Prevalence and molecular characterization of extended-spectrum ß-lactamase (ESBL) producing Escherichia coli isolated from dogs suffering from diarrhea in and around Kolkata.

Background: Dogs are the favorite companion animals among humans. The close interaction between dogs and people increases the risk of antibiotic resistance spreading. Surveillance for antimicrobial resistance and the identification of ESBL-producing Escherichia coli as an indicator bacterium is an important tool for managing antimicrobial drug therapy. Aims: The present study targeted to identify and characterize ESBL-producing E. coli among dogs suffering from diarrhea in and around Kolkata. Methods: Isolation and identification of E. coli from dogs suffering from diarrhea (n=70) along with screening for the production of both ESBL and AmpC. The isolates were further characterized through antimicrobial resistance profiling, resistance genes (bla CTX-M, bla TEM, and bla SHV) screening, and phylogenetic group study. Results: Among the 70 isolates, 21 (30%) were confirmed ESBL producers. An antibiogram typing of ESBL-producing E. coli revealed that the majority of them were resistant to norfloxacin (85.7%) followed by tetracycline (61.90%), doxycycline (57.14%), piperacillin/tazobactam (52.38%), cotrimoxazole (47.62%), gentamicin (42.62%), amikacin (23.81%), and chloramphenicol (19.05%). Major resistance genes included bla CTX-M (100%), bla TEM (28.57%), and bla SHV (9.50%). The predominant phylogenetic groups were phylogroup A (76%) followed by phylogroup D (24%). Conclusion: The current investigation reported a high prevalence of both ESBL and AmpC ß-lactamase (AmpC) producing E. coli, co-resistance to a distinct group of antibiotics, and co-existence of different ESBL genes in dogs. Our findings highlight the importance of diagnostic antimicrobial susceptibility testing for proper antimicrobial therapy and to prevent antimicrobial resistance from spreading to humans from dogs in Kolkata and the surrounding area.

Concurrent thyrolipomatosis and thymolipoma in a patient with myasthenia gravis: a case report and review of the literature.

We present a case of a man with a background of myasthenia gravis who presented with a neck lump, which was diagnosed as thyrolipomatosis in continuity with a very large thymolipoma. Following removal of these lesions, the patient's myaesthenic symptoms improved. While thymolipomas are often seen in the context of myasthenia gravis, thyrolipomatosis is a rare entity and to our knowledge the concurrent finding of both lesions with myasthenia gravis has never been reported. We highlight the important imaging features of both entities and the clinical importance of recognising them.

Participation of Phosphatidylinositol-3 Kinase Signalling in Human Chorionic Gonadotropin, Bovine Insulin (B-Insulin) and Human-Insulin-Like Growth Factor-I Induced Oocyte Maturation and Steroidogenesis in the Grey Mullet, Mugil Cephalus.

CONTEXT: The grey mullet, Mugil cephalus, is an edible fish of high economic importance. Breeding biology with reference to hormonal/growth factor regulation of oocyte maturation needs to be known for its commercial production. OBJECTIVE: The present study was conducted to examine the potency of maturation inducing hormones, chorionic gonadotropin (hCG), bovine-insulin, and insulin like growth factor1 (h-IGF-1) I on ovarian steroidogenesis and oocyte maturation. DESIGN: The role of hormones and growth factors on steroidogenesis and oocyte maturation was investigated using specific inhibitors, Wortmannin for phosphatidylinositol-3 (PI3) kinase, trilostane for 3ß-hydroxysteroid dehydrogenase, 1-octanol and 1-heptanol for gap junctions, actinomycin D for transcription and cycloheximide for translation of signal molecules. METHODS: Actions of hormonal and growth factors were examined for steroidogenesis, by radioimmunoassay and oocyte maturation by germinal vesicle breakdown (GVBD). Specific inhibitors were used to determine the cell signaling pathways, PI3 kinase. RESULTS: All the inhibitors attenuated the hCG-induced oocyte maturation (GVBD%), steroidogenesis including transcription, translation, gap junctions and PI3 kinase signaling. These inhibitors failed to inhibit h-IGF-I and b-insulin-induced oocyte maturation, steroidogenesis, translation and PI3 kinase signaling. CONCLUSION: hCG induces oocyte maturation via steroid dependent pathway involving gap junctions, transcription, translation and PI3 kinase signaling, unlike h-IGF-I and b-insulin in the mullet.

