Consensus guidelines for the management of HR-positive HER2/neu negative early breast cancer in India, SAARC region and other LMIC by DELPHI survey method.

BACKGROUND: Precise prognostication is the key to optimum and effective treatment planning for early-stage hormone receptor (HR) positive, HER2/neu negative breast cancer patients. Differences in the breast cancer incidence and tumor anatomical features at diagnosis, pharmacogenomics data between Western and Indian women along with the vast diversity in the economic status and differences in insurance policies of these regions; suggest recommendations put forward for Western women might not be applicable to Indian/Asian women. Opinions from oncologists through a voting survey on various prognostic factors/tools to be considered for planning adjuvant therapy are consolidated in this report for the benefit of oncologists of the sub-continent, SAARC and Asia's LMIC (low and middle-income countries). METHODS: A three-phase DELPHI survey was conducted to collect opinions on prognostic factors considered for planning adjuvant therapy in early-stage HR+/HER2/neu negative breast cancer patients. A panel of 25 oncologists with expertise in breast cancer participated in the survey conducted in 2021. The experts provided opinions as 'agree' or disagree' or 'not sure' in phases-1 and 2 which were conducted virtually; in the final phase-3, all the panel experts met in person and concluded the survey. RESULTS: Opinions on 41 statements related to prognostic factors/tools and their implications in planning adjuvant endocrine/chemotherapy were collected. All the statements were supported by the latest data from the clinical trials (prospective/retrospective). The statements with opinions of consensus less than 66% were disseminated in phase-2, and later in phase-3 with supporting literature. In phase-3, all the opinions from panelists were consolidated and guidelines were framed. CONCLUSIONS: This consensus guideline will assist oncologists of India, SAARC and LMIC countries in informed clinical decision-making on adjuvant treatment in early HR+/HER2/neu negative breast cancer patients.

Differentially expressed microRNAs in biochemically characterized FrieswalTM crossbred bull semen.

In addition to the transmission of paternal genome, spermatozoa also carry coding as well as noncoding microRNAs (miRNAs) into the female oocyte during the process of biological fertilization. Based on RNA deep sequencing, a total 28 number of differentially expressed miRNAs were cataloged in categorized FrieswalTM crossbred (Holstein Friesian X Sahiwal) bull semen on the basis of conception rate (CR) in field progeny testing program. Validation of selected miRNAs viz. bta-mir-182, bta-let-7b, bta-mir-34c and bta-mir-20a revealed that, superior bull semen having comparatively (p < .05) lower level of all the miRNAs in contrast to inferior bull semen. Additionally, it was illustrated that, bta-mir-20a and bta-mir-34c miRNAs are negatively (p < .01) correlated with seminal plasma catalase (CAT) activity and glutathione peroxidase (GPx) level. Interactome studies identified that bta-mir-140, bta-mir-342, bta-mir-1306 and bta-mir-217 can target few of the important solute carrier (SLC) proteins viz. SLC30A3, SLC39A9, SLC31A1 and SLC38A2, respectively. Interestingly, it was noticed that all the SLCs were significantly (p < .05) expressed at higher level in superior quality bull semen and they are negatively correlated (p < .01) with their corresponding miRNAs as mentioned. This study may reflect the role of miRNAs in regulating few of the candidate genes and thus may influence the bull semen quality traits.

Profiling of key heat shock proteins and their relationship with male sexual behavior and seminal characteristics in Kankrej (Bos indicus) breeding bulls during different seasons.

The goal of this study is to use indirect ELISA to determine the concentration of major heat shock proteins (Hsps) in Kankrej (Bos indicus) breeding bulls and their relationship with certain male phenotypic traits including sexual behavior, sperm quality, and bull fertility in different seasons. The seasonal fluctuation in the concentration of three major Hsps (60, 70, and 90) was determined using an indirect enzyme-linked immunosorbent assay (ELISA). According to the findings, Hsps levels are significantly higher during the summer season and are associated with both fresh and post-thawed semen quality traits in Kankrej breeding bulls. The better sexual behavior of bulls and seminal parameters of fresh or thawed semen was observed in the winter season together with the lower concentrations of HSPs. These could suggest negative association between HSPs with bull sexual behavior and seminal parameters. As a result, the concentration of Hsps in breeding bulls may be a useful indicator for determining fertility traits.

