Adult Renal Dysfunction and Risk of Dementia or Cognitive Decline: Brain-Kidney Axis Hypothesis Based on a Systematic Review and Meta-Analysis.

OBJECTIVE: The brain-kidney axis was proposed to emphasize roles of kidney functioning in modulating neurodegeneration. We aimed to evaluate the associations of renal diseases and blood markers with risk of dementia or cognitive decline among non-demented adults. METHODS: The PubMed, EMBASE, and Cochrane library were searched until February 1st, 2022, to include longitudinal studies. Multivariate adjusted effects were pooled by random-effects models. The robust error meta-regression models were used for dose-response analyses. The credibility of meta-analyses was graded and an innovative index (Sdifference) was developed to evaluate the evidence tendency. RESULTS: A total of 41 longitudinal studies (6,480,136 participants, mean age range: 58.5-83.5 years) were included, of which 33 were for meta-analyses. Though with low level of evidence, five indicators of kidney were associated with increased risk of dementia or cognitive decline, including acute kidney injury (hazard ratio [HR] = 2.24, p = 0.0001), chronic kidney disease (HR = 1.29, p = 0.0001), higher serum creatinine (HR = 1.35, p = 0.0001), higher urine albumin creatine ratio (UACR, HR = 1.23, p = 0.0001), and lower estimated glomerular filtration rate (eGFR, HR = 1.18, p = 0.0001). A linear relationship was revealed for eGFR (p = 0.0217) or UACR (p = 0.0006). Heterogeneity is a main concern to jeopardize the evidence robustness, especially for eGFR (Sdifference = 0.05). CONCLUSION: Some renal indicators were associated with a higher risk of dementia, though the evidence base warrants further strengthening. Renal function management might serve as a promising target for dementia prediction and prevention.

A novel multiplex polymerase chain reaction assay for detection of both HLA-A*31:01/HLA-B*15:02 alleles, which confer susceptibility to carbamazepine-induced severe cutaneous adverse reactions.

HLA-A*31:01 and HLA-B*15:02 have been widely reported to confer genetic susceptibility to carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCARs). Accordingly, the screening for these alleles has been highly recommended to prevent SCAR prior to introducing CBZ therapy. Although a number of methods are available for screening of HLA-A*31:01 or HLA-B*15:02 alleles separately, developing an assay that can detect both these alleles would be more clinically practical, cost-effective and less time-consuming. Therefore, in this study, a multiplex polymerase chain reaction (PCR) using TaqMan Probe was designed and validated to be able to detect HLA-A*31:01 and HLA-B*15:02. In comparison with Luminex-SSO/SBT/SSB, the multiplex PCR assay for detection of HLA-A*31:01 and HLA-B*15:02 had a perfect agreement in the validation group of 125 samples. The method was able to detect the target genes at the DNA concentration of 0.037 ng/µL. The unit cost of this assay is less than $5 USD with total time of 110 minutes.

Thyroid hormone protects hepatocytes from HBx-induced carcinogenesis by enhancing mitochondrial turnover.

Infection by hepatitis B virus (HBV) accounts for 50-80% of hepatocellular carcinoma (HCC) development worldwide, in which the HBV-encoded X protein (HBx) has critical role in the induction of carcinogenesis. Several studies have shown that thyroid hormone (TH) suppresses HCC development and protects hepatocytes from HBx-induced damage, thus it is of interest to examine whether TH can protect hepatocytes from HBx-induced carcinogenesis. By treating HBx- transgenic mice with or without TH, we confirmed the protective effects of TH on HBx-induced hepatocarcinogenesis, which was achieved via reduction of reactive oxygen species (ROS) inflicted DNA damage. We further found that TH induced biogenesis of mitochondria (MITO) and autophagy of HBx-targeted MITO simultaneously, consequently leading to suppression of HBx-promoted ROS and carcinogenesis. Using microarray data analysis, this protective effect of TH was found to be mediated via activation of PTEN-induced kinase 1 (PINK1) in hepatocytes. PINK1, in turn, activated and recruited Parkin, an E3 ligase, to ubiquitinate MITO-associated HBx protein and trigger selective mitophagy. The pathological significance of the TH/PINK1 pathway in liver protection was confirmed by the concomitant decrease in expression of both TR and PINK1 in matched HCC tumor tissues and negatively correlated with aggressive progression of cancer and poor prognosis. Our data indicate that TH/PINK1/Parkin pathway has a critical role in protecting hepatocytes from HBx-induced carcinogenesis. Notably, several liver-targeting therapeutic derivatives of TH facilitating prevention or therapy of steatosis have been identified. Furthermore, our proof-of-concept experiments suggest that application of T3 constitutes an effective novel therapeutic or preventive option for HCC. Thus, the utilization of the agonists of TRs could be the meaningful strategy in liver relative diseases, ranging from simple hepatic steatosis to HCC.

