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.

Tailoring spontaneous infrared emission of HgTe quantum dots with laser-printed plasmonic arrays.

Chemically synthesized near-infrared to mid-infrared (IR) colloidal quantum dots (QDs) offer a promising platform for the realization of devices including emitters, detectors, security, and sensor systems. However, at longer wavelengths, the quantum yield of such QDs decreases as the radiative emission rate drops following Fermi's golden rule, while non-radiative recombination channels compete with light emission. Control over the radiative and non-radiative channels of the IR-emitting QDs is crucially important to improve the performance of IR-range devices. Here, we demonstrate strong enhancement of the spontaneous emission rate of near- to mid-IR HgTe QDs coupled to periodically arranged plasmonic nanoantennas, in the form of nanobumps, produced on the surface of glass-supported Au films via ablation-free direct femtosecond laser printing. The enhancement is achieved by simultaneous radiative coupling of the emission that spectrally matches the first-order lattice resonance of the arrays, as well as more efficient photoluminescence excitation provided by coupling of the pump radiation to the local surface plasmon resonances of the isolated nanoantennas. Moreover, coupling of the HgTe QDs to the lattice plasmons reduces the influence of non-radiative decay losses mediated by the formation of polarons formed between QD surface-trapped carriers and the IR absorption bands of dodecanethiol used as a ligand on the QDs, allowing us to improve the shape of the emission spectrum through a reduction in the spectral dip related to this ligand coupling. Considering the ease of the chemical synthesis and processing of the HgTe QDs combined with the scalability of the direct laser fabrication of nanoantennas with tailored plasmonic responses, our results provide an important step towards the design of IR-range devices for various applications.

A framework for auralization of boundary element method simulations including source and receiver directivity.

The Boundary Element Method (BEM) is a proven numerical prediction tool for computation of room acoustic transfer functions, as are required for auralization of a virtual space. In this paper, it is validated against case studies drawn from the "Ground Truth for Room Acoustical Simulation" database within a framework that includes source and receiver directivity. These aspects are often neglected but are respectively important to include for auralisation applications because source directivity is known to affect how a room is excited and because the human auditory system is sensitive to directional cues. The framework uses weighted-sums of spherical harmonic functions to represent both the source directivity to be simulated and the pressure field predicted in the vicinity of the receiver location, the coefficients of the former being fitted to measured directivity and those of the latter computed directly from the boundary data by evaluating a boundary integral. Three validation cases are presented, one of which includes a binaural receiver. The computed results match measurements closely for the two cases conducted in anechoic conditions but show some significant differences for the third room scenario; here, it is likely that uncertainty in boundary material data limited modelling accuracy.

Downregulation of renal tubular Wnt/ß-catenin signaling by Dickkopf-3 induces tubular cell death in proteinuric nephropathy.

Studies on the role of Wnt/ß-catenin signaling in different forms of kidney disease have yielded discrepant results. Here, we report the biphasic change of renal ß-catenin expression in mice with overload proteinuria in which ß-catenin was upregulated at the early stage (4 weeks after disease induction) but abrogated at the late phase (8 weeks). Acute albuminuria was observed at 1 week after bovine serum albumin injection, followed by partial remission at 4 weeks that coincided with overexpression of renal tubular ß-catenin. Interestingly, a rebound in albuminuria at 8 weeks was accompanied by downregulated tubular ß-catenin expression and heightened tubular apoptosis. In addition, there was an inverse relationship between Dickkopf-3 (Dkk-3) and renal tubular ß-catenin expression at these time points. In vitro, a similar trend in ß-catenin expression was observed in human kidney-2 (HK-2) cells with acute (upregulation) and prolonged (downregulation) exposure to albumin. Induction of a proapoptotic phenotype by albumin was significantly enhanced by silencing ß-catenin in HK-2 cells. Finally, Dkk-3 expression and secretion was increased after prolonged exposure to albumin, leading to the suppression of intracellular ß-catenin signaling pathway. The effect of Dkk-3 on ß-catenin signaling was confirmed by incubation with exogenous Dkk-3 in HK-2 cells. Taken together, these data suggest that downregulation of tubular ß-catenin signaling induced by Dkk-3 has a detrimental role in chronic proteinuria, partially through the increase in apoptosis.

