DNA Repair Genetics and the Risk of Radiation Pneumonitis in Patients With Lung Cancer: A Systematic Review and Meta-analysis.

AIMS: ERCC1 rs11615 and ERCC2 rs238406 single nuclear polymorphism (SNPs) are known for their association with treatment outcome, likely related to radiosensitivity of both tumor and normal tissue in patients with non-small-cell lung cancer. This study aimed to review the effect of 1) these ERCC1/2 SNPs and 2) other SNPs of DNA repair genes on radiation pneumonitis (RP) in patients with lung cancer. MATERIALS AND METHODS: SNPs of our interest included ERCC1 rs11615 and ERCC2 rs238406 and other genes of DNA repair pathways that are functional and biologically active. DNA repair SNPs reported by at least two independent studies were pooled for meta-analysis. The study endpoint was radiation pneumonitis (RP) after radiotherapy. Recessive, dominant, homozygous, heterozygous, and allelic genotype models were used where appropriate. RESULTS: A total of 16 studies (3080 patients) were identified from the systematic review and 12 studies (2090 patients) on 11 SNPs were included in the meta-analysis. The SNPs were ATM rs189037, ATM rs373759, NEIL1 rs4462560, NEIL1 rs7402844, APE1 rs1130409, XRCC3 rs861539, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs238406, ERCC2 rs13181, and XRCC1 rs25487. ERCC1 rs11615 (236 patients) and ERCC2 rs238406 (254 patients) were not significantly associated with RP. Using the allelic model, the G allele for NEIL1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the C allele for rs7402844 (OR 0.70, 95% CI: 0.49, 0.99, P = 0.04). Similarly, the T allele for APE1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the G allele for rs1130409 (OR 0.59, 95% CI: 0.43, 0.81, P = 0.001). CONCLUSION: Genetic variation in the DNA repair pathway genes may play a significant role in the risk of developing radiation pneumonitis in patients with lung cancer. Further studies are needed on genotypic features of DNA repair pathway genes and their association with treatment sensitivity, as such knowledge may guide personalized radiation dose prescription.

The 100 most cited manuscripts in head and neck cancer: a bibliometric analysis.

OBJECTIVE: This study aimed to highlight the key studies that have led to the current understanding and treatment of head and neck cancer. METHOD: The Thomson Reuters Web of Science database was used to identify relevant manuscripts. The results were ranked according to the number of citations. The 100 most cited papers were analysed. RESULTS: A total of 63 538 eligible papers were returned. The median number of citations was 626. The most cited paper compared radiotherapy with and without cetuximab (3205 citations). The New England Journal of Medicine had the most citations (23 514), and the USA had the greatest number of publications (n = 66). The most common topics of publication were the treatment (n = 45) and basic science (n = 19) of head and neck cancer, followed by the role of human papillomavirus (n = 16). CONCLUSION: This analysis highlighted key articles that influenced head and neck cancer research and treatment. It serves as a guide as to what makes a 'citable' paper in this field.

[Association of sleep quality with hypertension in the elderly of Jino nationality: a multilevel model analysis].