Safe surgical tracheostomy in patients with COVID-19: key clinical considerations.

Surgical tracheostomy is a high aerosol-generating procedure that is an essential aid to the recovery of patients who are critically ill with COVID-19 pneumonia. We present a single-centre case series of 16 patients with COVID-19 pneumonia who underwent tracheostomy. We recommend that the patient selection criteria for achieving a favourable outcome should be based on fraction of inspired oxygen together with prone-position ventilation. As with any challenging situation, the importance of effective communication is paramount. The critical modifications in the surgical steps are clearly explained. Timely tracheostomy also leads to an earlier freeing up of ventilator space during a period of a rapidly escalating pandemic. The outcomes in terms of swallow and speech function were also assessed. The study has also helped to remove the anxiety around open a tracheostomy in patients who are COVID-19 positive.

DUAL ACTION OF ARECOLINE ON ADRENAL FUNCTION AND GLUCOSE-GLYCOGEN HOMEOSTASIS IN METABOLIC STRESS IN MICE.

BACKGROUND: People chew betel nut (Areca catechu) for physical work and stress reduction, but it contains arecoline, which has both therapeutic value and untoward effects on endocrine and gonadal functions. OBJECTIVE: Aim of the present study is to investigate its role on adrenal with its target in metabolic stress in mice. MATERIALS AND METHODS: Mice were deprived of water / food, each for 5 days / treated with arecoline (10 mg / kg body wt daily for 5 days) / arecoline after water or food deprivation, for 5 days each. RESULTS: Water or food-deprivation caused adrenocortical hyperactivity, evident from abundance of enlarged mitochondria and smooth endoplasmic reticulum (SER) with elevation of corticosterone level (C: 68.31 ± 2.30, WD: 159.31 ± 4.10 / FD: 194.12 ± 3.40 µg/ mL). Arecoline treatment alone or in water deprivation (C: 68.31 ± 2.30, AR: 144.50 ± 4.33, AR+WD: 194.42 ± 3.35 µg/ mL) / food deprivation (AR + FD: 180.89 ± 4.51 µg/ mL) stress also stimulated adrenocortical activity as recorded in metabolic stress. In contrast, adrenomedullary activity was not altered following water/ food deprivation. Arecoline treatment alone or in metabolic stress suppressed adrenomedullary activity by showing depletion of chromaffin granules (E/NE?), epinephrine (E) and norepinephrine (NE) concentrations. Both the stress decreased blood glucose and liver glycogen levels. Arecoline treatment decreased blood glucose level, with a rise in liver glycogen level, but elevated blood glucose level in water deprivation unlike in starvation. CONCLUSION: Arecoline alone or in metabolic stress involves adrenal and probably other endocrine glands (pancreas, posterior pituitary and rennin-angiotensin system) to maintain homeostasis in metabolic stress in mice.

Calcined magnesite as an adsorbent for cationic and anionic dyes: characterization, adsorption parameters, isotherms and kinetics study.