Cost-effectiveness of lenalidomide plus dexamethasone vs. bortezomib plus melphalan and prednisone in transplant-ineligible U.S. patients with newly-diagnosed multiple myeloma.

OBJECTIVE: To conduct a cost-effectiveness assessment of lenalidomide plus dexamethasone (Rd) vs bortezomib plus melphalan and prednisone (VMP) as initial treatment for transplant-ineligible patients with newly-diagnosed multiple myeloma (MM), from a U.S. payer perspective. METHODS: A partitioned survival model was developed to estimate expected life-years (LYs), quality-adjusted LYs (QALYs), direct costs and incremental costs per QALY and LY gained associated with use of Rd vs VMP over a patient's lifetime. Information on the efficacy and safety of Rd and VMP was based on data from multinational phase III clinical trials and a network meta-analysis. Pre-progression direct costs included the costs of Rd and VMP, treatment of adverse events (including prophylaxis) and routine care and monitoring associated with MM. Post-progression direct costs included costs of subsequent treatment(s) and routine care and monitoring for progressive disease, all obtained from published literature and estimated from a U.S. payer perspective. Utilities were obtained from the aforementioned trials. Costs and outcomes were discounted at 3% annually. RESULTS: Relative to VMP, use of Rd was expected to result in an additional 2.22 LYs and 1.47 QALYs (discounted). Patients initiated with Rd were expected to incur an additional $78,977 in mean lifetime direct costs (discounted) vs those initiated with VMP. The incremental costs per QALY and per LY gained with Rd vs VMP were $53,826 and $35,552, respectively. In sensitivity analyses, results were found to be most sensitive to differences in survival associated with Rd vs VMP, the cost of lenalidomide and the discount rate applied to effectiveness outcomes. CONCLUSIONS: Rd was expected to result in greater LYs and QALYs compared with VMP, with similar overall costs per LY for each regimen. Results of this analysis indicated that Rd may be a cost-effective alternative to VMP as initial treatment for transplant-ineligible patients with MM, with an incremental cost-effectiveness ratio well within the levels for recent advancements in oncology.

Ex-vivo haemodynamic models for the study of Stanford type B aortic dissection in isolated porcine aorta.

OBJECTIVES: The aim of this study is to present novel ex-vivo models in the study of complex haemodynamical changes in Stanford type B aortic dissection (TBAD). MATERIALS AND METHODS: Fifteen fresh porcine aortas were harvested and preserved with 4 °C saline. Ex-vivo models were developed to simulate TBAD in three different situations: model A with patent false lumen, model B with distal re-entry only and model C with proximal primary entry only. These models were connected to standardised pulsatile pumps and the pressure waveforms were monitored and compared. The aortas were scanned with ultrasonography and subjected to post-experiment autopsy. RESULTS: The three different models were successfully created (n = 13). Pulsatile flow testing was successful and the shapes of the pressure waveforms were similar to those taken from human aorta. Post-testing gross examination confirmed the success of modelling. CONCLUSION: Porcine aortas may prove to be useful ex-vivo models in the study of aortic dissection haemodynamics. These models are reproducible and may be used in the study of complex haemodynamic forces during the development and propagation of TBAD. Our three porcine models give a potential possibility in helping clinicians isolate and analyse complex haemodynamical factors in the development, propagation and prognosis of TBAD.

Common polymorphisms in TLR4 gene associated with susceptibility to pulmonary tuberculosis in the Sudanese.

SETTING: Host genetic risk factors influence susceptibility to tuberculosis (TB). There is ample evidence supporting the involvement of toll-like receptor 4 (TLR4) in mycobacterial infection. OBJECTIVE: To study the relationship between the TLR4 gene and TB susceptibility in the Sudanese population. DESIGN: A case-control study was conducted among 207 patients with pulmonary TB and 395 healthy controls. Ten tag single nucleotide polymorphisms (SNPs) of the TLR4 gene were genotyped using restriction digestion or hybridisation assays, and analysed. RESULTS: The genotypes were in Hardy-Weinberg equilibrium. After controlling for sex using the Mantel-Haenszel test, four SNPs showed significant differences between cases and controls, even after correction of multiple comparisons by Bonferroni procedure. The Mantel-Haenszel estimates of allelic odds ratios for the high-risk alleles were 1.67 for rs1927911 (P = 0.0001), 1.85 for rs5030725 (P = 0.0008), 2.14 for rs7869402 (P = 1.87e-07) and 2.31 for rs1927906 (P = 1.23e-10). Haplotype analysis showed that rs1927911 and rs5030725 were in one haplotype block, and rs7869402 and rs1927906 were in another haplotype block. Conditional haplotype analysis suggested the presence of one causal variant downstream of a recombination hot spot at the 3' region of the TLR4 gene. CONCLUSION: This is the first study to show that common TLR4 polymorphisms are associated with TB susceptibility in the Sudanese population.

