Improved life expectancy for Indigenous and non-Indigenous people in the Northern Territory, 1999-2018: overall and by underlying cause of death.

OBJECTIVES: To provide updated estimates of life expectancy at birth for Indigenous and non-Indigenous people in the Northern Territory, 1999-2018; to quantify the contributions of changes in life years lost to disease-specific causes of death to overall changes in life expectancy. DESIGN, SETTING, PARTICIPANTS: Analysis of Australian Coordinating Registry data on underlying and nine multiple causes of death (ICD-10) for deaths in the NT, by age, sex, and Indigenous status, 1 January 1999 - 31 December 2018. MAIN OUTCOME MEASURES: Life expectancy at birth by year and 5-year period, by Indigenous status and sex; change in life expectancy by year and 5-year period, by Indigenous status and sex; contributions in changes in life years lost to leading underlying causes of death, by 5-year period, Indigenous status and sex. RESULTS: Life expectancy for Indigenous men increased from 56.6 years in 1999 to 65.6 years in 2018 (change, 9.0 years; 95% CI, 7.9-10.0 years) and from 64.8 to 69.7 years for Indigenous women (4.9 years; 95% CI, 3.2-6.7 years); for non-Indigenous men, it increased from 77.4 to 81.0 years (3.6 years; 95% CI, 2.8-4.4 years), and from 84.3 to 85.1 years for non-Indigenous women (0.8 years; 95% CI, -0.4 to 1.9 years). Increased life expectancy for Indigenous men was primarily linked with fewer years of life lost to cancer (23% of overall change), unintentional injuries (18%), and cardiovascular disease (17%), and for Indigenous women with fewer life years lost to cancer (24%), intentional injuries (17%), and kidney disease (14%). During 1999-2018, the difference in life expectancy between Indigenous and non-Indigenous people declined by 26% for men (from 20.8 to 15.4 years) and by 21% for women (from 19.5 to 15.4 years). CONCLUSIONS: Life expectancy improved markedly during 1999-2018 for Indigenous people in the NT, particularly with respect to fewer years of life lost to cancer, injuries, and chronic disease. The smaller gains in life expectancy for non-Indigenous people were linked with improved survival for those with cancer and neurological conditions.

Does delay in planned diabetes care influence outcomes for aboriginal Australians? A study of quality in health care.

BACKGROUND: To examine the association between delay in planned diabetes care and quality of outcomes. METHODS: A retrospective analysis of primary care and inpatient records for 2567 Aboriginal patients, with diabetes, living in 49 remote communities in the Northern Territory of Australia. Poisson regression was used to estimate the association between delay from diagnosis to documented diabetes care plan and three outcome measures: mean HbA1c level, most recent blood pressure and number of diabetes-related hospital admissions. RESULTS: Compared with no delay (< 60 days), patients with delay had increased risk of elevated mean HbA1c: 60 days to < 2 years, incidence rate ratio (IRR), 1.2 (95% CI:1.07-1.39); 2 years to < 4 years, incidence rate ratio (IRR), 1.2 (95% CI:1.04-1.45); 4 years and over, incidence rate ratio (IRR), 1.3 (95% CI:1.12-1.52). There was no evidence of association between delay and optimal blood pressure control. Risk of diabetes-related admission increased with increased delay. Compared with no delay the IRRs for delay were: 60 days to < 2 years, 1.2 (95% CI:1.07-1.42); 2 to < 4 years, 1.3 (95% CI: 1.15-1.58): and 4 years and over, 2.6 (95% CI,2.28-3.08). CONCLUSION: The study found that a timely diabetes care plan was associated with better short-term blood glucose control and fewer diabetes-related admissions but not with improved blood pressure control. Delays may be a result of both patient and service-related factors.

Estimating the total prevalence and incidence of end-stage kidney disease among Aboriginal and non-Aboriginal populations in the Northern Territory of Australia, using multiple data sources.