[Association between XRCC1 polymorphisms and chromosome damage in workers exposed to benzene in jewelcrafting industry].

OBJECTIVE: To investigate the association between the gene polymorphisms of the DNA damage repair gene X-ray repair cross-complementing gene 1 (XRCC1) and susceptibility to chromosome damage in workers exposed to low-concentration benzene in the jewelcrafting industry. METHODS: A total of 286 workers exposed to benzene in jewelcrafting enterprises were enrolled as study subjects from January 2013 to December 2014. Gas chromatography was used to measure benzene concentration in workplace, cytokinesis-block micronucleus test was used to analyze the level of chromosome damage in peripheral blood, and the Sequenom technique was used to determine the single nucleotide polymorphisms of XRCC1. RESULTS: The time-weighted average concentration of benzene in workplace was <0.6~1.8 mg/m(3), lower than the national occupational exposure limit (6 mg/m(3)). The distribution of allele frequencies met the Hardy-Weinberg equilibrium in genetics (P>0.05). Increase in age (RR=1.38, 95%CI 1.06~3.75) and increase in working years (RR=1.45, 95%CI 1.18~2.58) were risk factors for the increase in micronucleus frequency. Compared with those with the wild-type homozygous genotype, the individuals with XRCC1 rs25487 CT genotype showed a significantly higher risk of increase in micronucleus frequency (RR=1.51, 95% CI 1.28~3.87, P<0.05) , and the individuals with XRCC1 rs1799782 AA genotype also showed a significantly higher risk of increase in micronucleus frequency (RR=1.65, 95% CI 1.30~3.12, P<0.05). There was no clear association between XRCC1 rs25489 polymorphisms and micronucleus frequency (P>0.05). CONCLUSION: Exposure to low-concentration benzene may cause chromosome damage in workers exposed to benzene, and the XRCC1 polymorphisms rs 25487 and rs1799782 may be associated with chromosome damage induced by benzene.

Thyroid hormone receptor represses miR-17 expression to enhance tumor metastasis in human hepatoma cells.

MicroRNAs (miRNAs) are thought to control tumor metastasis through direct interactions with target genes. Thyroid hormone (T3) and its receptor (TR) are involved in cell growth and cancer progression. However, the issue of whether miRNAs participate in T3/TR-mediated tumor migration is yet to be established. In the current study, we demonstrated that T3/TR negatively regulates mature miR-17 transcript expression, both in vitro and in vivo. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays localized the regions responding to TR-mediated repression to positions -2234/-2000 of the miR-17 promoter sequence. Overexpression of miR-17 markedly inhibited cell migration and invasion in vitro and in vivo, mediated via suppression of matrix metalloproteinases (MMP)-3. Moreover, p-AKT expression was increased in miR-17-knockdown cells that led to enhanced cell invasion, which was blocked by LY294002. Notably, low miR-17 expression was evident in highly metastatic cells. The cell migration ability was increased by T3, but partially reduced upon miR-17 overexpression. Notably, TRα1 was frequently upregulated in hepatocellular carcinoma (HCC) samples and associated with low overall survival (P=0.023). miR-17 expression was significantly negatively associated with TRα1 (P=0.033) and MMP3 (P=0.043) in HCC specimens. Data from our study suggest that T3/TR, miR-17, p-AKT and MMP3 activities are interlinked in the regulation of cancer cell metastasis.

Thyroid hormone suppresses cell proliferation through endoglin-mediated promotion of p21 stability.