Successful emergency endovascular treatment of juxtarenal and infrarental mycotic aortic aneurysms in patients with small diameter aortae using Cook(®) Zenith ESLE Stentgrafts.

BACKGROUND: Endovascular repair of mycotic aneurysm is an alternative to open repair if the patho-anatomy is suitable. The aortic size above and below the mycotic aneurysm may be small. METHODS: A retrospective review was made of prospectively collected departmental computerised database. RESULTS: Three oriental patients with juxta- and infra-renal mycotic aortic aneurysms with a small aortic diameter of 17 mm to 18 mm underwent successful emergency endovascular treatment using Cook(®) Zenith ESLE stentgrafts. These are ancillary devices aimed at iliac extensions usually. CONCLUSION: This is to our knowledge the first case series of Cook(®) Zenith ESLE iliac component endografts for the treatment of aortic mycotic aneurysms with small aortae, and short- and mid-term results are encouraging.

Endovascular repair for abdominal aortic aneurysms: the first hundred cases.

OBJECTIVE: To evaluate the early and mid-term results of the first 100 elective endovascular repairs for abdominal aortic aneurysms. DESIGN: Retrospective analysis of prospectively collected data. SETTING: University teaching hospital, Hong Kong. PATIENTS: The first 100 patients with infrarenal abdominal aortic aneurysms who underwent elective endovascular repair. MAIN OUTCOME MEASURES: Peri-operative data, mortality and morbidities as well as the follow-up details were recorded. Cumulative data on endoleaks, clinical failures, secondary procedures, and survival were evaluated with Kaplan-Meier analyses. RESULTS: There were 85 men and 15 women, with a mean age of 75 (range, 50-90) years. Failed implantations due to access difficulty occurred in two patients during the same period, giving a technical success rate of 98%. The mean aneurysm diameter was 6.2 cm. Access site injury requiring repair occurred in four (4%) of the patients, while wound problems were the most common complications (11%). The median hospital stay was 6 days, and there were two hospital deaths, giving a hospital mortality rate of 2%. During a mean follow-up of 36 (standard deviation, 24) months, there were three aneurysmal ruptures and four elective open conversions, with only one aneurysm-related death after hospital discharge. At 3 years, the cumulative rates of freedom from any endoleak, freedom from primary failure, freedom from secondary failure, freedom from secondary procedures, and survival were 60%, 84%, 89%, 88%, and 78%, respectively. CONCLUSIONS: The early and mid-term results of elective endovascular repair for abdominal aortic aneurysms appear promising. The procedure is effective in preventing aneurysm-related death in the mid-term. Nevertheless, the importance of constant surveillance cannot be over-emphasised, as clinical failures and ruptures are still a concern.

Angiotensin mediates renal fibrosis in the nephropathy of glycogen storage disease type Ia.

Patients with glycogen storage disease type Ia (GSD-Ia) develop renal disease of unknown etiology despite intensive dietary therapies. This renal disease shares many clinical and pathological similarities to diabetic nephropathy. We studied the expression of angiotensinogen, angiotensin type 1 receptor, transforming growth factor-beta1, and connective tissue growth factor in mice with GSD-Ia and found them to be elevated compared to controls. While increased renal expression of angiotensinogen was evident in 2-week-old mice with GSD-Ia, the renal expression of transforming growth factor-beta and connective tissue growth factor did not increase for another week; consistent with upregulation of these factors by angiotensin II. The expression of fibronectin and collagens I, III, and IV was also elevated in the kidneys of mice with GSD-Ia, compared to controls. Renal fibrosis was characterized by a marked increase in the synthesis and deposition of extracellular matrix proteins in the renal cortex and histological abnormalities including tubular basement membrane thickening, tubular atrophy, tubular dilation, and multifocal interstitial fibrosis. Our results suggest that activation of the angiotensin system has an important role in the pathophysiology of renal disease in patients with GSD-Ia.