Designing, optimization, and validation of whole blood direct T-ARMS PCR for precise and rapid genotyping of complex vertebral malformation in cattle.

BACKGROUND: DNA testing in the cattle industry undergoes multiple hurdles. Successful genotyping involves the transportation of samples from the field to the laboratory in a chilled environment followed by DNA extraction, and finally, a specific genotyping protocol is followed. Various researches are focused on overcoming these issues. Microcards offer blood transportation at ambient temperature. Direct PCR methods can save the time of DNA extraction but available only for simplex PCR. Tetra Primer-Amplification Refractory Mutation System based Polymerase Chain Reaction (T-ARMS PCR) can make DNA testing faster in a low-cost setting. The present study was aimed to design, optimize, and validate a T-ARMS PCR for faster DNA testing of SNP responsible for Complex Vertebral Malformation (CVM)-an important genetic disease of the cattle industry. Further, a direct T-ARMS PCR from whole blood was developed to avoid the DNA extraction steps. Lastly, using the optimized protocol, genotyping of blood spotted on Microcard eliminates the need for cold chain maintenance in the transportation of samples. RESULTS: The present study demonstrated a novel T-ARMS PCR-based genotyping of the SNP rs438228855, which is responsible for CVM. Here, wild genotypes were recognized by 389 bp and 199 bp bands in agarose gel, while the carrier genotype showed an additional 241 bp band. The developed protocol was validated using PCR-Primer Introduced Restriction Analysis (PCR-PIRA) and sequencing. The present study further established a direct T-ARMS PCR for this SNP from whole blood. Different conditions such as heparin and EDTA treated blood, the need for pre-treatment, and two different DNA Polymerases for the direct PCR were optimized. Finally, our optimized protocol successfully genotyped the whole blood samples dried on Insta™DNA cards. CONCLUSIONS: The present study reported the usefulness of primer modified T-ARMS PCR for detecting CVM for the first time. To the best of our knowledge, direct PCR in T-ARMS PCR has never been reported. Lastly, the use of microcards in the developed protocol can make the assay useful in the DNA testing of field samples.

Comparative CpG methylation kinetic patterns of cis-regulatory regions of heat stress-related genes in Sahiwal and Frieswal cattle upon persistent heat stress.

The kinetic patterns of CpG methylation of the cis-regulatory region of heat stress-related genes on exposed to heat stress (at 42 °C) between the Sahiwal and Frieswal cattle was compared in the present study. Using an in vitro whole blood culture model, cells were continuously exposed to heat stress (at 42 °C) for 6 h. Methylation levels of five genes, viz., GPX1, HSP70, HSP90, c-FOS, and JUN were estimated by SyberGreen-based quantitative methylation-specific PCR (qMSP) assay. CpG methylation kinetics at different time points of heat stress (0.5, 1, 2, 4, 6 h) were analyzed using mixed ANOVA. The initial methylation level, estimated at 37 °C, of HSP70 was significantly high in the Sahiwal breed. A significant (p<0.001) time-dependent hypomethylation of an antioxidant gene (GPX1) CpG islands was detected at the acute phase of the stress. Heat shock protein gene (HSP70) showed a similar CpG methylation kinetics where the hypomethylation was prominent from 1 h and persisted up to 4 h. The heat stress responses of both Sahiwal and Frieswal cattle were identical as there was no distinctiveness in the methylation kinetics of CpG islands of studied genes. The acclimatization of Frieswal cattle-a breed developed in India over the years to the tropical climatic conditions, maybe one of the reasons for this similarity. Thus, the present study results could pave a path to understand the molecular mechanism of heat stress and adaptation of indigenous and crossbred cattle populations to the changing scenario in tropical climate conditions.

