[Investigation and analysis of prevalence of musculoskeletal diseases among interventional surgeons in some top three hospitals in Tianjin].

Objective: To analyze the prevalence and risk factors of musculoskeletal diseases among interventional surgeons in top three hospitals, and to provide suggestions for prevention of musculoskeletal diseases. Methods: In June 2022, a self-designed questionnaire was used to collect general information of doctors engaged in interventional surgery (121) and non-interventional surgery (124) in some top three hospitals in Tianjin. The standard version of the Nordic Musculoskeletal Questionnaire was used to investigate information related to musculoskeletal diseases. The prevalence and risk factors of musculoskeletal diseases among interventional and non-interventional surgeons were analyzed. Results: The prevalence of musculoskeletal diseases among interventional surgeons and non-interventional surgeons was 59.50% (72/121) and 62.90% (78/124) . Compared with non-interventional surgeons, interventional surgeons had a higher prevalence of musculoskeletal diseases in the shoulders and upper back, and a lower prevalence of musculoskeletal diseases in the waist. The differences were statistically significant (P<0.05) . Multivariate logistic regression analysis showed that age, weekly time of physical exercise, time of intervention operation, and wearing protective clothing were independent risk factors for musculoskeletal diseases (P<0.05) . Conclusion: The prevalence rate of musculoskeletal diseases among doctors engaged in interventional surgery is relatively high in some top three hospitals in Tianjin, and proper enhancement of physical exercise and shortening of interventional time are conducive to reducing musculoskeletal diseases.

[Application of acellular bovine pericardium patch in implant based immediate breast reconstruction].

Objective: To examine the clinical effect of acellular bovine pericardium patch in implant based immediate breast reconstruction. Methods: The clinicopathological information of 141 breast cancer patients, who admitted to Department of Breast Reconstruction and Oncoplastic Surgery, Tianjin Medical University Cancer Hospital, underwent immediate mammoplasty with implants combined with acellular bovine pericardium patches were analyzed from June 2016 to October 2019. All patients were female, with the age of (38.8±8.5) years (range: 13 to 60 years). The body mass index was (21.9±2.5) kg/m2 (range: 16.0 to 32.3 kg/m2). There were 39 cases of duct carcinoma in situ, 46 cases of stage Ⅰ, 40 cases of stage Ⅱ and 16 cases of stage Ⅲ. All patients received nipple-areola-sparing mastectomy or skin-sparing mastectomy with sentinel lymph node biopsy or axillary lymph node dissection, and prosthesis implantation with sub-pectoralis combined with breast patch. The correlation of clinicopathological characters and complications was assessed by t test, χ2 test, Fisher's exact probability method and Logistic regression. Pre-and post-operative aesthetic, quality of life scores were recorded. Results: The operation time (M(IQR)) was 3.6(1.5) hours (range: 3.0 to 6.5 hours). The early postoperative complication rate was 22.0% (31/141), prosthesis removal was the main postoperative complication, accounting for 64.5% (20/31) of the total complications, of which 15 cases occurred in the first 30 patients. The follow-up time was 28(8) months (range: 20 to 53 months), The most frequent long-term complications were capsular contracture and implant displacement, with the incidence of 11.2% (14/125) and 10.4% (13/125), respectively. Multivariate analysis showed that prosthesis volume ≥300 ml (OR=8.173, 95%CI: 1.302 to 51.315, P=0.021) and peri-areolar incision (OR=7.809, 95%CI: 2.162 to 28.211, P<0.01) were independent relative factors for the occurrence of short-term postoperative local complications. After 2 years of operation, the score of breast appearance satisfaction was 71.7±15.5, postoperative effect satisfaction was 90.4±9.5, psychological satisfaction was 90.7±17.1, sexual satisfaction was 70.1±25.1. The immediate postoperative satisfaction rate at discharge was 95.4% (134/141), and 17.6% (22/125) of patients had the intention to received revision surgery. Conclusions: Prosthesis volume ≥300 ml and peri-areolar incision were independent realtive factors for short-term local complications after bovine pericardium patch combined with prosthesis implantation in the immediate breast reconstruction. After completing the learning curve, the postoperative complications of the procedure could be decreased.