Glucose-6-phosphate transporter gene therapy corrects metabolic and myeloid abnormalities in glycogen storage disease type Ib mice.

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT), an endoplasmic reticulum-associated transmembrane protein that is ubiquitously expressed. GSD-Ib patients suffer from disturbed glucose homeostasis and myeloid dysfunctions. To evaluate the feasibility of gene replacement therapy for GSD-Ib, we have infused adenoviral (Ad) vector containing human G6PT (Ad-hG6PT) into G6PT-deficient (G6PT(-/-)) mice that manifest symptoms characteristics of the human disorder. Ad-hG6PT infusion restores significant levels of G6PT mRNA expression in the liver, bone marrow and spleen, and corrects metabolic as well as myeloid abnormalities in G6PT(-/-) mice. The G6PT(-/-) mice receiving gene therapy exhibit improved growth; normalized serum profiles for glucose, cholesterol, triglyceride, uric acid and lactic acid; and reduced hepatic glycogen deposition. The therapy also corrects neutropenia and lowers the elevated serum levels of granulocyte colony-stimulating factor. The development of bone and spleen in the infused G6PT(-/-) mice is improved and accompanied by increased cellularity and normalized myeloid progenitor cell frequencies in both tissues. This effective use of gene therapy to correct metabolic imbalances and myeloid dysfunctions in GSD-Ib mice holds promise for the future of gene therapy in humans.

Salvianolic acid B, an aqueous component of danshen (Salvia miltiorrhiza), relaxes rat coronary artery by inhibition of calcium channels.

In this study, we have investigated the mechanism of action through which salvianolic acid, a constituent of the medicinal herb danshen (Salvia miltiorrhiza), causes relaxation of isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT). The vasorelaxant effects of salvianolic acid B were also compared with the aqueous extract of danshen. Extraction of the water-soluble fraction from danshen provided a yield of 17.5%. The amount of salvianolic acid B determined in this aqueous extract was 3.9%, and the extract was 6.3 times less potent than salvianolic acid B in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 930.3+/-133.5 microg/ml and 147.9+/-17.4 microg/ml, respectively. Removal of the endothelium did not significantly affect their vasodilator potencies; IC(50) values were 842.1+/-123.8 mictog/ml and 160.3+/-25.9 microg/ml. On the other hand, a potassium channel inhibitor tetraethylammonium (TEA, 10 mM) shifted their concentration-response curves by 1.7 and 2.9 folds. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT or 60 mM KCl for 5 min prior to adding CaCl(2) to elicit contraction. In 5-HT-primed preparations, 2 mg/ml danshen aqueous extract and 0.72 mg/ml salvianolic acid B abolished the CaCl(2)-induced vasoconstriction, whereas, in KCl-primed preparations, 10 mg/ml danshen aqueous extract and 1.44 mg/ml salvianolic acid B produced 90% inhibition. These findings suggest the vasorelaxant effects of danshen aqueous extract and salvianolic acid B were produced by inhibition of Ca(2+) influx in the vascular smooth muscle cells. The opening of K(+) channels had a minor contribution to their effects, but endothelium-dependent mechanisms were not involved. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen aqueous extract suggest it is an important vasodilator constituent in this medicinal herb.

Screening for colorectal cancer in Chinese: comparison of fecal occult blood test, flexible sigmoidoscopy, and colonoscopy.