Objective: To evaluate the association of sleep quality with hypertension in the elderly population aged 60 years and older of Jino nationality. Methods: In August 2015, a cross-sectional population-based survey was conducted to investigate the prevalence of hypertension in 805 subjects sampled by multistage stratified and cluster sampling from the elderly population of Jino nationality, the sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI, a poor sleep group was defined as having a global PSQI score>7, a good sleep group was with a score of 7 or less), and the multilevel Logistic regression model was applied to analyze the association of sleep quality with hypertension. Results: A total of 793 eligible participants were available for analysis. Overall, 118 participants (14.9%) were in the poor sleep group, and 675 participants (85.1%) were in the good sleep group. The prevalence of hypertension, prevalence of isolated systolic hypertension, average systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the poor sleep group were significantly high than those of the good sleep group[73.7%, 22.0%, (139.2±17.7) and (82.5±10.6) mmHg (1 mmHg=0.133 kPa) vs 33.0%, 9.0%, (131.2±15.0) and (78.5±8.9) mmHg, all P<0.05]. The results of covariate-adjusted multilevel Logistic regression model indicated that subjective sleep quality (OR=2.64, 95% CI: 1.08-6.44), sleep latency (OR=2.98, 95% CI: 1.52-5.86), sleep disturbance (OR=2.93, 95% CI: 1.06-8.10), daytime dysfunction (OR=3.86, 95% CI: 1.74-8.58) and poor sleep (OR=3.98, 95% CI: 2.05-7.73) had the positive correlation with hypertension. Conclusions: The elderly population of Jino nationality with poor sleep have high SBP and DBP. There are positive associations of PSQI and its components with hypertension in the elderly population of Jino nationality.

HLA-B*13:01 and the dapsone hypersensitivity syndrome.

BACKGROUND: Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome. METHODS: We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls. RESULTS: Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans. CONCLUSIONS: HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).

A comparative study of the H + FO (v = 0, j = 0) --> (OH + F)/(HF + O) reaction from QM and QCT methods.

The dynamics of the title reaction are investigated using both the time-dependent quantum wave packet and the quasi-classical trajectory methods and employing a recently developed adiabatic ground 1(3)A'' potential energy surface [Gomez-Carrasco et al. J. Chem. Phys. 2004, 121, 4605]. By comparison to the quantum J = 0 reaction probabilities, the QCT method is first validated for the title reaction and further employed to produce the integral cross sections and rate constants. No resonance structures have been observed in both the QCT J = 0 and the quantum reaction probabilities of OH + F as well as in the QCT integral cross sections of both product channels, while there are some undulations in the calculated quantum reaction probabilities of HF + O. It is also found that Coriolis coupling effects play a significant role in the quantum calculation and that formation of the OH product is favored over the HF product in the reactive system.

Candida tropicalis-associated bilateral renal papillary necrosis and emphysematous pyelonephritis.

Although the kidney is often involved in disseminated and localized candidiasis, bilateral emphysematous pyelonephritis (EPN) is infrequently reported. Renal papillary necrosis (RPN) caused by fungi is also rare. We describe a patient with bilateral RPN and EPN caused by Candida tropicalis, who suffered from recurrent hematuria, flank pain, acute fulminant renal failure, and obstruction by a sloughed papilla. He was treated successfully with antifungal therapy and percutaneous nephrostomy (PCN). This is the first case report of C. tropicalis-associated EPN and RPN.

Preoperative diagnosis and localization of aldosterone-producing adenoma by adrenal venous sampling after administration of metoclopramide.

BACKGROUND AND PURPOSE: Adrenal venous sampling is the most reliable test to distinguish aldosterone-producing adenoma (APA) from idiopathic hyperaldosteronism (IHA). The diagnostic accuracy can be improved by administration of adrenocorticotropin to minimize pulsatile secretion of aldosterone. Metoclopramide (MCP), a dopamine antagonist, can increase aldosterone secretion promptly without affecting cortisol secretion. This study investigated the diagnostic accuracy of adrenal venous sampling after MCP injection for the preoperative diagnosis and localization of APA. METHODS: Prospective diagnosis and adrenalectomy was based on adrenal venous sampling in 23 patients with a diagnosis of primary aldosteronism. Plasma aldosterone concentrations from adrenal veins and the inferior vena cava were measured before and 30 minutes after intravenous administration of 10 mg MCP. The ratio of bilateral adrenal venous aldosterone concentrations after MCP was used for diagnosis as follows: a ratio greater than 5 indicated APA, less than 3 indicated IHA, and 3-5 indicated an intermediate diagnosis. RESULTS: Catheterization of the right adrenal vein was unsuccessful in three patients. Twelve of 13 patients with an aldosterone ratio greater than 5 after MCP underwent unilateral adrenalectomy, and APA was confirmed in 11 of these patients. One patient with an intermediate diagnosis also had surgically confirmed APA. Six patients had a ratio less than 3. Before MCP administration, 10 of 13 patients with APA had a ratio greater than 5, and three patients had a ratio between 3 and 5; one patient with IHA had a ratio greater than 5. MCP improved the diagnosis of APA to an accuracy of 92% (12/13). Correct diagnosis of APA based on computerized tomography (CT) was 85% (11/13). There was discordance between the findings of adrenal venous sampling and CT in four of 20 patients. CONCLUSIONS: Administration of MCP to stimulate aldosterone secretion during adrenal venous sampling can improve the accuracy of differential diagnosis between APA and IHA.

