Incidence, prescription patterns, and determinants of antipsychotic use in patients with Parkinson's disease.

Empirical data regarding the choice of antipsychotics for the management of psychosis in patients with Parkinson's disease are limited. This study aimed to evaluate the incidence and prescribing patterns of antipsychotics and to determine the predictors associated with the prescribing of typical antipsychotics in patients with Parkinson's disease. This was a retrospective cohort study analyzing data from the National Health Insurance Research Database in Taiwan between January 1, 2000, and December 31, 2006, in which patients with Parkinson's disease (ICD-9-CM codes 332) initially receiving any antiparkinsonian drug (n = 2095) were followed up to evaluate the subsequent use of antipsychotics. Kaplan-Meier statistics and multiple logistic regression were employed to evaluate the cumulative probability of antipsychotic use and determinants of prescribing of typical antipsychotics, respectively. The cumulative probability of initiation of an antipsychotic within 6 years was found to be 51%, and the proportion of patients who began taking an atypical antipsychotic increased from 11.1% in 2001 to 36.1% in 2005. Physician specialty was found to be the most influential predictor of the prescribing of typical antipsychotics: physicians with an internal medicine specialty were 10.62 times more likely (95% confidence interval, 4.64-24.32) to prescribe typical antipsychotics than were neurologists. The use of antipsychotics in Parkinson's disease is common, and the use of typical antipsychotics dominates antipsychotic treatment. Particular attention needs to be paid to improving practice, including efforts that encourage primary care providers to have the appropriate choice of antipsychotics in patients with Parkinson's disease.

Risk of digoxin intoxication in heart failure patients exposed to digoxin-diuretic interactions: a population-based study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Increased frequency of electrolyte abnormalities and cardiac arrhythmias among patients exposed to digoxin-diuretic interactions has been well-documented in numerous descriptive studies. * Nonetheless, a clear causal relationship has not been established in these studies. WHAT THIS STUDY ADDS * The risks of digoxin intoxication associated with use of digoxin in combination with any diuretic use, types of diuretics, combinations of diuretics, and individual diuretics were quantified using a population-based nested case-control study design. * The combined therapy of digoxin with any diuretic is associated with a 3.08-fold increase in the risk of digoxin intoxication. * Regarding diuretic class, the risk carried by loop diuretics is greater than that of thiazides or potassium-sparing diuretics, and the risk varies with different combinations of diuretic classes and individual diuretics. AIMS To quantify the digoxin intoxication risk associated with exposure to digoxin-diuretic interactions, and evaluate whether the risk varies by diuretic type, individually or in combination. METHODS This was a population-based nested case-control study in which data from the National Health Insurance Research Database (NHIRD) in Taiwan were analysed. RESULTS The study cohort comprised 154 058 heart failure (HF) patients taking digoxin between 2001 and 2004, in whom digoxin intoxication requiring a hospitalization (ICD-9 code 972.1) occurred in 595 cases. A total of 28 243 matched controls were also selected for analysis. Cases were 3.08 times (adjusted OR 3.08, 95% CI 2.50, 3.79) more likely to have been prescribed diuretic medication in the previous month than controls. Regarding the class of diuretics, loop diuretics carried the greatest risk (adjusted OR 2.97, 95% CI 2.35, 3.75), followed by thiazides (OR 2.36, 95% CI 1.70, 3.29) and potassium-sparing diuretics (OR 1.72, 95% CI 0.83, 3.56). The risk was also observed to vary with different combinations of diuretics, and the loops/thiazides/potassium-sparing diuretics combination carried the greatest risk (adjusted OR 6.85, 95% CI 4.93, 9.53). Among the individual diuretics examined, hydrochlorothiazide carried the greatest risk (adjusted OR 4.63, 95% CI 2.50, 8.57). CONCLUSIONS This study provided empirical evidence that digoxin-diuretic interactions increased the risk of hospitalization for digoxin intoxication in HF patients. The risk was particularly high for concomitant use of digoxin with a combination of loop diuretics, thiazide and potassium-sparing diuretics. The combined use of digoxin and diuretics should be avoided if possible.

Conditional mutation of Pkd2 causes cystogenesis and upregulates beta-catenin.