Hypothyroidism has been associated with significantly elevated risk for hepatocellular carcinoma (HCC), although the precise underlying mechanisms remain unknown at present. Thyroid hormone (T3) and its receptor (TR) are involved in metabolism and growth. Endoglin is a T3/TR candidate target gene identified from our previous studies. Here, we demonstrated that T3 positively regulates endoglin mRNA and protein levels, both in vitro and in vivo. The thyroid hormone response elements of endoglin were identified at positions -2114/-2004 and -2032/-1973 of the promoter region using the electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Endoglin was downregulated in the subgroups of HCC patients and significantly associated with histology grade (negative association, P=0.001), and this expression level was significantly associated with TRα1 in these HCC patients. Our results clearly indicate that p21 is involved in T3-mediated suppression of cell proliferation. Knock down of endoglin expression in HCC cells facilitated p21 polyubiquitination and promoted cell proliferation in the presence of T3. The data collectively suggest that T3/TR signaling suppresses cell proliferation by upregulating endoglin, in turn, affecting p21 stability. The results indicate that endoglin has a suppressor role to inhibit cell proliferation in HCC cell lines.

Thyroid hormone receptors promote metastasis of human hepatoma cells via regulation of TRAIL.

Although accumulating evidence has confirmed the important roles of thyroid hormone (T(3)) and its receptors (TRs) in tumor progression, the specific functions of TRs in carcinogenesis remain unclear. In the present study, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was directly upregulated by T(3) in TR-overexpressing hepatoma cell lines. TRAIL is an apoptotic inducer, but it can nonetheless trigger non-apoptotic signals favoring tumorigenesis in apoptosis-resistant cancer cells. We found that TR-overexpressing hepatoma cells treated with T(3) were apoptosis resistant, even when TRAIL was upregulated. This apoptotic resistance may be attributable to simultaneous upregulation of Bcl-xL by T(3), because (1) knockdown of T(3)-induced Bcl-xL expression suppressed T(3)-mediated protection against apoptosis, and (2) overexpression of Bcl-xL further protected hepatoma cells from TRAIL-induced apoptotic death, consequently leading to TRAIL-promoted metastasis of hepatoma cells. Moreover, T(3)-enhanced metastasis in vivo was repressed by the treatment of TRAIL-blocking antibody. Notably, TRAIL was highly expressed in a subset of hepatocellular carcinoma (HCC) patients, and this high-level expression was significantly correlated with that of TRs in these HCC tissues. Together, our findings provide evidence for the existence of a novel mechanistic link between increased TR and TRAIL levels in HCC. Thus, TRs induce TRAIL expression, and TRAIL thus synthesized acts in concert with simultaneously synthesized Bcl-xL to promote metastasis, but not apoptosis.

Ergonomic study of a vertical rope-pulling task from a scaffolding.

The purpose of this study is to explore and assess manual material handling problems involving a vertical rope-pulling task from a scaffold (VRPS). Twenty-five young male Chinese subjects were recruited to participate in this study. The psychophysical method was used to investigate the effects of the rope material (nylon and hemp), rope diameter (6/8'' and 4/8''), object size (bucket diameter 28 cm and 36 cm), operating with and without gloves on the maximum acceptable rope-pulling weight (MAWR), rating of perceived exertion (RPE) and heart rate, respectively. The results showed that the maximum acceptable rope-pulling weights were significantly affected by the rope material, rope diameter, object size and wearing or not wearing gloves. The MAWR for the hemp rope, coarse rope, small object size and without gloves was significantly greater than that for the nylon rope, fine rope, large object size and with gloves, respectively. However, the effect of the rope material, rope diameter, object size and with and without gloves on heart rate was not significant. The mean RPE response was significantly influenced by the rope material, object size and wearing or not wearing gloves. The most stressed body parts were the arms, fingers and wrists. The interaction effect between the rope material and wearing or not wearing gloves was significant. Generally, the VRPS for workers using hemp rope without gloves or using nylon rope without gloves was better than that for the other combinations.

Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention-deficit/hyperactivity disorder (ADHD): increased prevalence of the 2-repeat allele.