Expression and localization of human dopamine D2 and D4 receptor mRNA in the adrenal gland, aldosterone-producing adenoma, and pheochromocytoma.

Aldosterone secretion is evidently regulated by a dopaminergic inhibitory mechanism. Pharmacological characterization and autoradiographic studies revealed D2-like receptors in the adrenal cortex, especially in the zona glomerulosa. However, the subtype of the dopamine receptors involving this regulation has not been elucidated. To investigate which subtype of receptors expresses in the adrenal cortex, we examined the messages of D2-like receptors, D2, D3, and D4, by RT-PCR and in situ hybridization of adrenal glands and adrenal neoplasm. Both D2 and D4 receptors were expressed in normal adrenal glands, pheochromocytoma, and aldosterone-producing adenoma. However, the D2 receptors were not universally expressed, in contrast with the D4 receptors that were detected in all cases of aldosterone-producing adenoma and adrenal remnant. No D3 receptor message was detected by RT-PCR in any adrenal sample. Both D2 and D4 receptors were expressed in significant amounts in the adrenal medulla and pheochromocytoma. In the adrenal cortex, the expression of the D2 receptors was in the zona glomerulosa and zona reticularis, with no different signal intensities between the two zones. D4 receptors were mainly localized in the zona glomerulosa and, to a lesser extent, in the zona reticularis. Both receptors were expressed at low levels in the zona fasciculata. In aldosterone-producing adenoma, the expression of D2 and D4 was especially found in nonzona fasciculata-like cells. To elucidate which dopamine receptor regulates aldosterone secretion, the effects of specific D2 and D4 antagonists, raclopride and clozapine, respectively, were examined in cultured NCI-H295 cells. Dopamine further increased angiotensin II-induced aldosterone secretion by 20%. In the presence of 1 microM dopamine and angiotensin II, 10(-5)-10(-7) M clozapine decreased aldosterone levels by 40-55%. The decrease in aldosterone secretion by clozapine was completely reversed when raclopride was added simultaneously. These data suggest that dopamine exerts dual effects on aldosterone secretion in NCI-H295 cells. Activation of D4 receptors can increase aldosterone secretion, whereas an inhibitory effect is mediated via D2 receptors. In summary, we demonstrated the existence of both D2 and D4 receptors in the human adrenal gland and adrenal neoplasm. Both receptors play significant roles in the modulation of aldosterone secretion, but in opposite directions.

Association of hypertriglyceridemia and insulin resistance in uremic patients undergoing CAPD.