[Clinical effect and economic benefit evaluation of minimally invasive surgery for drivers with lumbar disc herniation].

Objective: To investigate the clinical effect of minimally invasive surgery in the treatment of professional drivers with lumbar disc herniation. Methods: 126 patients with lumbar disc herniation admitted to hospital from June 1, 2015 to December 30, 2018 were selected and divided into observation group (59 cases treated by percutaneous transforaminal endoscopy) and control group (67 cases treated with conventional conservative treatment) according to the treatment methods. The Visual Analogue Scale (VAS) and Japanese Orthopaedic Association Scores (JOA) before and after treatment were analyzed retrospectively. Length of stay, time out of bed, hospitalization expenses and recurrence rate were evaluated. The measurement data was expressed by x±s, the comparison between groups was performed by t test, and the count data were analyzed by descriptive analysis. Results: Before treatment, there was no significant difference in gender, age, VAS score and JOA score between the two groups (P>0.05) . After treatment, compared with the control group, the VAS score of the observation group was lower, the JOA score was higher, the time out of bed was shorter, the average hospitalization time was reduced, the average hospitalization cost was higher, and the recurrence rates after Six months and one year were lower in the observation group, the differences were statistically significant (P<0.05) . Conclusion: The clinical effect of percutaneous transforaminal endoscopic treatment is better than that of conventional conservative treatment for driver＇s lumbar disc herniation.

[Study on purification effect of formaldehyde in cleanroom by new return air device].

Objective: To effectively reduce the concentration of poisons in cleanroom, protect the health of workers, realize the optimization and automatic control of the new return air device. And the influence of initial concentration, air volume, temperature and relative humidity of formaldehyde on the purification effect of the new return air device was explored. Methods: The purification effect of the new return air device installed with the activated carbon and the photocatalyst purification net or ordinary activated carbon purification network was tested in a 60 m(3) simulated cleanroom. The concentration of formaldehyde was determined by solution absorption-phenol reagent spectrophotometry. Based on the single factor experiment to determine the combination of two purification nets. The effects of air volume, initial formaldehyde concentration, temperature and relative humidity on the purification effect of the new return air device were investigated by orthogonal test. Then, the performance parameters of the return air device to purify formaldehyde were determined. Results: The formaldehyde purification efficiency of the two types of purification nets in the new return air device was higher than that of the ordinary activated carbon purification network (P<0.05) . The combination of activated carbon and photocatalyst purification net has no effect on the formaldehyde purification efficiency of the return air device (P>0.05) . According to the direct analysis and variance analysis, air volume was the most sensitive factor (F value is 18.894, P<0.05) , followed by initial concentration (F value is 16.128, P<0.05) , while temperature and relative humidity have little effect (F value is 0.041 and 0.599, respectively, P>0.05) . LSD analysis showed that there was no significant difference in the purification efficiency of formaldehyde between 475 m(3)/h and 626 m(3)/h (P>0.05) . From the perspective of formaldehyde purification efficiency and energy saving, when the air volume is set to 475 m(3)/h, the new return air device has higher purification efficiency for high concentration of formaldehyde. Conclusion: The new return air device consisting of activated carbon and photocatalyst purification net can play a good purification role in cleanroom with different temperatures and different humidity. Its formaldehyde purification efficiency is affected by air volume and initial concentration.

Effects of α-lipoic acid on chronic cerebrovascular hypoperfusion in an animal model of vascular dementia.