BACKGROUND: Most estimates for End Stage Kidney Disease (ESKD) prevalence and incidence are based on renal replacement therapy (RRT) registers. However, not all people with ESKD will commence RRT and estimates based only on RRT registry data will underestimate the true burden of ESKD in the community. This study estimates the total number of Northern Territory (NT) residents with ESKD including: those receiving RRT, those diagnosed but not receiving RRT and an estimate of "undiagnosed" cases. METHODS: Four data sources were used to identify NT residents with a diagnosis of ESKD: public hospital admissions, Australia and New Zealand Dialysis and Transplant Registry registrations, death registrations and, for the Aboriginal population only, electronic primary care records. Three data sources contained information recorded between 1 July 2008 and 31 December 2013, death registration data extended to 31 December 2014 to capture 2013 prevalent cases. A capture-recapture method was used to estimate both diagnosed and undiagnosed cases by making use of probability patterns of overlapping multiple data sources. RESULTS: In 2013, the estimated ESKD prevalence in the NT Aboriginal population was 11.01 (95% confidence interval (CI) 10.24-11.78) per 1000, and 0.90 (95% CI 0.76-1.05) per 1000 in the NT non-Aboriginal population. The age-adjusted rates were 17.97 (95% CI 17.82-18.11) and 1.07 (95% CI 1.05-1.09) per 1000 in the NT Aboriginal and non-Aboriginal populations respectively. The proportion of individuals receiving RRT was 71.4% of Aboriginal and 75.5% of non-Aboriginal prevalent ESKD cases. The age-adjusted ESKD incidence was also greater for the Aboriginal (5.26 (95% CI 4.44-6.08) per 1000 population) than non-Aboriginal population (0.36 (95% CI 0.25-0.47) per 1000). CONCLUSION: This study provides comprehensive estimates of the burden of ESKD including those cases that are not identified in relevant health data sources. The results are important for informing strategies to reduce the total burden of ESKD and to manage the potential unmet demand, particularly from comparatively young Aboriginal patients who may be suitable for RRT but do not currently access the services for social, geographic or cultural reasons.

Progress in closing the gap in life expectancy at birth for Aboriginal people in the Northern Territory, 1967-2012.

OBJECTIVES: To compare long term changes in mortality and life expectancy at birth (LE) of Aboriginal people in the Northern Territory and of the overall Australian population; to determine the contributions of changes in mortality in specific age groups to changes in LE for each population. DESIGN, SETTING, PARTICIPANTS: Retrospective trend analysis of death and LE data for the NT Aboriginal and Australian populations, 1967-2012. MAIN OUTCOME MEASURES: LE estimates based on abridged life tables; mortality estimates (deaths per 100 000 population); and age decomposition of LE changes by sex and time period. RESULTS: Between 1967 and 2012, LE increased for both NT Aboriginal and all Australians; the difference in LE between the two populations declined by 4.6 years for females, but increased by one year for males. Between 1967-1971 and 1980-1984, LE of NT Aboriginal people increased rapidly, particularly through reduced infant mortality; from 1980-1984 to 1994-1998, there was little change; from 1994-1998 to 2008-2012, there were modest gains in older age groups. Decomposition by age group identified the persistent and substantial contribution of the 35-74-year age groups to the difference in LE between NT Aboriginal people and all Australians. CONCLUSIONS: Early gains in LE for NT Aboriginal people are consistent with improvements in nutrition, maternal and infant care, and infectious disease control. A rapid epidemiological transition followed, when LE gains in younger age groups plateaued and non-communicable diseases became more prevalent. Recent LE gains, across all adult age groups, are consistent with improved health service access and chronic disease management. If LE is to continue improving, socio-economic disadvantage and its associated risks must be reduced.

Suppression of LPS-induced tau hyperphosphorylation by serum amyloid A.