OBJECTIVE: Hyperlipidemia is frequently encountered in uremic patients and may be worsened by continuous ambulatory peritoneal dialysis (CAPD) treatment. The lipid abnormalities in these patients may be multifactorial. Insulin resistance (or its compensatory hyperinsulinemia) is commonly observed in uremic patients, but its association with hyperlipidemia in these patients has not been studied. PATIENTS AND METHODS: Lipid profiles of 35 nondiabetic nonobese patients undergoing CAPD for more than 1 year (mean 52.3 months) were studied. Current laboratory data and parameters related to peritoneal dialysis (PD) within the previous 3 months were recorded. After overnight fasting and interruption of PD, an oral 75-g glucose tolerance test (OGTT) was examined. RESULTS: After CAPD treatment for more than 12 months, these patients had higher serum triglyceride (TG) (p = 0.001) and total cholesterol (p = 0.0058) levels than their values before commencing CAPD. Twelve of 14 patients with serum TG higher than 200 mg/dL (high-TG) were diagnosed de novo, in contrast with only 1 patient diagnosed of de novo hypercholesterolemia (total cholesterol > 240 mg/dL). There was no difference in age, gender, body mass index (BMI), duration of PD treatment, serum albumin, hematocrit, intact serum parathyroid hormone (iPTH), peritoneal glucose load, solute transport, or weekly Kt/V urea between normal-TG and high-TG patients. After adjusting for age, gender, BMI, weekly Kt/V urea, and iPTH, the high-TG patients had higher levels of area under the curve for glucose (AUC(Glu)), area under the curve for insulin (AUC(Ins)), and AUC(Ins)/AUC(Glu) ratios (F = 10.63, 10.14, and 8.65; p = 0.0029, 0.0035, and 0.0065, respectively), indicating that the high-TG patients were more insulin resistant. There were 24 patients with normal glucose tolerance (NGT), and 11 patients with impaired glucose tolerance (IGT). The IGT group had higher serum TG (F = 10.43, p = 0.003) and total cholesterol (F = 8.05, p = 0.009) than the NGT group, after adjusting for BMI, duration of CAPD treatment, peritoneal glucose load, solute transport, serum albumin, and lipid levels before PD treatment. TheTG levels after CAPD treatment were positively correlated with AUC(Glu), AUC(Ins), and AUC(Ins)/AUC(Glu) ratio (r = 0.48, 0.53, and 0.49; p = 0.0037, 0.001, and 0.0028, respectively). CONCLUSIONS: These results indicate that insulin resistance is an important factor in the development of hypertriglyceridemia in CAPD patients.

Dimethylacetamide, ethylenediamine, and diphenylmethane diisocyanate poisoning manifest as acute psychosis and pulmonary edema: treatment with hemoperfusion.

CASE REPORT: A 27-year-old man, employed by a synthetic fiber company, had been exposed to dimethylacetamide, ethylenediamine, and diphenylmethane diisocyanate in a confined space continuously for 4-6 hours per day for 3 days before admission. Hallucinations and delusions were noted at admission; pulmonary edema developed subsequently. The electroencephalogram showed diffuse moderate cortical dysfunction and slow waves at 4-7 Hz, 20-80 microV. Seizures, liver injury, and rhabdomyolysis were noted on the 4th hospital day. The patient was treated by hemoperfusion with a decrease in urine dimethylacetamide from 3,265 mg/g to 4 mg/g creatinine over 4 days. Serial urinary dimethylacetamide and electroencephalogram correlated with the clinical condition.

Idiopathic multicentric osteolysis with nephropathy.

Idiopathic multicentric osteolysis is a rare syndrome that manifests with progressive loss of carpal and tarsal bones in childhood. Affected children have arthritic-like episodes, followed by progressive deformities, radiographic osteolytic changes, and variable degrees of disability. A rare form of this disease (type III, sporadic) is associated with serious nephropathy. We present the first reported case of type III idiopathic multicentric osteolysis in a Chinese woman. The patient, a 34-year-old woman with normal mental development and no family history of bone or kidney disease, presented with a 4-day history of nausea and vomiting. She had shortening and swelling of the hands, which had occurred in childhood and persisted at the time of admission. X-ray studies showed disappearance of the carpal bones, and multiple osseous erosions of the tarsal bones. Hypertension, severe azotemia, and metabolic acidosis were also noted. Advanced renal disease was documented after a series of investigations, including renal biopsy. She is now dialysis-dependent. This case illustrates the importance of early diagnosis and management of idiopathic multicentric osteolysis with nephropathy.