OBJECTIVE: Given the aging population, the treatment of vascular dementia (VaD) is becoming increasingly important. The antioxidant α-lipoic acid (α-LA) protects against neurodegeneration in VaD, but the underlying mechanisms remain unclear. Hence, we aimed to identify the effects of α-LA on cognitive function following chronic cerebrovascular hypoperfusion in a VaD animal model. MATERIALS AND METHODS: Mice were categorized into the sham, bilateral common carotid artery stenosis (BCAS), or BCAS + α-LA group. The BCAS + α-LA group was intraperitoneally injected (100 mg/kg) once daily with α-LA for 4 weeks after BCAS surgery, while the BCAS and sham groups were injected with saline. After the last injection, we examined cognitive function and exploration behavior using the Morris water maze. Mice brains were then harvested for Western blot analyses. RESULTS: The BCAS group, but not the BCAS + α-LA group, showed cognitive dysfunction in the Morris water maze. Apoptosis pathways involving poly (ADP-ribose) polymerase (PARP) cleavage, phosphorylated-mammalian target of rapamycin (p-mTOR), phosphorylated-3-phosphoinositide-dependent protein kinase-1, and phosphorylated-protein kinase B (p-AKT) were enhanced in the BCAS group than the α-LA group. The BCAS + α-LA group demonstrated less PARP cleavage and p-mTOR function than did the BCAS group. The activity of autophagy pathways involving LC3B was higher in the BCAS and BCAS + α-LA groups than the sham group, but there were no significant differences between the BCAS and BCAS + α-LA groups. CONCLUSIONS: In the BCAS rodent model, cognitive dysfunction and apoptosis mediated by the phosphatase and tensin homolog/AKT/mTOR pathway were observed in the hippocampus. However, acting on the mTOR pathway, α-LA improved cognitive function and led to hippocampal cell survival. Thus, α-LA may be useful for treating VaD.

Effects of phyto-oestrogen quercetin on productive performance, hormones, reproductive organs and apoptotic genes in laying hens.

Quercetin, a polyphenolic flavonoid with diverse biological activities including anti-inflammatory and antiviral, inhibits lipid peroxidation, prevents oxidative injury and cell death. The purpose of the research was to investigate the effect of quercetin on productive performance, reproductive organs, hormones and apoptotic genes in laying hens between 37 and 45 weeks of age, because of the structure and oestrogenic activities similar to 17ß-oestradiol. The trial was conducted using 240 Hessian laying hens (37 weeks old), housed in wire cages with two hens in each cage. These hens were randomly allotted to four treatments with six replicates, 10 hens in each replicate and fed with diets containing quercetin as 0, 0.2, 0.4 and 0.6 g/kg feed for 8 weeks. The results showed that dietary quercetin significantly increased (p < .05) the laying rate and was higher in group supplemented with 0.4 g/kg, and feed-egg ratio was decreased (p < .05) by quercetin. Dietary quercetin has no effect (p > .05) on average egg weight and average daily feed intake. Compared with control, secretion of hormones, oestradiol (E2 ), progesterone (P4), follicle-stimulating hormone (FSH), luteinizing hormone (LH), insulin-like growth factors-1 (IGF-1) and growth hormone (GH), was found to be significantly higher (p < .05) in quercetin-supplemented groups. Also ovary index, uterus index and oviduct index were not significantly influenced (p > .05) by quercetin, whereas magnum index, isthmus index, magnum length, isthmus length and follicle numbers were significantly increased (p < .05) with quercetin supplementation. Additionally, expression of apoptotic genes was significantly (p < .05) up-regulated or down-regulated by quercetin. These results indicated that quercetin improved productive performance, and its mechanism may be due to the oestrogen-like activities of quercetin.

[Interleukin-17-mediated inflammation promotes nonalcoholic fatty liver disease in mice with regulation of M1-type macrophage polarization].