BACKGROUND: Accumulation of hyperphosphorylated tau is a major neuropathological feature of tauopathies including Alzheimer's disease (AD). Serum amyloid A (SAA), an acute-phase protein with cytokine-like property, has been implicated in amyloid deposition. It remains unclear whether SAA affects tau hyperphosphorylation. METHODS: Potential involvement of SAA in tau hyperphosphorylation was examined using intracerebral injection of SAA, and in Saa3 (-/-) mice receiving systemic administration of lipopolysaccharide (LPS). Induced SAA expression and microglial activation were evaluated in these mice using real-time PCR and/or immunofluorescence staining. Cultured primary neuronal cells were treated with condition media (CM) from SAA-stimulated primary microglial cells. The alteration in tau hyperphosphorylation was determined using Western blotting. RESULTS: Saa3 is the predominant form of SAA proteins induced by LPS in the mouse brain that co-localizes with neurons. Overexpression of SAA by intracerebral injection attenuated tau hyperphosphorylation in the brain. Conversely, Saa3 deficiency enhanced tau phosphorylation induced by systemic LPS administration. Intracerebral injection of SAA also induced the activation of microglia in the brains. IL-10 released to CM from SAA-stimulated microglia attenuated tau hyperphosphorylation in cultured primary neurons. IL-10 neutralizing antibody reversed the effect of SAA in the attenuation of tau phosphorylation. CONCLUSIONS: LPS-induced expression of SAA proteins in the brain leads to the activation of microglia and release of IL-10, which in turn suppresses tau hyperphosphorylation in a mouse model of systemic inflammation.

Trends in hospital admissions involving suicidal behaviour in the Northern Territory, 2001-2013.

OBJECTIVE: To investigate trends in hospital admissions involving suicidal behaviour in the Northern Territory (NT) resident population over the period 2001-2013. METHODS: Estimates of age-standardised rates and average changes in the annual rate of hospital admissions involving suicidal behaviour were calculated by socio-demographic characteristics and types of suicidal behaviour. RESULTS: Overall rates for Indigenous admissions were 2.7 times higher than non-Indigenous admissions and had increased by almost twice as much. While male and female rates of admission were similar for both Indigenous and non-Indigenous residents, the average annual change in rates was greater for Indigenous females (13.4%) compared to males (8.8%) and for non-Indigenous males (7.7%) compared to females (5.2%). Younger and middle-aged Indigenous admissions experienced increasing rates of admissions, whilst trends were similar across age groups for non-Indigenous admissions. Admissions with a diagnosis of suicidal ideation increased the most across all groups. Trends in intentional self-harm admissions differed according to Indigenous status and sex. CONCLUSIONS: There have been substantial increases in hospital admissions involving suicidal behaviour in the NT, most markedly for Indigenous residents. Indigenous females and youth appear to be at increasing risk. The steep increase in suicidal ideation across all groups warrants further investigation.

Deficiency of macrophage migration inhibitory factor attenuates tau hyperphosphorylation in mouse models of Alzheimer's disease.

BACKGROUND: Pathological features of Alzheimer's disease (AD) include aggregation of amyloid beta (Aß) and tau protein. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been implicated in the toxicity of aggregated Aß. It remains unclear whether MIF affects hyperphosphorylation and aggregation of tau. METHODS: The effects of MIF deficiency in tau hyperphosphorylation were examined in Mif (-/-) mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ) and in APP/PS1 transgenic mice mated with Mif (-/-) mice. MIF expression and astrocyte activation were evaluated in ICV-STZ mice using immunofluorescence staining. Cultured primary astrocytes were treated with high glucose to mimic STZ function in vitro, and the condition medium (CM) was collected. The level of tau hyperphosphorylation in neurons treated with the astrocyte CM was determined using Western blotting. RESULTS: MIF deficiency attenuated tau hyperphosphorylation in mice. ICV injection of STZ increased astrocyte activation and MIF expression in the hippocampus. MIF deficiency attenuated astrocyte activation in ICV-STZ mice. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in cultured primary neurons, an effect absent from Mif (-/-) astrocytes and WT astrocytes treated with the MIF inhibitor ISO-1. ISO-1 had no direct effect on tau phosphorylation in cultured primary neurons. CONCLUSIONS: These results suggest that MIF deficiency is associated with reduced astrocyte activation and tau hyperphosphorylation in the mouse AD models tested. Inhibition of MIF and MIF-induced astrocyte activation may be useful in AD prevention and therapy.