The ability of calcined magnesite for Methylene Blue (MB), Direct Red 81 (DR81), Methyl Orange (MO) and Crystal Violet (CV) dye removal was evaluated in this study. The experiments were designed to test the hypothesis that alkaline earth carbonates can remove dyes from water through a combination of sorption and coagulative reactions involving Mg2+. To achieve that, several operational factors like residence time, dosage, adsorbent concentration and temperature were appraised. The batch study proved that calcined magnesite is effective in the treatment of MB, DR81, CV and MO contaminated water and moreover it performed well in terms of color removal. The adsorption equilibrium data were analysed by the Langmuir, Freundlich, Dubinin-Radushkevich and Temkin isotherm models, and the Dubinin-Radushkevich and Temkin models were found to be the most appropriate fit to MB and MO dyes respectively. The adsorption kinetics process primarily followed the Elovich and Pseudo-second order model, a possible indication that chemisorption was the rate limiting step during the dye uptake process. With the adsorption-desorption cycle repeated four times, the calcined magnesite regeneration efficiency for DR81 and MO loaded dyes remained very high. According to the results of this study, it can be concluded that calcined magnesite can be used effectively for the adsorption of MB, DR81, CV and MO from wastewater.

Ethmoidal metastasis as a first presentation of breast cancer: a case report.

Distant metastasis in advanced breast cancer is not uncommon; however, spread to the paranasal sinuses is extremely rare. We present a case of a woman who presented to our ophthalmology colleagues with worsening unilateral proptosis secondary to a tumour mass within her ethmoid sinuses. Biopsy of the ethmoid tumour showed adenocarcinoma of unknown origin. Whole-body positron emission computed tomography demonstrated a breast primary lesion. The patient was treated with palliative chemotherapy, and the patient remains well at this point. The importance of specialist head and neck radiological interpretation of imaging cannot be underestimated. Early tissue diagnosis is essential before ascribing patients with orbital symptoms to non-malignant process.

Effect of elevated temperature on soil hydrothermal regimes and growth of wheat crop.

An attempt has been made to study the effect of elevated temperature on soil hydrothermal regimes and winter wheat growth under simulated warming in temperature gradient tunnel (TGT). Results showed that bulk density (BDs) of 0, 0.9, and 2.5 °C were significantly different whereas BDs of 2.8 and 3.5 °C were not significantly different. Water filled pore space (WFPS) was maximum at 3.5 °C temperature rise and varied between 43.80 and 98.55%. Soil surface temperature (ST) at different dates of sowing increased with rise in sensor temperature and highest ST was observed at S5 sensors (3.5 °C temperature rise). Temperature and its difference were high for the top soil, and were stable for the deep soil. Photosynthesis rate (µmol CO2 m-2 s-1) of wheat was lower at higher temperature in different growth stages of wheat. In wheat, stomatal conductance declined from 0.67 to 0.44 mol m-2 s-1 with temperature rise. Stomatal conductance decreased with increase in soil temperature and gravimetric soil moisture content (SWC). In TGT, 0 °C temperature rise showed highest root weight density (RWD) (5.95 mg cm-3); whereas, 2.8 and 3.5 °C showed lowest RWD (4.90 mg cm-3). Harvest index was maximum (0.37) with 0 °C temperature rise, and it decreased with increase in temperature, which indicated that both grain and shoot biomass decreased with increase in temperature. Intensive studies are needed to quantify the soil hydrothermal regimes inside TGT along with the crop growth parameters.

Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma.

BACKGROUND: We investigated early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL). PATIENTS AND METHODS: From June 2008 through August 2015, 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT. Patients were excluded due to relapsed or refractory disease. Involved-site radiotherapy field designs were used for all patients. Pediatric patients received a median dose of 21 Gy(RBE) [range 15-36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range, 20-45 Gy(RBE)]. Patients receiving PT were young (median age, 20 years; range 6-57). Overall, 42% were pediatric (≤18 years) and 93% were under the age of 40 years. Thirty-eight percent of patients were male and 62% female. Stage distribution included 73% with I/II and 27% with III/IV disease. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), whereas 37% had B symptoms. The median follow-up was 32 months (range, 5-92 months). RESULTS: The 3-year relapse-free survival rate was 92% for all patients; it was 96% for adults and 87% for pediatric patients (P = 0.18). When evaluated by positron emission tomography/computed tomography scan response at the end of chemotherapy, patients with a partial response had worse 3-year progression-free survival compared with other patients (78% versus 94%; P = 0.0034). No grade 3 radiation-related toxicities have occurred to date. CONCLUSION: Consolidative PT following standard chemotherapy in HL is primarily used in young patients with mediastinal and bulky disease. Early relapse-free survival rates are similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed. Continued follow-up to assess late effects is critical.