Loss of polycystin-2 (PC2) in mice (Pkd2(-/-)) results in total body edema, focal hemorrhage, structural cardiac defects, abnormal left-right axis, hepatorenal and pancreatic cysts, and embryonic lethality. The molecular mechanisms by which loss of PC2 leads to these phenotypes remain unknown. We generated a model to allow targeted Pkd2 inactivation using the Cre-loxP system. Global inactivation of Pkd2 produced a phenotype identical to Pkd2(-/-) mice with undetectable PC2 protein and perinatal lethality. Using various Cre mouse lines, we found that kidney, pancreas, or time-specific deletion of Pkd2 led to cyst formation. In addition, we developed an immortalized renal collecting duct cell line with inactive Pkd2; these cells had aberrant cell-cell contact, ciliogenesis, and tubulomorphogenesis. They also significantly upregulated beta-catenin, axin2, and cMyc. Our results suggest that loss of PC2 disrupts normal behavior of renal epithelial cells through dysregulation of beta-catenin-dependent signaling, revealing a potential role for this signaling pathway in PC2-associated ADPKD.

[Retracted] Pathogenetic mechanism of lipoid proteinosis caused by mutation of the extracellular matrix protein 1 gene.

After the publication of the above article, the Editor of Molecular Medicine Reports received an accusation that this paper contained material taken from the PhD thesis of Dr Xiao Bai of the China Academy of Medical Science & Peking Union Medical College, whose thesis entitled "Study on mutations of ECM1 in lipoid proteinosis" was published online in 2015. After having enquired with the authors regarding this allegation, the first author and the corresponding author, Dr Dong Gao, admitted that she had infringed the rights of Dr Bai, and that it was not appropriate that the following figures were published in the research article: Figs. 1, 2, 4, 5, 6 and 7, which coincided with Figs. 3, 19, 27, 29, 31, and 32 in her PhD thesis, respectively. Furthermore, the above article was submitted to Molecular Medicine Reports by Dr Gao without the prior knowledge of all the other authors. Therefore, Dr Gao has agreed with the recommendation of the Editor of Molecular Medicine Reports that the above article should be retracted from the publication on account of the inappropriate use of the figures, and for submitting the article without having received the approval of all the authors. All the named authors on the paper agree to the retraction. Dr Gao regrets her actions and the inconvenience that this retraction has caused, and sincerely apologizes to Dr Bai, to the Editor, and to the readership of the Journal. [the original article was published in Molecular Medicine Reports 17: 8087­8090, 2018; DOI: 10.3892/mmr.2018.8928].

Pathogenetic mechanism of lipoid proteinosis caused by mutation of the extracellular matrix protein 1 gene.

Lipoid proteinosis (LP) is a rare form of dermatosis with autosomal recessive inheritance. The present study hypothesized that an extracellular matrix protein 1 (ECM1) gene mutation forms the pathological basis of LP. The association between ECM1 mutation and LP; however, requires further investigation and was thus investigated in the present study. Injury skin tissue samples from patients with LP were collected, along with venous blood samples for genomic DNA extraction. Immunohistochemical staining was performed. Polymerase chain reaction (PCR) was then used to obtain an ECM1 gene fragment, which was sequenced and compared with healthy individuals. Histopathological examination revealed that all included patients fitted the features of LP and PCR amplification of the ECM1 gene in all patients obtained positive results. Patients with LP in the present study exhibited point mutations in the ECM1 gene, including one homozygous mutation (C220G) as previously reported, and one novel homozygous mutation c.508insCTG and two heterozygous mutations (C220G/P.R481X and c507delT/c.l473delT). LP is correlated with ECM1 gene mutation.

Expression and Significance of Cyclophilin J in Primary Gastric Adenocarcinoma.