Objective: To study the mechanism of interleukin (IL)-17 in mice with non-alcoholic fatty liver disease for promoting M1-type macrophage polarization to exacerbate liver inflammation, and to provide references for the mechanism of NAFLD occurrence and development. Methods: A mouse model of NAFLD was constructed by high-fat diet. Mice were divided into control group, model group, IL-17 group, and anti IL-17 group. Histopathological changes of the liver were observed by HE staining. The serum levels of ALT and AST in peripheral blood of mice was detected by chemical colorimetry. Macrophages labeled with F4/80-PE, CD11C-FITC was designated as M1-type macrophages, those labeled with F4/80-PE, and CD206-APC was designated as M2-type macrophages. The proportion of M1 and M2 macrophages infiltrated into the liver tissues of mice were measured by flow cytometry. CD168 expression level of liver tissues was detected using immunohistochemistry. Protein and mRNA levels of the marker molecules (iNOS, TNF-alpha and IL-6) of M1 macrophages were detected using ELISA and RT-Q PCR. Western blot was used to detect the protein expression of JAK-STAT signal pathway and the expression level of MCP-1. Data were analyzed using one-way ANOVA and t-test. Results: High-fat diet NAFLD mice model was successfully constructed. IL-17 had increased the proportion of M1 macrophages in mice liver tissues and decreased the proportion of M2 macrophages (P < 0.05). The proportion of M1 and M2 macrophages in the liver tissues of normal mice was 7.9% ± 1.1% and 19.2% ± 1.8%. The proportion of M1 and M2 macrophages in the model group was 17.3% ± 2.5% and 15.0% ± 2.1. The proportion of M1 macrophages (33.8% ± 4.2%) in IL-17 group was higher than model group, while the proportion of M2 macrophages (7.8% + 1.0%) in IL-17 group was lower than model group. Protein and mRNA marker levels of M1 macrophage (iNOS, IL-12, TNFα and IL-6) in liver tissues were significantly higher than model group, control group, and anti-IL-17 group (P < 0.05). The expression levels of JAK1, STAT1, MCP-1, and CD168 in mice liver tissues of IL-17 group had increased (P < 0.05). The levels of aspartate and alanine aminotransferases in peripheral blood of mice in IL-17 group were significantly higher than other three groups (P < 0.05). Conclusion: IL-17 can promote M1-type macrophage polarization, and exacerbates the liver inflammatory response to accelerate the progression of NAFLD in mice.

[Analysis of short-term respiratory adverse events in 183 bronchial thermoplasty procedures].

Objective: To analyze the short-term (3 weeks) adverse respiratory events after bronchial thermoplasty(BT) in patients with severe asthma. Methods: The China-Japan Friendship Hospital recruited 62 patients with severe asthma for BT treatment from March 2014 to July 2016, with a total of 183 BT procedures. The data of adverse respiratory events within 3 weeks after procedure were collected to analyze the factors that might potentially influence the occurrence of adverse events. Results: Forty-three patients (69.4%) experienced adverse respiratory events within 3 weeks after treatment. Totally 153 adverse respiratory events occurred after 87 procedures(47.5%). The main adverse events were cough (15 events, 8.20%), sputum production (37 events, 20.22%), temporary PEF reduction (37 events, 20.22%), chest distress (12 events, 6.56%), blood in sputum (11 events, 6.01%), asthma exacerbation (10 events, 5.46%), and pneumonia(6 events, 3.28%). Most events were relieved or resolved with standard therapy in 1 week. No severe adverse events including tracheal intubation, malignant arrhythmias or death occurred within 3 weeks after procedure. The baseline eosinophil percentage in induced sputum and blood, operation times, and preoperative FEV(1) (% predicted) might influence the occurrence of adverse events after treatment. Patients with preoperative FEV(1) (% predicted) ≥60% had lower risk of adverse events. Conclusion: BT showed a good security profile in treating patients with severe asthma within 3 weeks after procedure.

[Body mass index, waist circumference and waist-to-height ratio associated with the incidence of type 2 diabetes mellitus: a cohort study].