Impact of perinatal health and socio-demographic factors on school education outcomes: A population study of Indigenous and non-Indigenous children in the Northern Territory.

AIM: This study investigated the association between early-life risk factors and school education outcomes. METHODS: This is an historical cohort study of 7601 children (61% were Indigenous) born in the Northern Territory between 1999 and 2004. Information was linked, for each child on: perinatal health, student enrolment and National Assessment Program - Literacy and Numeracy (NAPLAN) Year 3 results. Logistic regression was used to estimate the association between selected risk factors and a NAPLAN result 'below' the national minimum standard (NMS) in reading and numeracy. RESULTS: Indigenous children had much higher odds, than non-Indigenous children, of a result below the NMS for both reading (odds ratio (OR): 8.58, 95% confidence interval (CI): 7.55-9.74) ) and numeracy (OR: 11.52, 95% CI: 9.94-13.35). When adjusted for all other variables, the increased odds were attenuated for both reading (OR: 2.89, 95% CI: 2.46-3.40) and numeracy (OR: 3.19, 95% CI: 2.65-3.84). Common risk factors for Indigenous and non-Indigenous children included higher birth order, maternal smoking in pregnancy and being a boy. There were gradients of decreasing risk with increasing education level of primary care giver and increasing maternal age. Among Indigenous children only, risks increased when living in remote areas, with younger age (<8 years) and low birthweight. CONCLUSIONS: The study highlights that many of the risk factors associated with poor education outcomes among Indigenous children are shared with the general population. The results inform a targeted, cross-agency response to address modifiable early-life risk factors for educational disadvantage. Data linkage, using existing administrative datasets, provides a useful addition to methods that identify priority areas for prevention and early intervention.

Dementia prevalence and incidence among the Indigenous and non-Indigenous populations of the Northern Territory.

OBJECTIVE: To estimate the prevalence and incidence of dementia in Northern Territory Indigenous and non-Indigenous populations. DESIGN, SETTING AND PARTICIPANTS: Four data sources were used to identify clients with a diagnosis of dementia, from 1 January 2008 to 31 December 2011. The data sources included hospital admissions, aged care services, primary care and death registration. A capture-recapture method was used to estimate prevalence and incidence, including both diagnosed and unknown cases. MAIN OUTCOME MEASURES: Prevalence and incidence of dementia among the NT Indigenous and non-Indigenous populations. RESULTS: In 2011, the estimated prevalence in the NT Indigenous population aged 45 years and over was 3.7 per 100, and 1.1 per 100 in the corresponding NT non-Indigenous population. The age-adjusted prevalence for the NT Indigenous population was 6.5 per 100, compared with the NT non-Indigenous prevalence of 2.6 per 100, which was similar to the national rate. The prevalence rate ratios of NT Indigenous to NT non-Indigenous men and women, respectively, were: 6.5 and 5.5 for the 45-64-years age group, 4.0 and 4.1 for those aged 65-74 years and 2.1 and 1.9 for those aged 75 years and over. The age-adjusted incidence among the NT Indigenous population aged 45 years and over (27.3 per 1000 person-years) was higher than that among the NT non-Indigenous population (10.7 per 1000 person-years). CONCLUSION: The NT Indigenous population has a much higher prevalence and incidence of dementia and younger onset of disease compared with their non-Indigenous counterparts. The results highlight the urgent need for interventions to moderate the emerging impact of dementia in the Australian Indigenous population.

Development and validation of a neoadjuvant chemotherapy pathological complete remission model based on Reg IV expression in breast cancer tissues: a clinical retrospective study.