BACKGROUND/AIM: Biomarkers are essential in early diagnosis and understanding of the molecular mechanism of human cancer. The expression of cyclophilin J, a novel member of the cyclophilin family, was investigated in primary gastric adenocarcinoma. MATERIALS AND METHODS: Western blot analysis was carried out on 36 paired tumor and normal tissue samples; immunohistochemical analysis was carried out on 120 gastric carcinoma tissues and normal adjacent tissue. RESULTS: Cyclophilin J protein was overexpressed in 72.2% of gastric carcinoma tissues compared to adjacent normal tissues. Immunohistochemical analysis revealed that cyclophilin J was overexpressed in 49.2% (59/120) and 23.3% (28/120) of gastric carcinoma tissues and adjacent tissues, respectively (p<0.05). Expression of cyclophilin J was associated with the degree of differentiation, but not with lymph node metastasis, gender or depth of tumor infiltration. The overall survival of patients showed no association with the overexpression of cyclophilin J protein. CONCLUSION: Cyclophilin J expression was up-regulated in gastric carcinoma compared to normal gastric tissues. However, in order to confirm its association with the survival of patients with gastric cancer, more cases need to be studied.

Better Clinical Efficiency of TILs for Malignant Pleural Effusion and Ascites than Cisplatin Through Intrapleural and Intraperitoneal Infusion.

BACKGROUND/AIM: To evaluate the clinical efficiency of tumor-infiltrating lymphocytes (TILs) compared to cisplatin for malignant pleural effusion and ascites through intrapleural and intraperitoneal infusion. PATIENTS AND METHODS: Thirteen patients with malignant pleural effusion and ascites were divided into a TIL-treated group and a cisplatin-treated group. Patients were given TILs or cisplatin, through intrapleural and intraperitoneal infusion respectively, after drainage of the malignant serous effusion by thoracentesis or abdominocentesis. RESULTS: The overall response rate and disease control rate of the TIL-treated group (33.33% and 83.33%) were higher than that of the cisplatin-treated group (28.57% and 71.43%). The progression-free survival for the TIL-treated group was significantly longer (p=0.002) and better than that of the cisplatin-treated group (66.67% vs. 28.57%). Quality of life apparently improved in the TIL-treated group and was clearly higher than that in the cisplatin-treated group. CONCLUSION: The use of TILs has a better clinical efficiency for malignant pleural effusion and ascites than cisplatin through intrapleural and intraperitoneal infusion without severe adverse effects.

The Efficacy of CIK-Based Immunotherapies for Advanced Solid Tumors.

OBJECTIVE: To investigate the efficacy of cytokine-induced killer cell-based immunotherapies in patients with advanced malignant solid tumors and the difference in clinical efficiency among 3 kinds of cytokine-induced killer cell-based immunotherapies. METHODS: One hundred forty-six cases with advanced solid tumor, 230 cycles of cytokine-induced killer cell-based immunotherapies, were involved in this study. T-lymphocyte subsets, carcinoembryonic antigen, and adverse reactions were recorded. RESULTS: CD3+ T lymphocyte, Th, NKT, and Th/Tc were increased after cytokine-induced killer cell-based treatment, from 55.67 ± 3.64 to 84.12 ± 5.15, 26.56 ± 4.47 to 42.76 ± 3.68, 1.82 ± 0.58 to 7.08 ± 0.92, 0.79 ± 3.64 to 1.35 ± 0.20, respectively ( P < .001). Carcinoembryonic antigen was decreased from 398.39 ± 219.16 to 127.26 ± 153.41 ( P < .001). Difference values were greater than 0 ( P < .001). Difference value of carcinoembryonic antigen was obviously less than 0 ( P < .001). There was no obvious difference in all variations between cytokine-induced killer cell and DC+CIK groups ( P > .05). The highest amount of CD3+ T lymphocyte and Th was recorded after at least 4 cycles of immunotherapy. And CD8+ T/CD4+ T also began to decrease after 4 cycles of immunotherapy. Difference value of T lymphocyte and Tc of patients with surgery is higher than that of patients without surgery. CONCLUSION: Cytokine-induced killer cell-based immunotherapy is capable of increasing T-lymphocyte subsets, recovering cellular immunity without severe side effects, and is suitable for different kinds of solid cancer. Clinical efficiency of cytokine-induced killer cell-based immunotherapy is influenced by many factors such as surgery, stage.

Interaction of cyclophilin A with a novel binding protein, SR-25, and characterization of their expression pattern in Chinese hepatocellular carcinoma patients.