There is an increased prevalence of the 7-repeat (7R) allele of the dopamine receptor D4 (DRD4) gene in attention-deficit/hyperactivity disorder (ADHD). However, the population prevalence of the 7R allele varies considerably across ethnicity and is very low in Asians. To test whether this 7R allele/ADHD association still held in a Chinese clinical sample, 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate-responders were genotyped. None of them had a DRD4 7R allele. Instead, we observed a significantly increased prevalence of the 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically-matched controls (20%) (chi(2)(1d.f.) = 5.90, P = 0.015). This approximately 1.65-fold increase of the 2R allele in our probands is close to the observed increase of the 7R allele in European-ancestry ADHD children. Recent genetic studies have indicated that the 2R allele in Asians is likely derived from the 7R allele. Further, available biochemical data indicate that both the 2R and 7R protein have blunted responses to dopamine compared to the 4R protein. Based on these results, we propose that the observed increased prevalence of the 2R allele in our Han Chinese ADHD probands is still consistent with the 7R allele hypothesis of ADHD in European-ancestry children. Recent studies have suggested that any variant from the conserved ancestral 4R allele might potentially alter biochemistry/phenotype. We hypothesize that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD that holds across ethnicity. The present findings, however, obtained with a small ADHD sample size, should be replicated.

High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder.

Associations have been reported of the 7-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention-deficit/hyperactivity disorder (ADHD). The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. Recently, based on the unusual DNA sequence organization and strong linkage disequilibrium surrounding the DRD4 7R allele, we proposed that this allele originated as a rare mutational event, which nevertheless increased to high prevalence in human populations by positive selection. We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. Interestingly, however, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in our prior population studies). Over 10 percent of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this high incidence of novel alleles occurred by chance in our ADHD sample is much less than 0.0001. These results suggest that allelic heterogeneity at the DRD4 locus may also contribute to the observed association with ADHD.

A sequence-ready map of the human chromosome 1q telomere.

A 260-kb half-YAC clone derived from human chromosome 1q was mapped at high resolution using cosmid subclone fingerprint analysis and was integrated with overlapping clones from the telomeric end of a separately derived 1q44 BAC contig to create a sequence-ready map extending to the molecular telomere of 1q. Analysis of 100 kb of sample sequences from across the 260-kb region encompassed by the half-YAC revealed the presence of EST sequence matches corresponding to 12 separate Unigene clusters and to 12 separate unclustered EST sequences. Low-copy subtelomeric repeats typical of many human telomere regions are present within the distal-most 30 kb of 1q. The previously isolated and radiation hybrid-mapped markers Bda84F03, 1QTEL019, and WI11861 localized at distances approximately 32, 88, and 99 kb, respectively, from the 1q terminus. This sequence-ready map permits high-resolution integration of genetic maps with the DNA sequences directly adjacent to the tip of human chromosome 1q and will enable telomeric closure of the human chromosome 1q DNA reference sequence by connecting the molecular 1q telomere to an internal BAC contig.

Integration of telomere sequences with the draft human genome sequence.

Telomeres are the ends of linear eukaryotic chromosomes. To ensure that no large stretches of uncharacterized DNA remain between the ends of the human working draft sequence and the ends of each chromosome, we would need to connect the sequences of the telomeres to the working draft sequence. But telomeres have an unusual DNA sequence composition and organization that makes them particularly difficult to isolate and analyse. Here we use specialized linear yeast artificial chromosome clones, each carrying a large telomere-terminal fragment of human DNA, to integrate most human telomeres with the working draft sequence. Subtelomeric sequence structure appears to vary widely, mainly as a result of large differences in subtelomeric repeat sequence abundance and organization at individual telomeres. Many subtelomeric regions appear to be gene-rich, matching both known and unknown expressed genes. This indicates that human subtelomeric regions are not simply buffers of nonfunctional 'junk DNA' next to the molecular telomere, but are instead functional parts of the expressed genome.

Population structure and history in East Asia.

Archaeological, anatomical, linguistic, and genetic data have suggested that there is an old and significant boundary between the populations of north and south China. We use three human genetic marker systems and one human-carried virus to examine the north/south distinction. We find no support for a major north/south division in these markers; rather, the marker patterns suggest simple isolation by distance.

Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention.

