or beta-cell function (homeostasis model assessment of beta-cell function [HOMA-B], BIGTT-acute insulin response surrogate measure [BIGTT-AIR]). Changes in insulin resistance over time were not strongly related to changes in BMI or waist circumference during study drug treatment. CONCLUSIONS: The increase in insulin levels during olanzapine treatment may compensate for the increase in insulin resistance and serve to reduce fasting and postprandial glucose levels. This may contribute to the lack of differences between olanzapine and risperidone in indices of diabetic or prediabetic glucose levels or glycohemoglobin. How many years this compensatory mechanism will persist needs further investigation. Periodic OGTT tests measuring glucose and insulin levels would be helpful in assessing the status of beta-cell insulin reserve in patients treated with olanzapine and other second-generation antipsychotics and assessing an individual patient's risk for conversion to type 2 diabetes. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00287820.

Lithium effect on renal glomerular function in individuals with intellectual disability.

OBJECTIVE: The current study evaluated the effects of chronic administration of lithium on renal functioning in an intellectually disabled population. METHODS: Fifty-seven lithium-treated individuals were compared with 24 behaviorally symptomatic controls using a retrospective chart review method. Serum creatinine levels and creatinine clearance activities were compared at baseline, at the time of peak creatinine levels, and at the end of the study in 2006. RESULTS: The mean length of lithium administration was 8.76 years (range, 1-23 years). Chronic lithium administration yielded a significant increase in peak serum creatinine levels and a decrease in the corresponding creatinine clearance activity. Of the subjects, 22.8% had peak creatinine levels of 1.5 mg or higher per 100 mL (a common threshold for renal insufficiency). This contrasted with 0% (none) for the symptomatic control subjects (P = 0.008). In addition, 26.3% of the lithium-treated subjects had creatinine clearance activities less than 55 mL/min and 17.5% had less than 50 mL/min, both indicative of renal insufficiency, versus none of the symptomatic control subjects (P = 0.004 and P = 0.029, respectively). With lithium withdrawal, further deterioration of renal function did not occur in most cases, and many showed improvement, with decreases in serum creatinine levels and increases in creatinine clearance activity. CONCLUSIONS: Chronic administration of lithium led to clinically significant increases in serum creatinine levels and decreases in creatinine clearance in lithium-treated intellectually disabled individuals.

Feasibility of reducing the duration of placebo-controlled trials in schizophrenia research.

Use of placebo-controlled trials in medical and psychiatric research has been controversial, although a consensus is emerging about conditions under which placebo-controlled trials are ethical. In schizophrenia research, the paradigm of slow onset of antipsychotic effects has led to a model in which placebo-controlled trials of 6-8 weeks duration have been used to demonstrate efficacy. Recent evidence that the largest symptom reductions are typically seen in the first weeks of treatment suggests that shorter placebo-controlled studies to demonstrate antipsychotic efficacy are possible. In a pilot study of the feasibility of shortening placebo-controlled studies, we reanalyzed data from placebo-controlled registry trials of olanzapine and risperidone and found that trials as short as 4 weeks could have similar power to longer term 6-8 week studies, given the estimated time course of treatment effects. Although fuller evaluation is required, the results suggest future antipsychotic trials could be shortened from 6-8 weeks to 3-4 weeks with a relatively low increase in sample size requirements. Shortening placebo-controlled trials would reduce patient burden and ethical objections to prolonged administration of placebo and reduce potential bias due to high dropout rates in longer clinical trials.

Functional interactions between Dlx2 and lymphoid enhancer factor regulate Msx2.

Dlx2, Lymphoid Enhancer Factor (Lef-1) and Msx2 transcription factors are required for several developmental processes. To understand the control of gene expression by these factors, chromatin immunoprecipitation (ChIP) assays identified Msx2 as a downstream target of Dlx2 and Lef-1. Dlx2 activates the Msx2 promoter in several cell lines and binds DNA as a monomer and dimer. A Lef-1 beta-catenin-dependent isoform minimally activates the Msx2 promoter and a Lef-1 beta-catenin-independent isoform is inactive, however co-expression of Dlx2 and both Lef-1 isoforms synergistically activate the Msx2 promoter. Co-immunoprecipitation and protein pull-down experiments demonstrate Lef-1 physically interacts with Dlx2. Deletion analyses of the Lef-1 protein reveal specific regions required for synergism with Dlx2. The Lef-1 beta-catenin binding domain (betaDB) is not required for its interaction with Dlx2. Msx2 can auto-regulate its promoter and repress Dlx2 activation. Msx2 repression of Dlx2 activation is dose-specific and both bind a common DNA-binding element. These transcriptional mechanisms correlate with the temporal and spatial expression of these factors and may provide a mechanism for the control of several developmental processes. We demonstrate new transcriptional activities for Dlx2, Msx2 and Lef-1 through protein interactions and identification of downstream targets.