Cyclophilin (Cyp) A has been reported to be overexpressed in the majority of cancer cells, including hepatocellular carcinoma (HCC). However, the biological functions of CypA in HCC are far from being understood. To determine the biological functions of CypA in HCC, the present study screened human fetal liver complementary DNA for proteins interacting with CypA using the yeast two-hybrid system. A nuclear protein, serine/arginine-rich (SR)-25, was isolated as a novel CypA-binding protein that is distinct from those previously described in the literature. Binding assays and co-immunoprecipitation confirmed the physical association between CypA and SR-25. The present study demonstrated that CypA may interact with SR-25 through its peptidyl-prolyl isomerase domain. In addition, CypA may induce the expression of SR-25 in Hep3B cells. The messenger RNA levels of CypA and SR-25 in HCC indicated that there was a significant correlation between the expression of CypA and the expression of SR-25 in HCC. It can be speculated that the interaction between CypA and SR-25 proteins may be involved in potential carcinogenic functions of CypA in HCC. Further studies will focus on elucidating in detail the molecular mechanisms of the interaction between CypA and SR-25.

[Expression and biology identification of the human epididymis-specific gene ESC42 in E. coli].

OBJECTIVE: To provide materials for the study of the function of ESC42 protein specifically expressed in the human epididymis. METHODS: The ESC42 gene was amplified from the human epididymis cDNA library by PCR and then cloned into prokaryotic expression vector pGEX-4T-1, expressed and purified by recombinant DNA techniques. The specificity of ESC42 protein was identified by Western blot and MALDI-TOF-MS. The database was searched by Ms-Fit. RESULTS: The recombinant plasmid expressed a Mr 38 x 10(3) fusion protein in E. coli at a level of 30% of the total protein, and the purity was as high as 99%. The ESC42 protein was identified by ESC42 monoclonal antibody and its molecular weight was 11 978.12, tested by MALDI-TOF-MS. The peptide mass fingerprint analysis showed that the coverage rate of the sequence reached 48% with 100% matching. The motif scan in Prosite database reveal that ESC42 belonged to the beta-defensin family and had antibacterial activity. CONCLUSION: Obtaining high purity of rhESC42 protein may lay a foundation for the study of its functions.

Multiple biomarkers of the cytotoxicity induced by BDE-47 in human embryonic kidney cells.

Polybrominated diphenyl ethers (PBDEs) are widely used as brominated flame-retardants in a variety of industrial products. Among these PBDEs, 2,2',4,4'-tetra-bromodiphenyl ether (BDE-47) is one of the most predominant congeners inducing multiple toxicities, including hepatotoxicity, neurotoxicity, cytotoxicity, genotoxicity, carcinogenecity and immunotoxicity in human body. In this study, the cytotoxicity of BDE-47 in human embryonic kidney cells (HEK293) was investigated by a set of bioassays, including cell proliferation, apoptosis, oxidative stress and metabolic responses as well as gene expressions related to apoptosis. Results showed that BDE-47 induced an inverted U-shaped curve of cell proliferation in HEK293 cells from 10(-6) to 10(-4) M. Cell apoptosis and ROS overproduction were detected at 10(-5) M of BDE-47 (p<0.05). In addition, the expressions of Bcl-2 family-encoding genes (Bad, Hrk and Bcl-2) increased significantly in 10(-4)M group (p<0.05). Metabolic responses indicated that BDE-47 mainly caused disturbance in energy metabolism marked by differentially altered ethanol, glutathione, creatine, aspartate, UDP-glucose and NAD(+). The increased lactate/alanine ratios indicated the higher reductive state induced by BDE-47 in all exposures confirmed by the overproduction of ROS.

Mycophenolate mofetil inhibits hypertrophy and apoptosis of podocyte in vivo and in vitro.