OBJECTIVE: To investigate the association between body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and the incidence risk of type 2 diabetes mellitus (T2DM). METHODS: In total, 20 194 participants ≥18 years old were selected randomly by cluster sampling from two township (town) of the county in Henan province from July to August of 2007 and July to August of 2008 and the investigation included questionnaires, anthropometric measurements, fasting plasma glucose, and lipid profile examination were performed at baseline; 17 236 participants were enrolled in this cohort study. 14 720 (85.4%) were followed up from July to August 2013 and July to October 2014. Finally, 11 643 participants (4 301 males and 7 342 females) were included in this study. Incidence density and Cox proportional hazards regression models were used to evaluate the risk of T2DM associated with baseline BMI, WC, WHtR, and their dynamic changes. RESULTS: After average of 6.01 years following up for 11 643 participants, 613 developed T2DM and the incidence density was 0.89 per 100 person-years. After adjusted for baseline sex, age, smoking, drinking, family history of diabetes, as well as the difference of fasting plasma-glucose (FPG), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP) between baseline and follow-up, Cox Proportional-Hazards regression analysis indicated that T2DM risk of baseline BMI overweight group, BMI obesity group, abnormal WC group and abnormal WHtR group were significantly higher than that of the corresponding baseline normal groups , and the incidence risk of T2DM reached the highest for those whose baseline BMI, WC and WHtR were all abnormal, the corresponding HR (95%CI) were 2.05 (1.62-2.59), 3.01 (2.33-3.90), 2.34 (1.89-2.90), 2.88 (2.21-3.74), 3.32 (2.50-4.40), respectively. Whether baseline BMI/WC was normal or not, T2DM risk increased if baseline WHtR was abnormal, and the HR (95%CI) of baseline normal BMI/abnormal WHtR group, baseline abnormal BMI/abnormal WHtR group, baseline normal WC/abnormal WHtR group, baseline abnormal WC/abnormal WHtR group were 1.88 (1.29-2.74), 3.08 (2.34-4.05), 2.15(1.53-3.00), 3.22 (2.45-4.23), respectively. The analysis for dynamic changes of BMI, WC, and WHtR indicated that in baseline normal WC or WHtR group, T2DM risk increased when baseline normal WC or WHtR developed abnormal at follow-up, and the corresponding HR (95%CI) were 1.79 (1.26-2.55), 2.12(1.32-3.39), respectively. In baseline abnormal WC or WHtR group, T2DM risk decresed when baseline abnormal WC or WHtR reversed to normal at follow-up, and the corresponding HR (95%CI) were 2.16 (1.42-3.29), 2.62 (1.63-4.20), respectively. CONCLUSION: BMI, WC, and WHtR were associated with increased T2DM risk. The more abnormal aggregation of BMI, WC, and WHtR presents, the higher T2DM risk was. T2DM risk could be decreased when abnormal WC or WHtR reversed to normal.

The orphan nuclear receptor small heterodimer partner as a novel coregulator of nuclear factor-kappa b in oxidized low density lipoprotein-treated macrophage cell line RAW 264.7.

Small heterodimer partner (SHP), specifically expressed in liver and a limited number of other tissues, is an unusual orphan nuclear receptor that lacks the conventional DNA binding domain. In this work, we found that SHP expression is abundant in murine macrophage cell line RAW 264.7 but was suppressed by oxidized low density lipoprotein (oxLDL) and its constituent 13-hydroxyoctadecadienoic acid, a ligand for peroxisome proliferator-activated receptor gamma. Furthermore, SHP acted as a transcription coactivator of nuclear factor-kappa B (NF kappa B) and was essential for the previously described NF kappa B transactivation by palmitoyl lysophosphatidylcholine, one of the oxLDL constituents. Accordingly NF kappa B, which was transcriptionally active in the beginning, became progressively inert in oxLDL-treated RAW 264.7 cells as oxLDL decreased the SHP expression. Thus, SHP appears to be an important modulatory component to regulate the transcriptional activities of NF kappa B in oxLDL-treated, resting macrophage cells.

Depletion of mitochondrial DNA alters glucose metabolism in SK-Hep1 cells.