Clinical and biochemical profile of Guillain Barré Syndrome in Pakistan.

OBJECTIVES: To evaluate the frequency, distribution, characteristics, and biochemical features of Guillain-Barré syndrome (GBS). METHODS: This retrospective, case-control study was conducted between November 2018 and February 2020 at PIMS Hospital, Islamabad and Arid Agriculture University, Rawalpindi, Pakistan. The GBS patients were diagnosed through physical examination and nerve conduction study (NCS). Hemoglobin (Hb), liver function tests, renal function tests, lipid profile, and interleukin-17 levels were investigated through the blood. Cerebrospinal fluid analysis (CSF) was performed to measure albuminocytological dissociation (ACD). RESULTS: One hundred and ten patients and 130 controls participated in this study. Fifty-nine (53.63 %) patients had gastrointestinal infection while 52 (47.27 %) had AIDP. IL-17 serum levels were associated with GBS showing elevated values 18.49 pg/mL (SD=4.10) in cases as compared to controls 10.66 (SD=2.09), p<0.001. The CSF proteins were statistically significant in GBS patients, 127.93 mg/dL (SD=51.28), p=0.002. Ascending weakness was observed in 82 (74.5 %) patients. The results showed that the mean age value of GBS patients was 41.27 years, showing males preponderance. The mean Hb value for males and females was 14.83 g/dL and 10.88 g/dL respectively. Seasonal trends in the disease showed that 40% of GBS patients had infections during the spring. CONCLUSION: The results of the current study suggest that IL-17 levels trigger autoimmunity in GBS patients. The ACD could be used as a diagnostic marker of GBS along with NCS. Antecedent infections were common in a majority of GBS patients.

Effect of heat stress on superoxide anion production in native and crossbred cattle under in vitro whole blood culture model.

Impact of global warming on the dairy industry has gained attention due to huge economic losses through low production and fertility caused by heat stress. Exposure to hyperthermia provokes a series of complex responses in mammals which are been related to morphological and physiological alterations including the production of reactive oxygen species (ROS). A quantitative spectrophotometric based nitroblue tetrazolium (NBT) reduction assay was used to estimate the superoxide anion (•O2-) level in heat stressed (at 42 °C) whole blood cultures of native and crossbred bulls (Sahiwal and Frieswal), in vitro. The breed effect in the kinetics of •O2- production at different time periods of continual heat stress was analyzed by repeated measures ANOVA. Comparison between different time periods in reference to 37 °C was analyzed by paired t-test. The •O2- level was significantly different (p < 0.05) between cells at 37 °C and 42 °C at different periods of incubation. Kinetics study showed increment of •O2- production on the acute phase of stress followed by a reduction in both Sahiwal and Frieswal breeds. In Sahiwal breed, the inflated superoxide level continued abated till 4 h and raised again at 6 h, while in Frieswal •O2- level reverted to raise sooner with in 2 h of incubation itself. Contrarily, kinetic of •O2- level in plasma showed a significant reduction (p < 0.001) at 30 min of 42 °C incubation followed by increment of •O2- level. Further, the breed variation was significant (p < 0.05) and a significant high reduction of •O2- level was observed in Sahiwal breed. Our finding indicates that, a better and longer •O2- production homeostasis and higher plasma scavenging ability of native breed may be one of the reasons for the higher thermal tolerance of these breeds in tropical climate.

Retrospective Study of Nephrotoxicity Rate among Adult Patients Receiving Colistin Compared to ß-lactam Antibiotics.