OBJECTIVE: To develop and authenticate a neoadjuvant chemotherapy (NACT) pathological complete remission (pCR) model based on the expression of Reg IV within breast cancer tissues with the objective to provide clinical guidance for precise interventions. METHOD: Data relating to 104 patients undergoing NACT were collected. Variables derived from clinical information and pathological characteristics of patients were screened through logistic regression, random forest, and Xgboost methods to formulate predictive models. The validation and comparative assessment of these models were conducted to identify the optimal model, which was then visualized and tested. RESULT: Following the screening of variables and the establishment of multiple models based on these variables, comparative analyses were conducted using receiver operating characteristic (ROC) curves, calibration curves, as well as net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Model 2 emerged as the most optimal, incorporating variables such as HER-2, ER, T-stage, Reg IV, and Treatment, among others. The area under the ROC curve (AUC) for Model 2 in the training dataset and test dataset was 0.837 (0.734-0.941) and 0.897 (0.775-1.00), respectively. Decision curve analysis (DCA) and clinical impact curve (CIC) further underscored the potential applications of the model in guiding clinical interventions for patients. CONCLUSION: The prediction of NACT pCR efficacy based on the expression of Reg IV in breast cancer tissue appears feasible; however, it requires further validation.

Survey of human papillomavirus types and their vertical transmission in pregnant women.

BACKGROUND: The prevalence, genotypes, and vertical transmission characteristics of human papillomavirus (HPV) among pregnant women from Nanjing, China was investigated. METHODS: Cervical cells were collected from healthy pregnant women (n = 3139; stage of gestation, 24.6 ± 2.1 weeks) for cytological evaluation and determination of HPV infection status. Exfoliated oral and genital cells were collected from neonates (<1-day-old, n = 233) whose mothers were positive for HPV DNA. We used HPV Gene Chip technology with 23 HPV genotype probes to conduct our analysis. RESULTS: Overall prevalence of HPV DNA among pregnant women was 13.4% (422/3139). The most frequently detected HPV genotypes were HPV-16 (29.6%, 125/422), -18 (14.7%, 62/422), and -58 (14.2%, 60/422). The rate of concordance for HPV DNA in maternal-neonatal pairs was 23.6% (55/233), with HPV type-specific concordance occurring in 26 cases. A higher prevalence of HPV DNA was apparent in female neonates compared with males (17.7 vs. 11.6%). CONCLUSIONS: The prevalence of cervical HPV DNA in pregnant women from Nanjing was low, with vertical transmission rates slightly higher. From our findings, we concluded that there was efficient vertical transmission of three HPV genotypes, with HPV-16 the most prevalent type in pregnant women and newborn babies.

Trends in alcohol-attributable hospitalisation in the Northern Territory, 1998-99 to 2008-09.

OBJECTIVE: To examine trends in hospitalisation for alcohol-attributable conditions in the Northern Territory Aboriginal and non-Aboriginal populations between the financial years 1998-99 and 2008-09. DESIGN AND SETTING: Retrospective descriptive analysis of inpatient discharge data from NT public hospitals. MAIN OUTCOME MEASURES: Alcohol-attributable hospitalisation by age, sex, Aboriginality, region of residence and medical conditions, with annual time trends. RESULTS: Annual rates of hospitalisation for alcohol-attributable conditions across the NT increased from 291.3 per 10,000 population to 460.0 per 10,000 (57.9%) among Aboriginal males and from 181.8 per 10,000 to 387.4 per 10,000 (113.1%) among Aboriginal females over the study period. The alcohol-attributable hospitalisation rate also increased from 58.8 per 10,000 population to 87.4 per 10,000 (48.6%) among non-Aboriginal males and from 16.8 per 10,000 to 37.2 per 10,000 (121.4%) among non-Aboriginal females. Alcohol-attributable hospitalisation rates among Aboriginal people living in Central Australia were much higher than in the Top End. In Central Australia, the rates for Aboriginal females increased throughout the study period, but for Aboriginal males declined from 2004-05 onwards. CONCLUSION: Rates of hospitalisation for alcohol-attributable conditions were high among NT Aboriginal people and increased during the study period. Although not statistically significant, the moderation in rates among Central Australian Aboriginal males after 2004-05 is encouraging. This apparent improvement is consistent with another recent study and provides tentative support that recent policy changes and interventions may be having an impact. The results of this study highlight the burden of alcohol use in the NT and emphasise the need for ongoing investment in comprehensive alcohol-management programs.