OBJECTIVE: The present study aimed to examine the effect of mycophenolate mofetil (MMF), a new immunosuppressive agent, on hypertrophy and apoptosis of podocyte, and investigate the underlying mechanisms. METHODS: Cultured rat podocyte were exposed to 5.6 mmol/L normal glucose or 25 mmol/L high glucose with mycophenolic acid (MPA) or Valsartan for 72 h. For animal studies, streptozotocin-induced diabetic rats were untreated or treated with MMF or Valsartan for 16 weeks. After 16 weeks of treatment, the weight of kidney and body, 24 hours urinary protein excretion and serum glucose was detected. Histomorphology of renal tissue was observed by optical microscope and electron microscope. Apoptosis of podocytes were determined by transferase-mediated dUTP nick-end labeling (TUNEL) test. The protein expressions of p21(cip1), p27(kip1), bax and bcl-2 were examined by Western blot. RESULTS: p27(kip1), p21(cip1) protein expression in podocytes exposed to high glucose for 72 h and in 16 weeks diabetic glomeruli significantly increased (P<0.01). The expressions of bax, cleaved caspase-3 increased while the expression of bcl-2 decreased in diabetic glomeruli as well as in high glucose. But they were all ameliorated in the groups treated with either MMF or Valsartan. CONCLUSION: MMF can inhibit abnormal hypertrophy and apoptosis of podocytes in the early stage of diabetes, partly by regulating the expression of cell cycle related protein p27(kip1), p21(cip1) and apoptosis related genes, such as bax, bcl-2 and cleaved caspase-3. These suggest that the protective effects of MMF on renal function maybe partly through inhibiting abnormal renal cell growth by regulating cell cycle or apoptosis related genes.

Priapism as the initial symptom of primary penile lymphoma: A case report.

Primary penile lymphoma presenting with priapism as the initial symptom is extremely rare. In total, <10 cases have been previously reported. The diagnosis can be difficult and patients often develop metastasis. The current study reports the case of a 48-year-old male, who presented with a one-month history of painless priapism. On admission to Yantai Yuhuangding Hospital Affiliated to Qingdao University (Yantai, China), examination revealed an erect penis, enlarged lymph nodes in the bilateral inguinal and swelling in the thighs. A biopsy was taken from the right inguinal lymph node and the pathological diagnosis confirmed a diffuse large B-cell type of non-Hodgkin's lymphoma, while an enhanced computed tomography scan of the chest revealed evidence of the invasion of malignant lymphoma cells. Priapism disappeared two days following the completion of the first cycle of chemotherapy with the E-CHOP regimen (cyclophosphamide, vincristine, prednisone, epirubicin and etoposide); however, evidence of brain metastases was observed one month later, which was confirmed by magnetic resonance imaging. The patient received cranial radiotheraphy and systemic treatment for cerebral edema. The patient did not respond well to treatment and succumbed to the disease three months following the initial diagnosis of lymphoma. Lymphoma may be difficult to diagnose, depending on the initial symptoms; therefore, the patient history must be carefully assessed so as to determine an early diagnosis and prevent metastasis, thus improving the prognostic outcome.

Loss of polycystin-1 inhibits Bicc1 expression during mouse development.

Bicc1 is a mouse homologue of Drosophila Bicaudal-C (dBic-C), which encodes an RNA-binding protein. Orthologs of dBic-C have been identified in many species, from C. elegans to humans. Bicc1-mutant mice exhibit a cystic phenotype in the kidney that is very similar to human polycystic kidney disease. Even though many studies have explored the gene characteristics and its functions in multiple species, the developmental profile of the Bicc1 gene product (Bicc1) in mammal has not yet been completely characterized. To this end, we generated a polyclonal antibody against Bicc1 and examined its spatial and temporal expression patterns during mouse embryogenesis and organogenesis. Our results demonstrated that Bicc1 starts to be expressed in the neural tube as early as embryonic day (E) 8.5 and is widely expressed in epithelial derivatives including the gut and hepatic cells at E10.5, and the pulmonary bronchi at E11.5. In mouse kidney development, Bicc1 appears in the early ureteric bud and mesonephric tubules at E11.5 and is also expressed in the metanephros at the same stage. During postnatal kidney development, Bicc1 expression gradually expands from the cortical to the medullary and papillary regions, and it is highly expressed in the proximal tubules. In addition, we discovered that loss of the Pkd1 gene product, polycystin-1 (PC1), whose mutation causes human autosomal dominant polycystic kidney disease (ADPKD), downregulates Bicc1 expression in vitro and in vivo. Our findings demonstrate that Bicc1 is developmentally regulated and reveal a new molecular link between Bicc1 and Pkd1.

Differentiation of fetal pancreatic stem cells into neuron-like and islet-like cells in vitro.