Maternally inherited mitochondrial DNA (mtDNA) has been suggested to be a genetic factor for diabetes. Reports have shown a decrease of mtDNA content in tissues of diabetic patients. We investigated the effects of mtDNA depletion on glucose metabolism by use of rho(0) SK-Hep1 human hepatoma cells, whose mtDNA was depleted by long-term exposure to ethidium bromide. The rho(0) cells failed to hyperpolarize mitochondrial membrane potential in response to glucose stimulation. Intracellular ATP content, glucose-stimulated ATP production, glucose uptake, steady-state mRNA and protein levels of glucose transporters, and cellular activities of glucose-metabolizing enzymes were decreased in rho(0) cells compared with parental rho(+) cells. Our results suggest that the quantitative reduction of mtDNA may suppress the expression of nuclear DNA-encoded glucose transporters and enzymes of glucose metabolism. Thus this may lead to diabetic status, such as decreased ATP production and glucose utilization.

The angiopoietin-tie2 system in coronary artery endothelium prevents oxidized low-density lipoprotein-induced apoptosis.

OBJECTIVES: A healthy, intact coronary artery endothelium is important because most common coronary artery diseases result from loss of endothelial integrity. In this study, we explored the biological significance of the angiopoietin-Tie2 system in porcine coronary artery. METHODS: Cultured porcine coronary artery endothelial cells and explanted coronary arteries were used. RESULTS: Immunohistochemical analyses indicated that Ang1 is selectively expressed in vascular muscular cells, whereas angiopoietin-2 (Ang2) and Tie2 are selectively expressed in endothelial cells. Accordingly, Ang1 mRNA is mainly expressed in cultured porcine coronary artery vascular smooth muscle cells, whereas Ang2 and Tie2 mRNAs are mainly expressed in cultured porcine coronary artery endothelial cells (PCAECs). Ang1 (200 ng/ml) induced Tie2 phosphorylation, while Ang2 (200 ng/ml) did not produce Tie2 phosphorylation. Ang1 increased the survival of cultured PCAECs during apoptosis induced by oxidized low-density lipoprotein (OxLDL). This survival effect was does-dependent and PI. Furthermore, Ang1 also protected endothelial cells of explanted coronary artery against OxLDL-induced apoptosis artery. CONCLUSION: These results suggest that adult coronary artery contains Ang1-Tie2 components that enhance endothelial cell survival to help maintain the normal integrity of the coronary artery endothelium.

Role of endocytosis in the transactivation of nuclear factor-kappaB by oxidized low-density lipoprotein.

Oxidized low-density lipoprotein (oxLDL) has been shown to modulate transactivation by the peroxisome proliferator-activated receptor (PPAR)-gamma and by nuclear factor-kappaB (NF-kappaB). In the present study, the oxLDL signalling pathways involved in NF-kappaB transactivation were investigated by utilizing a reporter construct driven by three upstream NF-kappaB binding sites, and various pharmacological inhibitors. OxLDL and its constituent lysophophatidylcholine (lysoPC) induced a rapid and transient increase in intracellular calcium and stimulated NF-kappaB transactivation in resting RAW264.7 macrophage cells in an oxidation-dependent manner. NF-kappaB activation by oxLDL or lysoPC was inhibited by inhibitors of protein kinase C or by a chelator of intracellular calcium. Tyrosine kinase or phosphatidylinositol 3-kinase inhibitors did not block NF-kappaB transactivation. Furthermore, oxLDL-induced NF-kappaB activity was abolished by PPAR-gamma ligands. When the endocytosis of oxLDL was blocked by cytochalasin B, NF-kappaB transactivation by oxLDL was synergistically increased, while PPAR transactivation was blocked. These results suggest that oxLDL activates NF-kappaB in resting macrophages via protein kinase C- and/or calcium-dependent pathways, and that this does not involve the endocytic processing of oxLDL. The endocytosis-dependent activation of PPAR-gamma by oxLDL may function as a route of inactivation of the oxLDL-induced NF-kappaB signal.

Oxidation-dependent effects of oxidized LDL: proliferation or cell death.