Trend analysis of hospital admissions attributable to tobacco smoking, Northern Territory Aboriginal and non-Aboriginal populations, 1998 to 2009.

BACKGROUND: Tobacco smoking is a well-recognised risk factor for many diseases [1]. This study assesses the extent of smoking-attributable hospitalisation in the Northern Territory (NT) Aboriginal and non-Aboriginal populations, and examines smoking-attributable hospitalisation trends for the years 1998/99 to 2008/09. METHODS: Hospital discharge data were used for the analysis. The proportion of conditions attributable to tobacco smoking was calculated using the aetiological fraction method. Age-adjusted smoking-attributable hospitalisation rates were calculated to describe the impact of tobacco smoking on the health of Territorians. A negative binominal regression model was applied to examine trends in smoking-attributable hospitalisations. RESULTS: Aboriginal Territorians were found to have higher rates of smoking-attributable hospitalisation, with Aboriginal males more than three times and Aboriginal females more than four times more likely to be hospitalised for smoking-attributable conditions than their non-Aboriginal counterparts. The age-adjusted hospitalisation rate for Aboriginal males increased by 31% and for Aboriginal females by 18% during the study period. There were more modest increases for NT non-Aboriginal males and females (5% and 17% respectively). The increase among Aboriginal males occurred up until 2005/06 followed by moderation in the trend. There were small reductions in smoking-attributable hospitalisation rates among all populations in younger age groups (less than 25 years). CONCLUSIONS: Aboriginal Territorians experience much higher smoking-attributable hospitalisation rates than non-Aboriginal Territorians. The scale of the smoking burden and suggestion of recent moderation among Aboriginal men reinforce the importance of tobacco control interventions that are designed to meet the needs of the NT's diverse population groups. Preventing smoking and increasing smoking cessation rates remain priorities for public health interventions in the NT.

[Association between polymorphism of IRF6 rs2235371 locus and nonsyndromic cleft lip with or without cleft palate].

OBJECTIVE: To assess the association between polymorphism of interferon regulatory factor 6 (IRF6) gene rs2235371 locus and nonsyndromic cleft lip with or without cleft palate in Chinese population. METHODS: Blood samples from 106 patients and their parents and 129 controls and their parents were collected. The polymorphism of IRF6 rs2235371 locus was determined with PCR-restriction fragment length polymorphism (PCR-RFLP) method. Case-control analysis, transmission disequilibrium test(TDT), haplotype-based haplotype relative risk analysis (HHRR) and family-based association test (FBAT) were carried out. RESULTS: By case-control analysis, no significant difference was found in the frequencies of GG, GA and AA genotypes of rs2235371 locus between the patient group and control group (P> 0.05), but there was a significant difference in allelic frequencies (P< 0.05). There was also a significant difference in genotype and gene frequencies of rs2235371 variant between family members from cleft lip only group and control group. However, in cleft lip with cleft palate group, no such difference was observed. TDT analysis suggested a linkage in the presence of disequilibrium (chi-square=5.56, P=0.024). Results of HHRR analysis (chi-square=5.115, P=0.024) and FBAT (Z=2.218, P=0.027) also indicated an association between IRF6 rs2235371 variant and the risk of NSCL with or without cleft palate. CONCLUSION: Genetic polymorphism of IRF6 gene rs2235371 locus is associated with NSCL with or without cleft palate.

Efficacy and Safety of Emricasan in Liver Cirrhosis and/or Fibrosis.