BACKGROUND AND AIMS: Fecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), and colonoscopy are the most commonly recommended screening tests for colorectal cancer. The aim of this study was to compare the accuracy and safety of these 3 screening procedures in a general population of ethnic Chinese. METHODS: Asymptomatic adults older than 50 years were recruited from the general public through health exhibitions. All enrolled subjects were offered FOBT and full colonoscopy under sedation. Advanced colonic lesions (defined as adenoma > or = 10 mm, villous adenoma, adenoma with moderate or severe dysplasia, or invasive cancer) were recorded. Lesions at the distal 40 cm in the left colon and rectum were taken as findings of FS. RESULTS: A total of 505 subjects (56% women; mean age +/- SD, 56.5 +/- 5.4 years) were enrolled, and 476 (94.3%) had a complete colonoscopy. Advanced colonic neoplasms were documented in 63 subjects (12.5%), of which 45 had lesions in the distal colon and 26 in the proximal colon. Among the 385 subjects with a normal distal colon, 14 (3.6%) had advanced lesions in the proximal colon that would be missed by FS alone. The sensitivity and specificity of FOBT for advanced colonic lesions were 14.3% and 79.2% and the sensitivity and specificity of FS were 77.8% and 83.9%, respectively. Combining FOBT with FS would not significantly improve the results of FS alone. Among these 505 subjects who underwent colonoscopy and 148 who underwent polypectomy, there was no perforation and only one occurrence of postpolypectomy bleeding recorded. CONCLUSIONS: Colonoscopy is a safe and accurate method for the screening of colorectal neoplasms in Chinese subjects.

Cervical necrotizing fasciitis of odontogenic origin: a report of 11 cases.

PURPOSE: Although most cases of cervical necrotizing fasciitis (CNF) are odontogenic in origin, reports of this disease in the dental literature are sparse. The purpose of this study was to review the cases treated on our service, and to analyze the features of this disease and the responses to management, to supplement the understanding of this relatively rare and life-threatening disease. PATIENTS AND METHODS: All cases of infection admitted to the OMS service in a period of 10.5 years were studied retrospectively. The diagnosis of CNF was established by the findings on surgical exploration and histologic examination. The patients' age, sex, medical status, causes of the infection, bacteriology, computed tomography scan findings, surgical interventions, complications, survival, and other clinical parameters were reviewed. RESULTS: A total of 422 cases of infection were admitted, and 11 cases of cervical necrotizing fasciitis were found. The incidence of CNF was 2.6% among the infections hospitalized on the OMS service. There were 7 male and 4 female patients. Eight patients were older than 60 years of age. Seven patients had immunocompromising conditions, including diabetes mellitus in 4, concurrent administration of steroid in 2, uremia in 1, and a thymus carcinoma in 1. All patients showed parapharyngeal space involvement; four also showed retropharyngeal space involvement. Gas was found in the computed tomography scan in 6 patients, extending to cranial base in 3 of them. Anaerobes were isolated in 73% of the infections, whereas Streptococcus species were uniformly present. All patients received 1 or more debridements. Major complications occurred in 4 patients, including mediastinitis in 4, septic shock in 2, lung empyema in 1, pleural effusion in 2, and pericardial effusion in 1. All major complications developed in the immunocompromised patients, leading to 2 deaths. CONCLUSION: The mortality rate in this study was 18%. Early surgical debridement, intensive medical care, and a multidisciplinary approach are advocated in the management of CNF.

Amyloid peptide channels: blockade by zinc and inhibition by Congo red (amyloid channel block).

Amyloid peptides are the major constituents of amyloid deposits in various amyloid diseases including Alzheimer's disease, type II diabetes mellitus, prion diseases and others. The hallmark of amyloid is the binding of the dye, Congo red, which creates characteristic staining due to the dye's ability to bind the beta sheet aggregates referred to as amyloid. Previous reports have demonstrated that several cytotoxic, amyloidogenic peptides can form ion channels in planar phospholipid bilayer membranes and have suggested that these channels may represent the pathogenic mechanism of cell and tissue destruction in amyloid disease. Furthermore, zinc and Congo red can ameliorate or prevent the pathogenic effect of certain amyloidpeptides. We report here that zinc at micromolar concentrations caused a reversible blockade of islet amyloid polypeptide (IAPP, amylin) and PrP 106-126 channels whereas calcium and magnesium did not. Congo red completely inhibited channel formation if preincubated with amyloid peptides, but had no effect on IAPP or PrP 106-126 channels once formed. These results suggest a requirement for aggregation for the formation of amyloid peptide channels and are consistent with the "channel hypothesis" of amyloid disease. They also suggest potential avenues for ameliorative therapy of these illnesses.