Pancreatic stem cells were isolated and cultured from aborted human fetal pancreases of gestational age 14-20 weeks. They were seeded at a density of 1 × 10(4) in serum-free media for differentiation into neuron-like cells, expressing ß-tubulin III and glial fibrillary acidic protein. These neuron-like cells displayed a synapse-like morphology and appeared to form a neuronal network. Pancreatic stem cells were also seeded at a density of 1 × 10(5) for differentiation into islet-like cells, expressing insulin and glucagon, with an islet-like morphology. These cells had glucose-stimulated secretion of human insulin and C-peptide. Results suggest that pancreatic stem cells can be differentiated into neuron-like and islet-like cells.

[Preparation and characterization of a polyclonal antibody against human Fibrocystin-L].

AIM: PKHDL1 (the gene for Polycystic Kidney and Hepatic Disease Like-1) had been recently identified, but characteristics of the gene product, Fibrocystin-L (FPC-L), still remain unknown. We therefore produced a rabbit polyclonal antibody hFL-Np to explore the cellular characteristics of this novel protein. METHODS: Based on the hydrophobic/hydrophilic analyses, chose a cDNA fragment which encodes 633L-768K amino acids of the FPC-L and amplified it by RT-PCR. The PCR product was then cloned into a prokaryotic expression vector pGEX-GST. With IPTG induction, the antigen hFL-N was produced and further purified. A rabbit was immunized with the antigen and its antiserum was collected. Applied Western blot with the polyclonal antiserum hFL-Np and validated the antibody specific for FPC-L protein. In addition, also used immunofluorescence staining with hFL-Np to detect the subcellular distribution in cultured HEK293 cells. RESULTS: The prokaryotic expression vector pGEX-hFL-N was successfully constructed and a hFL-N antigen was produced in E.coli Rossetta cells. Using the antigen, a polyclonal antibody hFL-Np was produced and the specificity for FPC-L was also proved by biochemistry and cellular assays. Using the antibody, the cellular staining reveals that FPC-L was a cytosolic protein. CONCLUSION: We produced an anti-FPC-L polyclonal antibody hFL-Np. By biochemistry and cellular characterization, proved that the polyclonal antibody hFL-Np is specific for FPC-L and demonstrated FPC-L is a cytosolic protein. The finding provides a platform for further dissecting FPC-L functions in mammalian development.

Loss of Bicc1 impairs tubulomorphogenesis of cultured IMCD cells by disrupting E-cadherin-based cell-cell adhesion.

The Bicaudal-C (Bic-C) gene was originally discovered in Drosophila melanogaster. The gene product Bic-C is thought to serve as an RNA-binding molecule targeting diverse proteins at the post-transcriptional level. Recent research has shown this gene to be conserved in many species, from Caenorhabditis elegans to humans. Disruption of this protein can disturb the normal migration direction of the anterior follicle cell of Drosophila oocytes, while mutation of a mouse Bicc1 (a mouse homologue of Bic-C) results in phenotypes mimicking human hereditary polycystic kidney disease (PKD). However, the cellular function of Bicc1 gene products in mammalian systems remains largely unknown. In this study, we established stable IMCD (mouse inner medullary collecting duct) cell lines, in which Bicc1 was silenced by short hairpin RNA inhibition (shRNA). We show that inhibition of Bicc1 disrupted normal tubulomorphogenesis and induced cystogenesis of IMCD cells grown in three dimensional cultures. To determine what factors contributed to the defect, we systematically examined biological changes of Bicc1-silenced IMCD cells. We found that the cells had significant defects in E-cadherin-based cell-cell adhesion, along with abnormalities in actin cytoskeleton organization, cell-extracellular matrix interactions, cell proliferation, and apoptosis. These findings suggest that lack of Bicc1 leads to disruption of normal cell-cell junctions, which in turn impedes establishment of epithelial polarity. These cellular defects may initiate abnormal tubulomorphogenesis and cystogenesis of IMCD cells grown in vitro. The observation of aberrant cellular behaviors in Bicc1-silenced IMCD cells reveal functions for Bicc1 in renal epithelial cells and provides insight into a potential pathogenic mechanism of polycystic kidney disease.