This study aimed to perform a meta-analysis to determine the efficacy and safety of emricasan. Nine databases were searched for clinical trials investigating the efficacy of emricasan treatment in patients with liver cirrhosis or fibrosis. A manual search was conducted to identify the missing trials. The quality of the included studies was assessed using the revised Cochrane risk of bias tool. Efficacy of emricasan treatment was defined as a positive change in apoptosis-related parameters from baseline to the last follow-up visit. Overall, emricasan treatment is more effective in patients with liver cirrhosis or fibrosis than placebo (standardized mean difference [SMD] [95% confidence intervals (CI)]=0.28 [0.14; 0.41]). No significant change in model for end-stage liver disease (MELD) score between the emricasan and placebo groups was noted (SMD [95% CI]=0.18 [-0.01; 0.36]; p=0.058). A 50 mg dose of emricasan had the highest efficacy rate compared to placebo (SMD [95% CI]=0.28 [0.06; 0.50]; p=0.012), followed by the 5 mg dosing regimen (SMD [95% CI]=0.28 [0.06; 0.50]; p=0.012). Treatment with emricasan resulted in significant reductions in ALT (mean difference (MD) [95% CI]=-5.89 [-10.59; -1.20]; p=0.014) and caspase3/7 levels (MD [95%CI]=-1215.93 [-1238.53; -1193.33]; p<0.001), respectively. No significant increase in the rate of overall adverse events was noted (OR [95% CI]=1.52 [0.97; 2.37]; p=0.069). Treatment with emricasan is more effective in improving liver function and apoptosis parameters compared to placebo, with a well-tolerated safety profile. However, due to the poor quality of the analyzed studies, the small number of trials and patients, and the short follow-up periods, more robust trials are still warranted.

Genome-wide and interaction linkage scan for nonsyndromic cleft lip with or without cleft palate in two multiplex families in Shenyang, China.

OBJECTIVES: To identify the loci involved in nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Northern Chinese people in Shenyang by using genomewide and interaction linkage scan. METHODS: Two multiplex families in Shenyang from North China were ascertained through probands with NSCL/P. Blood of every member was drawn for DNA extraction and analysis. Genotypes were available for 382 autosomal short tandem repeat (STR) markers from the ABI Prism Linkage Mapping Set version 2.5. Linkage between markers and NSCL/P was assessed by 2-point parametric LOD scores, multipoint-heterogeneity parametric LOD scores (HLODs), and multipoint nonparametric linkage score (NPL). RESULTS: The initial scan suggested linkage on Chromosomes 1, 2, and 15. In subsequent fine mapping, 1q32-q42 showed a maximum multipoint LOD score of 1.9(empirical P=0.013) and an NPL score of 2.35 (empirical P=0.053). For 2p24-p25, the multipoint NPL increased to 2.94 (empirical P=0.007). 2-locus interaction analysis obtained a maximum NPL score of 3.73 (P=0.00078) and a maximum LOD score of 3 for Chromosome 1 (at 221 cM) and Chromosome 2 (at 29 cM). CONCLUSION: Both parametric and nonparametric linkage scores greatly increased over the initial linkage scores on 1q32-q42, suggesting a susceptibility locus in this region. Nonparametric linkage gave a strong evidence for a candidate region on chromosome 2p24-p25. The superiority of 2-locus linkage scores compared to single-locus scores gave additional evidence for linkage on 1q32-q42 and 2p24-p25, and suggested that certain genes in the two regions may contribute to NCSL/P risks with interaction.

The Role of Formyl Peptide Receptor 1 Gene Polymorphisms in Human Colorectal Cancer.