Endothelin-1 chronically inhibits Na/H exchanger-3 in ET(B)-overexpressing OKP cells.

Endothelin-1 (ET-1) acutely increases Na/H antiporter activity in OKPET(B)6 cells, an opossum kidney proximal tubule cell line transfected with ET(B) receptor cDNA. The purpose of the present study was to examine the chronic effect of ET-1 on Na/H antiporter activity in OKP cells and to examine whether Na/H exchanger (NHE)-3 mRNA and protein abundance are regulated by ET-1. Quiescent OKPET(B)6 cells were treated with 10 nM ET-1 for 3, 6 or 24 h and Na/H antiporter activity was assayed. The Na/H antiporter activity in 3-h ET-1-treated cells was not different from controls. However, Na/H antiporter activity was significantly decreased by 29% at 6 h and 72% at 24 h. The effect of ET-1 on Na/H antiporter activity was blocked by BQ788, an ET(B) receptor antagonist, but not BQ123, an ET(A) receptor antagonist. The NHE-3 mRNA abundance in ET-1-treated cells was not different from controls at 3 h. However, there was a significant decrease in NHE-3 mRNA abundance at 6 and 24 h. There was also a significant decrease in NHE-3 protein abundance at 6 and 24 h. In summary, ET-1 chronically inhibits NHE-3 in OKPET(B)6 cells.

Adrenal cancer with hypertension but low plasma renin and aldosterone.

Patients with malignant lesions of the adrenal gland may present with a syndrome of excess mineralocorticoids. Both primary hyperaldosteronism and excess mineralocorticoids other than aldosterone resulting from adrenal carcinoma have rarely been reported. In most patients with adrenal tumors secreting mineralocorticoids other than aldosterone, distant metastasis had already occurred at the time of diagnosis and the prognosis was poor. We present a rare case of adrenal cancer with hypertension in a patient with low plasma renin activity and a low plasma aldosterone concentration. The patient's blood pressure returned to normal after removal of the tumor. The patient is still alive and without recurrence 6 years after surgery. This case illustrates the value of thorough evaluation of hypertension and prompt surgical treatment for patients with adrenal cancer.

Urinary endothelin-1 in patients with renal disease.

The purpose of this study was to investigate the usefulness of urinary endothelin-1 (ET-1) as a marker of renal disease. We measured urinary excretion of ET-1 in 28 patients with glomerulonephritis (GN), 22 patients with chronic renal failure (CRF), 40 patients with end-stage renal disease (ESRD), and 17 healthy volunteers. There was no significant difference in 24-hour urinary ET-1 excretion among the four groups (mean +/- SEM, 0.49 +/- 0.22 ng in controls, 0.79 +/- 0.37 ng in GN patients, 0.39 +/- 0.18 ng in CRF patients, and 0.28 +/- 0.11 ng in ESRD patients). The 24-hour urinary excretion of ET-1 in patients with GN or CRF showed significant correlation with the urinary excretion of sodium (r = 0.27, p < 0.05). The 24-hour urinary beta 2-microglobulin (beta 2M) excretion in patients with CRF (18.4 +/- 2.6 mg) or ESRD (9.7 +/- 1.1 mg) was significantly higher than in normal control subjects (0.23 +/- 0.11 mg). Serum creatinine concentration was positively correlated with the 24-hour urinary excretion of beta 2M in patients with GN or CRF (r = 0.50, p < 0.001). These findings indicate that urinary ET-1 is not as good a marker of renal disease as urinary beta 2M. However, it may be responsible for urinary sodium excretion in patients with GN or CRF.

Role of tyrosine kinase pathways in ETB receptor activation of NHE3.