PURPOSE: Patients receiving colistin for carbapenem-resistant gram-negative bacteria (CR-GNB) infections generally have multiple risk factors for nephrotoxicity, so it might be possible that colistin may be erroneously blamed for the nephrotoxicity. MATERIALS AND METHODS: We retrospectively analyzed case records of patients who received colistin and those who received antibiotics other than colistin [carbapenem or ß-lactam-ß-lactamases inhibitors (ßL-ßLI)] for gram-negative bacteremia. Those patients with preexisting renal failure and those who received antibiotics for <72 hours were excluded from the study. Nephrotoxicity was assessed using the risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, end-stage kidney disease (RIFLE) criteria. RESULTS: Out of the 222 patients, the colistin arm had 118 and the noncolistin arm had 104 patients. Even though the colistin arm had significantly higher number of sicker patients with neutropenia (40.7% vs 14.4%, p = 0.0001), mechanical ventilation (0.0001), having lines (0.0001), on inotropes (0.003), receiving other nephrotoxic drugs (0.0001), and higher Pitt score (p = 0.0001), there was no significant difference in the nephrotoxicity between the two arms (10.2% vs 9.6%, p = 0.89). Logistical regression showed a higher Pitt bacteremia score (p = 0.03) and a higher Charlson comorbidity index (p = 0.02), but not colistin administration (p = 0.32), were independently associated with nephrotoxicity. CONCLUSION: Administration of colistin was not associated with higher rates of nephrotoxicity than carbapenems or ßL-ßLI agents. HOW TO CITE THIS ARTICLE: Ghafur A, Bansal N, Devarajan V, Raja T, Easow J, Raja MA, et al. Retrospective Study of Nephrotoxicity Rate among Adult Patients Receiving Colistin Compared to ß-lactam Antibiotics. IJCCM 2019;23(11):518-522.

A Synonymous Mutation at Bovine Alpha Vitronectin Domain of Integrin Host Receptor (ITGAV) Gene Effect the Susceptibility of Foot-and-Mouth Disease in Crossbred Cattle.

Integrins are one of the major biologically active proteins responsible for Foot-and-mouth disease virus (FMDV)- host interaction. Out of various heterodimeric integrins discovered, αVß6 heterodimer serves as the chief receptor for FMDV host tropism. Earlier studies reported that, SNPs at beta 6 subunit (ITGB6) were associated with the occurrence of the diseases in cattle. In this study we report the association between a synonymous SNP (rs719257875) at bovine alpha vitronectin domain of integrin receptor (ITGAV) gene and FMD susceptibility in cattle. A strong significant association (P < 0.0001) of the genotypes with FMD susceptibility were obtained, where the CC genotypes play a major role in occurrence of FMD in crossbred cattle.

Functional proteomic analysis of crossbred (Holstein Friesian × Sahiwal) bull spermatozoa.

Male infertility is one of the prime concerns of dairy cattle production. The study was designed to find out differentially expressed proteins in categorized crossbred (Holstein Friesian × Sahiwal) bull semen to serve as potential biomarkers for male infertility. Frozen crossbred bull semen with satisfactory phenotypic records were defined as "good" and "poor" based on their fertility rates. A total of 1,547 proteins were detected in bull spermatozoa using liquid chromatography-mass spectrometer (LC-MS/MS) analysis. Results revealed that 558 (36.1%) and 653 (42.2%) proteins were expressed to good and poor quality bull spermatozoa, respectively. A total of 336 proteins (21.7%) were reported to be unique for both good and poor quality bull semen, and among the common proteins, 224 (66.7%) and 112 (33.3%) were up- and downregulated in good and poor quality categorized bull semen, respectively. Gene Ontology analysis of global proteomes identified different signalling pathways, and most of them were related to cellular motility, immune systems as well as cellular metabolisms. The distinctive presence of some of the proteins may provide an insight into the molecular mechanistic role played by these proteins in crossbred bull infertility.

RT-LAMP assay: an alternative approach for profiling of bovine heat shock protein 70 gene in PBMC cultured model.