An association of the dopamine receptor D4 (DRD4) gene located on chromosome 11p15.5 and attention deficit/hyperactivity disorder (ADHD) has been demonstrated and replicated by multiple investigators. A specific allele [the 7-repeat of a 48-bp variable number of tandem repeats (VNTR) in exon 3] has been proposed as an etiological factor in attentional deficits manifested in some children diagnosed with this disorder. In the current study, we evaluated ADHD subgroups defined by the presence or absence of the 7-repeat allele of the DRD4 gene, using neuropsychological tests with reaction time measures designed to probe attentional networks with neuroanatomical foci in D4-rich brain regions. Despite the same severity of symptoms on parent and teacher ratings for the ADHD subgroups, the average reaction times of the 7-present subgroup showed normal speed and variability of response whereas the average reaction times of the 7-absent subgroup showed the expected abnormalities (slow and variable responses). This was opposite the primary prediction of the study. The 7-present subgroup seemed to be free of some of the neuropsychological abnormalities thought to characterize ADHD.

Genetic analysis of West Nile New York 1999 encephalitis virus.

Analysis of the genome of the flavivirus responsible for the 1999 New York City encephalitis epidemic cloned from human brain by reverse-transcription polymerase chain reaction Indicates its identity as a lineage I West Nile virus (WNV; WNV-NY1999) closely related to WNVs previously isolated In the Middle East.

An integrated physical map of human chromosome 16.

We describe an integrated physical, genetic and cytogenetic map of human chromosome 16 comprising both a low-resolution megaYAC map and a high-resolution cosmid contig/miniYAC map, which provides nearly complete coverage of the euchromatic arms of the chromosome. The physical map is anchored to a high-resolution cytogenetic breakpoint map and is integrated with genetic and gene transcript maps of the chromosome by sequence-tagged sites and clone hybridizations.

Structure of the Drosophila gene for the laminin B2 chain.

We isolated and sequenced a Drosophila genomic DNA sequence that encodes the entire coding region of the laminin B2 chain. The 11,464-bp genomic sequence contains a 2.1-kb of 5'-flanking DNA, ten exons, nine introns, and the 3'-flanking region. The first exon encodes a 5' untranslated region; the ATG translational start codon is in exon 2. The entire translated region is within a 8.3-kb Eco RI fragment. The Drosophila laminin B2 gene differs substantially in size and exon pattern from those of the human B1 and B2 genes. However, as in the case of the human B1 gene, the overall exon pattern of the Drosophila B2 gene does not correlate well with the highly conserved structural domains and internal repeats of the B2 polypeptide chain. Unlike the human and mouse B1 and B2 genes, the 2.1-kb 5'-flanking region of the Drosophila B2 gene contains a TATA box and two CAAT boxes. Other potential transcriptional regulatory sequences include two reverse complementary cAMP response element sequences; two sequences that are homologous to the retinoic acid response element motifs of the mouse B1 gene; and sequences homologous to the binding sites for transcription factors dFRA and dJRA, zeste, and possibly GAGA. When transfected into Drosophila SL-2 cells, pCAT plasmid containing 2,090 bp of 5'-flanking region shows a 3.0- to 3.5-fold increase in chloramphenicol acetyltransferase activity after induction with retinoic acid and/or 8-bromo-cAMP. These results suggest that this 5'-flanking promoter region may contain DNA sequences that can regulate the expression of the laminin B2 gene.

Primary structure of the Drosophila laminin B2 chain and comparison with human, mouse, and Drosophila laminin B1 and B2 chains.

Laminin, a major component of basement membranes, is a large glycoprotein consisting of three disulfide-bonded subunits, A, B1, and B2. We have isolated and sequenced a Drosophila laminin B2 chain cDNA clone that spans 5737 nucleotides. The deduced amino acid sequence predicts that the mature and nonglycosylated polypeptide has a chain length of 1606 residues (Mr = 178,665). This B2 chain contains 100 half-cystine residues, most of which are located in two cysteine-rich domains, and 11 N-X-S or N-X-T sequences which are potential sites of N-linked glycosylation. The predicted secondary structure reveals the presence of six structurally distinct domains, of which two are mainly alpha-helical, two are cysteine-rich with homologous repeats, and two are globular regions. The Drosophila B2 chain is 40.3 and 41.1% identical to the human and mouse B2 chains, respectively, and 29.6, 30.0, and 29.4% identical to the Drosophila, human, and mouse B1 chains, respectively.