Formyl peptide receptor 1 (FPR1) belongs to G protein-coupled receptors expressed mainly in phagocytic leukocytes. The gene encoding FPR1 is highly polymorphic and related to inflammation. In this study, we investigated the single nucleotide polymorphisms (SNPs) of Fpr1 in human colorectal cancer (CRC), and analyzed the association of Fpr1 SNPs with clinicopathological parameters and some specific diagnostic markers of CRC. Although the allele and genotype frequencies of Fpr1 SNPs in CRC tissues were not significantly different from that in whole blood cells derived from healthy Chinese subjects. Significant associations were observed between genotypes of c.289C>A and distant metastasis (P=0.001), and between genotypes of c.306T>C and tumor size (P=0.016). Genotypes of c.546C>A was closer to tumor size and lymphatic invasion (P=0.012 and P=0.043, respectively). Meanwhile, genotypes of c.1037C>A was related with tumor location and differentiation (P=0.000 and P=0.005, respectively). Besides, genotypes of c.576T>C>G was related with pathological type (P=0.000). Furthermore, several Fpr1 SNP positions including c.289 (C>A) and c.576 (G>C>T) were related to the expression of P53 (P=0.004 and P=0.008, respectively), and similar results were observed between other Fpr1 SNP positions and CEA, HER2 and Ki-67 (P<0.05). Our data demonstrate that Fpr1 SNPs may play the important role in the progression and metastasis of CRC.

Activation of NMDA receptor is associated with up-regulation of COX-2 expression in the spinal dorsal horn during nociceptive inputs in rats.

Cyclooxygenases-2 (COX-2) in the spinal dorsal horn is up-regulated and plays an important role in pain and hyperalgesia induced by nociceptive stimulation. The mechanisms involved in the up-regulation of spinal COX-2 during nociceptive stimulation are yet not well understood. Because the important role of NMDA and its receptor in transmission of nociceptive information in the spinal cord, activation of the spinal NMDA receptor might contribute to the up-regulation of spinal COX-2 expression. The present study was undertaken to demonstrate the above hypothesis by observing changes of COX-2 expression in the spinal dorsal horn in rats subjected to formalin test and intrathecal administration of NMDA, a selective NMDA receptor agonist, in conditions with or without presence of MK-801, an antagonist of NMDA receptor, using methods of Western blotting, reverse transcription polymerase chain reaction and immunohistochemistry. The results showed that intrathecal injection of MK-801, a noncompetitive antagonist of NMDA receptor, significantly suppressed the up-regulation of the COX-2 expression and characteristic pain behavior responses evoked in formalin test. Whereas, intrathecal injection of NMDA significantly up-regulated the expression of COX-2 in the spinal dorsal horn in a time course corresponding to that of nociceptive behavioral responses elicited by the intrathecal NMDA administration. In addition, the up-regulation of the COX-2 expression induced by the intrathecal NMDA was dose-dependent and blocked by prior administration of MK-801. These findings proved that activation of NMDA receptor is associated with the up-regulation of COX-2 expression in the spinal dorsal horn during nociceptive stimulation in rats.

Fluorocitrate, an inhibitor of glial metabolism, inhibits the up-regulation of NOS expression, activity and NO production in the spinal cord induced by formalin test in rats.

Previous experiments have suggested that nitric oxide plays an important role in nociceptive transmission in the spinal cord. In order to explore the involvement of glia in the NO-mediated nociceptive transmission, the present study was undertaken to investigate the effect of fluorocitrate (FC), an inhibitor of glial metabolism, on NOS expression and activity and NO production in the spinal cord during the process of peripheral inflammatory pain and hyperalgesia induced by formalin test in rats. Sixty adult male Sprague-Dawley rats were randomly assigned into sham, formalin, formalin + normal saline (NS), and formalin + FC groups. The NOS expression, NOS activity and NO production was detected by NADPH-d histochemistry staining, NOS and NO assay kit, respectively. It was found that formalin test significantly up-regulated NOS expression and activity and NO production in the laminae I-II of the dorsal horn and the grey matter around the central canal in the lumbar spinal cord at 1 h after the formalin test. Selective inhibition of glia metabolism with intrathecal administration of FC (1 nmol) significantly inhibited the up-regulation in NOS expression and activity and NO production normally induced by the formalin test, which was represented with decreases in the number and density of the NADPH-d positive cells in the dorsal horn and grey matter around the central canal, and decrease in density of NADPH-d positive neuropil in the dorsal horn in formalin + FC group compared with formalin group. The results suggested that glia may be involved in the NO-mediated nociceptive transmission in the spinal cord.