The purpose of this study is to develop a novel Reverse Transcriptase Loop-mediated isothermal amplification (RT-LAMP) based assay for in vitro profiling of heat shock protein 70 (Hsp70) in bovine peripheral blood mononuclear cell (PBMC) culture model utilizing the absorbance level of magnesium pyrophosphate-a by-product of LAMP reaction. A set of bovine Hsp70 specific RT-LAMP primers were designed to detect the differential absorbance level of magnesium pyrophosphate by-product which signifies the degree of Hsp70 amplification from cDNA of thermally induced cultured cells at different recovery periods. The study revealed significant (P < 0.05) correlation between absorbance level and the fold change of Hsp70 transcripts at different kinetic intervals of heat stress recovery in bovine PBMC cell culture models. RT-LAMP based absorbance assay can be used as an indicator to measure the degree of bovine Hsp70 transcripts produced during thermal stress and can be used as an alternative to the traditional Real time PCR assay. Developed RT-LAMP assay can be used as a cost-effective method for profiling of bovine HSP70 gene.

Comparative expression profile of NOD1/2 and certain acute inflammatory cytokines in thermal-stressed cell culture model of native and crossbred cattle.

Thermotolerance depends mainly on the health and immune status of the animals. The variation in the immune status of the animals may alter the level of tolerance of animals exposed to heat or cold stress. The present study was conducted to investigate the expression profile of two important nucleotide binding and oligomerization domain receptors (NLRs) (NOD1 and NOD2) and their central signalling molecule RIP2 gene during in vitro thermal-stressed bovine peripheral blood mononuclear cells (PBMCs) of native (Sahiwal) and crossbred (Sahiwal X HF) cattle. We also examined the differential expression profile of certain acute inflammatory cytokines in in vitro thermal-stressed PBMC culture among native and its crossbred counterparts. Results revealed that the expression profile of NOD1/2 positively correlates with the thermal stress, signalling molecule and cytokines. Present findings also highlighted that the expression patterns during thermal stress were comparatively superior among indigenous compared to crossbred cattle which may add references regarding the better immune adaptability of Zebu cattle.

Monotherapy versus Combination Therapy against Nonbacteremic Carbapenem-resistant Gram-negative Infections: A Retrospective Observational Study.

BACKGROUND: Superiority of colistin-carbapenem combination therapy (CCCT) over colistin monotherapy (CMT) against carbapenem-resistant Gram-negative bacterial (CRGNB) infections is not conclusively proven. AIM: The aim of the current study was to analyze the effectiveness of both strategies against CRGNB nonbacteremic infections. DESIGN: This was a retrospective observational cohort study. SUBJECTS AND METHODS: Case record analysis of patients who had CRGNB nonbacteremic infections identified over a period of 4 years (January 2012-December 2015) was done by medical record review at a tertiary care center in India. STATISTICAL ANALYSIS: P < 0.05 was considered as significant. Multivariate analysis was performed using Cox regression. RESULTS: Out of 153 patients (pneumonia 115, urinary tract infection 17, complicated skin and soft-tissue infection 18, intra-abdominal infection 1, and meningitis 2), 92 patients received CCCT and 61 received CMT. Univariate analysis revealed higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, pneumonia as the diagnosis, and Klebsiella as the causative organism to be the risk factors for higher 28-day mortality (P = 0.036, 0.006, 0.016, respectively). Combination therapy had no significant impact on mortality (odds ratio [OR] = 0.91, 95% confidence interval [CI] = 0.327-2.535, P = 0.857). Multivariate analysis revealed that higher APACHE II score and infection due to Klebsiella were found to be independent risk factors for higher mortality (OR = 3.16 and 4.9, 95% CI = 1.34-7.4 and 2.19-11.2, P = 0.008 and 0.0001, respectively). CONCLUSIONS: In our retrospective single-center series of CRGNB nonbacteremic infections, CCCT was not superior to CMT. Multicenter large observational studies or prospective randomized clinical trials are the need of the hour.

Colistin Nephrotoxicity in Adults: Single Centre Large Series from India.