Oxidized low-density lipoprotein (oxLDL) induces a wide range of cellular responses to produce atherosclerotic lesion, but key factors determining the response are not understood. In this study, purified LDL was oxidized with copper sulfate, and its physical properties and the related biological responses were investigated. The average hydrodynamic diameter of the lightly oxidized LDL was approximately 25 nm and its Rf value relative to nLDL on agarose gel was between 1.0 and 1.25. The diameter of the extensively oxidized LDL was over 30 nm, the Rf value was over 2.0. A 24 h-exposure of resting RAW264.7 macrophage cells to 100 microg/ml of the lightly oxidized LDL induced proliferation and macrophage activation whereas the extensively oxidized LDL induced cell death at the same concentration. In contrast, 200 microg/ml of oxLDL caused cell death regardless of oxidation degree. Short incubation (4-6 h) of the highly oxidized LDL (100 microg/ml) also resulted in cell proliferation. OxLDL-induced cell death showed mixed characteristics of apoptosis and/or necrosis depending on the strength and duration of the insult. These results suggest that cellular responses induced by oxLDL be dependent on the oxidation degree, the duration of exposure, and the concentration of oxLDL.

Acetylation polymorphism and prevalence of colorectal adenomas.

Polymorphic N-acetyltransferase (NAT2), an enzyme present in the colon, may effect incidence of colon cancer. Individuals with NAT2 fast acetylator genotypes may have higher colon cancer risks due to faster conversion of certain carcinogens to mutagens. We determined NAT2 genotypes in 447 subjects with distal colon adenomas and in 487 controls. No significant increase in adenoma prevalence among fast acetylators was observed. However, there was a suggestion of ethnic differences in NAT2 effects. For example, white fast acetylators potentially had slightly increased risks for adenomas (odds ratio, 1.29; 95% confidence interval, 0.90-1.84), whereas fast acetylation was potentially protective among blacks (odds ratio, 0.64; 95% confidence interval, 0.32-1.28). The apparent difference between blacks and whites may simply reflect random variation around an overall null effect, or it could represent a real difference. There was preliminary evidence for a possible interaction between NAT2 and the glutathione transferase M1 null genotype. Smokers' adenoma prevalence was 10-fold higher for fast acetylators with the null genotype compared to slow acetylators without the null genotype. Large, multiethnic populations and analysis of combinations of genes for carcinogen metabolism may be needed to further assess the role of NAT2 in colorectal tumorigenesis.

Glutathione transferase (GSTM1) null genotype, smoking, and prevalence of colorectal adenomas.

Colorectal cancer is caused by environmental exposures and genetic predisposition. However, little is known of hereditary factors that influence development of common, non-Mendelian forms of this cancer. Interactions among carcinogen exposure, hereditary variants of enzymes involved in carcinogen metabolism, and other host factors may play a role. Genetic polymorphisms of carcinogen metabolism, such as the glutathione transferase M1 (GSTM1) null genotype, are thus possibly related to cancer risk. The GSTM1 enzyme detoxifies mutagens formed from polycyclic aromatic hydrocarbons which are found in tobacco smoke. We analyzed GSTM1 genotypes and smoking among 488 controls and 446 individuals with a first time diagnosis of colorectal adenomas which are precursors to cancer. Subjects were from two Kaiser Permanente sigmoidoscopy clinics in southern California. We observed no overall effect of the GSTM1 null genotype on the risk for colorectal adenomas (odds ratio, 0.85; 95% confidence interval = 0.65-1.10). The odds ratio for smokers with the null genotype was 2.07 (95% confidence interval = 1.14-3.77) when compared to "never smokers" without the null genotype. Using this same reference group, the odds ratio for smokers without the null genotype was 1.73 (95% confidence interval = 1.03-2.90). These two odds ratios were not significantly different (P = 0.30).

Ethnic distribution of slow acetylator mutations in the polymorphic N-acetyltransferase (NAT2) gene.