Endothelin-1 (ET-1) binding to ETB receptors increases the activity of the apical membrane Na+/H+ antiporter (NHE3) of renal proximal tubule and cultured OKP cells. In OKPETB6 cells, a clonal cell line of OKP cells that overexpresses ETB receptors, ET-1-induced increases in Na+/H+ antiporter activity are mediated 50% by Ca2(+)-dependent pathways and 50% by tyrosine kinase pathways. ET-1 induces tyrosine phosphorylation of proteins of 68, 110, 125, 130, and 210 kDa. ET-1-induced tyrosine phosphorylation is mediated by the ETB receptor and is not dependent on increases in cell Ca2+ or protein kinase C. The 68-, 110-, 125-, and 130-kDa phosphoproteins are cytosolic, whereas the 210-kDa phosphoprotein is an integral membrane protein. Immunoprecipitation studies showed that the 68-kDa protein is paxillin and the 125-kDa protein is p125FAK (focal adhesion kinase). Cytochalasin D, which disrupts focal adhesions, prevented ET-1-induced tyrosine phosphorylation of paxillin, p110, p125FAK, and p130 but did not prevent tyrosine phosphorylation of p210 and did not prevent ET-1-induced increases in Na+/H+ antiporter activity. Thus 50% of ETB receptor-induced Na+/H+ antiporter activation is mediated by tyrosine kinase pathways, possibly involving p210. ETB receptor activation also induces tyrosine phosphorylation of focal adhesion proteins, but this is not required for antiporter activation.

Endothelin(B) receptor activates NHE-3 by a Ca2+-dependent pathway in OKP cells.

To examine the mechanisms by which endothelin (ET) regulates the Na/H antiporter isoform, NHE-3, OKP cells were stably transfected with ET(A) and ET(B) receptor cDNA. In cells overexpressing ET(B), but not ET(A) receptors, ET-1 increased Na/H antiporter activity (JNa/H). This effect was inhibited by a nonselective endothelin receptor blocker and by a selective ET(B) receptor blocker but was not inhibited by an ET(A) selective receptor blocker. In ET(B)-overexpressing cells, 10(-8) M ET-1 inhibited adenylyl cyclase, but protein kinase A inhibition and pertussis toxin pretreatment did not affect Na/H antiporter activation by ET-1. ET-1 caused a transient increase in cell [Ca2+], followed by a sustained increase. Increases in cell [Ca2+] were partially inhibited by pertussis toxin. ET-1-induced increases in J(Na/H) were 50% inhibited by clamping cell [Ca2+] low with BAPTA, and by KN62, a Ca-calmodulin kinase inhibitor. Inhibitors of protein kinase C, cyclooxygenase, lipoxygenase, and cytochrome P450 and cyclic GMP were without effect. In ET(A)-overexpressing cells, ET-1 increased cell [Ca2+] but did not increase JNa/H. In summary, binding of ET-1 to ET(B) receptors increases Na/H antiporter activity in OKP cells, an effect mediated in part by increases in cell [Ca2+] and Ca-calmodulin kinase. Increases in cell [Ca2+] are not sufficient for Na/H antiporter activation.

Correlation between renin responsiveness to furosemide and antihypertensive effect of captopril in patients with normal-renin essential hypertension.

The relationship between renin responsiveness to furosemide and the antihypertensive effect of captopril in patients with normal-renin essential hypertension were studied in 23 patients including nine men (mean age, 41 years) and 14 women (mean age, 40 years). Those who had an increment of more than 50% in plasma renin activity (PRA) two hours after an intravenous injection of 20 mg furosemide were classified as group A (n = 13) and the others were classified as group B (n = 10). Baseline PRA, plasma aldosterone and mean blood pressure (MBP) were not different between the two groups. Both groups showed no significant difference in natriuresis following furosemide administration. Significant change in MBP was observed after an oral dose of 100 mg captopril within four hours in group A, but not in group B. These data suggest that renin responsiveness to a single intravenous dose of furosemide can be a useful test for predicting the therapeutic response to captopril in patients with normal-renin essential hypertension. The furosemide test had a sensitivity of 75%, a specificity of 64%, a positive predictive value of 69% and a negative predictive value of 70%.