CONTEXT: Limited Indian data are available on the rate of colistin nephrotoxicity and other risk factors contributing to the development of this important side effect. AIM: This study aims to generate data on colistin nephrotoxicity from a large cohort of Indian patients. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: Case record analysis of patients who received colistin, in an oncology center in India, between January 2011 and December 2015. Nephrotoxicity was assessed using risk, injury, failure, loss, and end-stage (RIFLE) criteria. STATISTICAL ANALYSIS: P < 0.05 was considered as statistically significant. RESULTS: Out of the 229 patients, 13.1% (30/229) developed abnormal RIFLE. Abnormal RIFLE group (n = 30), in comparison to the normal renal function group (n = 199), had higher number of patients in intensive care unit (ICU) (96% vs. 79%, P = 0.02), higher Acute Physiology and Chronic Health Evaluation (APACHE II) score (23 vs. 19 P = 0.0001), Charlson score (5.9 vs. 4.3, P = 0.001), mechanical ventilation (90% vs. 67%, P = 0.016), 28 days mortality (63% vs. 25%, P = 0.0001), and abnormal baseline creatinine (36% vs. 8%, P = 0.001). Coadministration of vancomycin had higher rates of nephrotoxicity (P = 0.039). There was no significant difference in nephrotoxicity between 6 and 9 MU/day dosing pattern (8.8% vs. 13.8%, P = 0.058). CONCLUSION: Nephrotoxicity rate in our retrospective single center large series of patients receiving colistin was 13.1%. Patients with abnormal baseline creatinine, ICU stay, and higher disease severity are at higher risk of nephrotoxicity while on colistin. A daily dose of 9 million does not significantly increase nephrotoxicity compared to the 6 million. Concomitant administration of vancomycin with colistin increases the risk of nephrotoxicity.

Nanocrystalline Gd2Ti2O7 Pyrochlore Material for NIR Reflective Pigment Application: Micro-Structural and Optical Studies.

In this interesting article, the synthesis of nanocrystalline Gd2Ti2O7 material by ball milling followed by annealing, characterization and its application are reported. The Rietveld structural refinement data confirm the cubic pyrochlore Gd2Ti2O7 phase with lattice parameter, a = 1.022(9) nm. The particle size observed by HRSEM image concurs with the average crystalline sizes of particles extracted from XRD data. The optical properties of pyrochlore nanocrystalline Gd2Ti207 material are explored from UV-visible, FT-IR, NIR, PL, and Raman spectroscopic measurements. From the present investigation, it is identified that the Gd2Ti2O7 nanopowder may be used as solar reflective as well as color pigment due to its high NIR reflectivity (85-95%) under the wavelength of 750-2500 nm.

Differential effect of thermal stress on HSP70 expression, nitric oxide production and cell proliferation among native and crossbred dairy cattle.

In a tropical country like India, thermal stress is one of the major factors which significantly affects the productivity of dairy cattle. The present study was aimed to identify the effect of heat and cold stress on cell viability, mitogen stimulation indices, nitric oxide production and HSP70 expression in Sahiwal and Holstein crossbred (Frieswal) population in India. The results indicated that the Sahiwal breed can better withstand the effect of heat and cold stress significantly (P<0.05) when compared to the crossbred cattle due to the higher survivability of the Peripheral Blood Mononuclear Cells (PBMCs) and Phytohemagglutinin (PHA-P) mitogen based stimulation indices. The study also revealed the significant differences (P<0.05) in the level of nitric oxide (µM) production amongst the pre and post thermal stressed samples of Sahiwal and Frieswal crossbred samples. Further, the expression of HSP70 was significantly (P<0.05) higher in Sahiwal compared to Frieswal immediately after heat/cold shock to 6h of recovery as indirect ELISA analysis showed gradual rise in the Hsp70 protein concentration (ng/ml) immediately after heat and cold stress (0h) and reached the peak at 6h of recovery. Western blot and immune fluorescent assay results were also corroborated with the findings of indirect ELISA. In Sahiwal cattle the mRNA expression of HSP70 and its protein concentration were higher (P<0.05) during peak summer (44°C) and winter (10°C) as compared to Frieswal cattle. This investigation supports the earlier information on the higher adaptability of indigenous cattle breeds to hot and humid conditions compared to the crossbreds of temperate cattle breeds.