The acetylation polymorphism may affect rates of activation or detoxification of common carcinogens, thereby influencing cancer risk. Our aim was to define the ethnic distribution of the major slow acetylator mutations in the polymorphic N-acetyltransferase gene, in order to provide background data for epidemiological studies. Our results contain new analyses on 803 individuals, including 365 new specimens and 438 specimens that had been partly characterized in an earlier study. Tests were done to establish the specificity and reproducibility (98%) of our PCR assays. The recognized slow acetylator mutations, 191A, 481T, 590A, and 857A (which correspond to alleles M4 and M4b; M1 and r3; M2/r2; and M3 and S3, respectively), accounted for nearly all slow acetylator alleles among blacks, whites, Asian Indians, Hispanics, Koreans, Japanese, Hong Kong Chinese, Taiwanese, Filipinos and Samoans. The ethnic distribution supports an interpretation that the acetylation polymorphism existed before Paleolithic splitting of human populations from Africa. We identified two additional NAT2 mutations, suggesting that other rare alleles are likely to be found.

Ethnic distribution of the glutathione transferase Mu 1-1 (GSTM1) null genotype in 1473 individuals and application to bladder cancer susceptibility.

Polycyclic aromatic hydrocarbons, found in cigarette smoke, food and industrial materials, are potential human carcinogens. Deficiency of detoxifying enzymes, such as glutathione transferases, may affect the metabolic fates of these chemicals and raise cancer risks in exposed individuals. The GSTM1 null genotype is a common form of glutathione transferase deficiency. Because knowledge of its ethnic distribution would be useful in epidemiologic studies, we measured the frequencies of the GSTM1 null genotype among healthy blacks, whites, Asian Indians, Chinese, Japanese, Koreans, Filipinos, Samoans and Hispanics. Rapid genotyping was done by use of a PCR assay, with dried blood spots on blotter paper as DNA templates. The frequency of the null genotype ranged from 0.31 among blacks to 0.88 among Samoans. The PCR assay was also applied to a pilot study of 114 bladder cancer cases from Kaiser Permanente Medical Center, Harbor City, California. DNA for these cases was obtained from paraffin-embedded surgical specimens. The overall odds ratio for bladder cancer with the GSTM1 null genotype was 1.4 (95% confidence interval 0.94-2.1), indicating no statistical difference in null genotype frequencies among bladder cancer patients compared to a healthy population. Large epidemiologic studies, which can be accomplished with dried blood spots or paraffin-embedded tissue specimens, may be useful for further assessment.

Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics, and whites: application to metabolic epidemiology.

Our aim was to determine the population frequencies of the major slow acetylator alleles of the polymorphic N-acetyltransferase (NAT2) gene, whose locus maps to chromosome 8. We used allele-specific PCR amplification on 786 dried blood spots obtained from Hong Kong Chinese, U.S. Koreans, U.S. blacks, U.S. Hispanics, Germans, and U.S. whites. Our results show that four slow acetylator alleles can be detected as mutations at positions 481, 590, and 857 in the NAT2 gene. Recognized base substitutions at positions 341 and 803 need not be determined, because they were almost always associated with the 481T mutation. The known mutation at position 282 was strongly associated with the 590A mutation. The 481T, 590A, and 857A mutations accounted for virtually all of the slow acetylator alleles in Asian and white populations. The 857A mutation proved to be an Asiatic allele. The results will be useful in large-scale epidemiologic studies of cancer and other conditions potentially associated with the acetylator polymorphism.

Functional profile of the human fetal gamma-globin gene upstream promoter region.

We performed a systematic functional analysis of the human gamma-globin promoter to identify its activator domains. We used a panel of truncation and scanning mutants as well as transfection in human K562 fetal erythroid cells. The various mutations produced relatively small changes in promoter function in both transient and stable transfection assays. The CACCC region and the region containing the binding sites for protein GATA-1 behaved as activator domains. We also obtained evidence for a minor activator site in the - 200 to - 190 region. The results are consistent with the interpretation that gamma-globin gene regulation may occur in part through multiple small effects of promoter elements.