Understanding the mechanisms of ATPase beta family genes for cellular thermotolerance in crossbred bulls.

Na+/K+-ATPase is an integral membrane protein composed of a large catalytic subunit (alpha), a smaller glycoprotein subunit (beta), and gamma subunit. The beta subunit is essential for ion recognition as well as maintenance of the membrane integrity. Present study was aimed to analyze the expression pattern of ATPase beta subunit genes (ATPase B1, ATPase B2, and ATPase B3) among the crossbred bulls under different ambient temperatures (20-44 °C). The present study was also aimed to look into the relationship of HSP70 with the ATPase beta family genes. Our results demonstrated that among beta family genes, transcript abundance of ATPase B1 and ATPase B2 is significantly (P < 0.05) higher during the thermal stress. Pearson correlation coefficient analysis revealed that the expression of ATPase Β1, ATPase B2, and ATPase B3 is highly correlated (P < 0.01) with HSP70, representing that the change in the expression pattern of these genes is positive and synergistic. These may provide a foundation for understanding the mechanisms of ATPase beta family genes for cellular thermotolerance in cattle.

Dynamic Harmony Search with Polynomial Mutation Algorithm for Valve-Point Economic Load Dispatch.

Economic load dispatch (ELD) problem is an important issue in the operation and control of modern control system. The ELD problem is complex and nonlinear with equality and inequality constraints which makes it hard to be efficiently solved. This paper presents a new modification of harmony search (HS) algorithm named as dynamic harmony search with polynomial mutation (DHSPM) algorithm to solve ORPD problem. In DHSPM algorithm the key parameters of HS algorithm like harmony memory considering rate (HMCR) and pitch adjusting rate (PAR) are changed dynamically and there is no need to predefine these parameters. Additionally polynomial mutation is inserted in the updating step of HS algorithm to favor exploration and exploitation of the search space. The DHSPM algorithm is tested with three power system cases consisting of 3, 13, and 40 thermal units. The computational results show that the DHSPM algorithm is more effective in finding better solutions than other computational intelligence based methods.

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema.

Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes. Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed. The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted. We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation.

Expression of matrix metalloproteinase-1 in alveolar macrophages, type II pneumocytes, and airways in smokers: relationship to lung function and emphysema.

BACKGROUND: An imbalance between proteolytic enzymes and their inhibitors is thought to be involved in the pathogenesis of chronic obstructive pulmonary disease. Matrix metalloproteinase-1, also known as interstitial collagenase, has been implicated as a potentially important proteinase in the genesis of chronic obstructive pulmonary disease and, more specifically, emphysema. METHODS: We performed quantitative immunohistochemical assessment of matrix metalloproteinase-1 expression in the resected lung of 20 smokers/ex-smokers who had varying severity of airflow obstruction and emphysema and compared this with the lungs of 5 nonsmokers. Emphysema was measured using a morphometric measure of the lungs' surface area/volume ratio and with qualitative and quantitative computed tomography (CT) measures of emphysema. RESULTS: There were significantly more matrix metalloproteinase-1-expressing alveolar macrophages and type II pneumocytes as well as a greater percentage of small airways that stained positively for matrix metalloproteinase-1 in the lungs of smokers than in those of nonsmokers (p < 0.0001, p < 0.0001, and p = 0.0003, respectively). The extent of staining of type II pneumocytes and airways for matrix metalloproteinase-1 was significantly related to the extent of smoking (p = 0.012 and p = 0.013, respectively). In addition, the extent of matrix metalloproteinase-1 staining of alveolar macrophages was related to the lung surface area/volume ratio and to qualitative estimates of emphysema on CT. CONCLUSION: These findings suggest that cigarette smoking increases expression of matrix metalloproteinase-1 in alveolar macrophages as well as in alveolar and small airway epithelial cells. Smokers who develop emphysema have increased alveolar macrophage expression of matrix metalloproteinase-1.