White-light emission by phonon assisted coherent mixing of excitons in Au8-CdS hybrid nanorods.

Gold cluster (Au8) coated CdS hybrid nanorods (HNRs), synthesized using a sonication assisted assembly route, exhibit phonon assisted coherent mixing of excitons. As observed from optical absorption, Raman scattering, x-ray diffraction and transmission electron microscopic studies, the Au8 modulates the crystal-and electronic-structure of the CdS nanorods, effecting enhancement of exciton-phonon (e-p) interactions. The e-p interaction and entropy effect mediated phase matching of the excitonic transitions, leading-via cooperative and coherent mixing of the excitons' color-to the emission of white light, has been confirmed from room temperature and time resolved photoluminescence measurements.

Flocculation and adsorption properties of biodegradable gum-ghatti-grafted poly(acrylamide-co-methacrylic acid) hydrogels.

This study reports the microwave-assisted synthesis of gum-ghatti (Gg)-grafted poly(acrylamide-co-methacrylic acid) (AAm-co-MAA) hydrogels for the development of biodegradable flocculants and adsorbents. The synthesized hydrogels were characterized using TGA, FTIR and SEM. TGA studies revealed that the synthesized hydrogels were thermally more stable than pristine Gg and exhibited maximum swelling capacity of 1959% at 60°C in neutral pH. The optimal Gg-cl-P(AAm-co-MAA) hydrogel was successfully employed for the removal of saline water from various petroleum fraction-saline emulsions. The maximum flocculation efficiency was achieved in an acidic clay suspension with a 15 mg polymer dose at 40°C. Moreover, the synthesized hydrogel adsorbed 94% and 75% of Pb(2+) and Cu(2+), respectively, from aqueous solutions. Finally, the Gg-cl-P(AAm-co-MAA) hydrogel could be degraded completely within 50 days. In summary, the Gg-cl-P(AAm-co-MAA) hydrogel was demonstrated to have potential for use as flocculants and heavy metal absorbents for industrial waste water treatment.

Variable Selection in Generalized Functional Linear Models.

Modern research data, where a large number of functional predictors is collected on few subjects are becoming increasingly common. In this paper we propose a variable selection technique, when the predictors are functional and the response is scalar. Our approach is based on adopting a generalized functional linear model framework and using a penalized likelihood method that simultaneously controls the sparsity of the model and the smoothness of the corresponding coefficient functions by adequate penalization. The methodology is characterized by high predictive accuracy, and yields interpretable models, while retaining computational efficiency. The proposed method is investigated numerically in finite samples, and applied to a diffusion tensor imaging tractography data set and a chemometric data set.

Qualitative and quantitative differentiation of gases using ZnO thin film gas sensors and pattern recognition analysis.

In the present work we have grown highly textured, ultra-thin, nano-crystalline zinc oxide thin films using a metal organic chemical vapor deposition technique and addressed their selectivity towards hydrogen, carbon dioxide and methane gas sensing. Structural and microstructural characteristics of the synthesized films were investigated utilizing X-ray diffraction and electron microscopy techniques respectively. Using a dynamic flow gas sensing measurement set up, the sensing characteristics of these films were investigated as a function of gas concentration (10-1660 ppm) and operating temperature (250-380 °C). ZnO thin film sensing elements were found to be sensitive to all of these gases. Thus at a sensor operating temperature of ~300 °C, the response% of the ZnO thin films were ~68, 59, and 52% for hydrogen, carbon monoxide and methane gases respectively. The data matrices extracted from first Fourier transform analyses (FFT) of the conductance transients were used as input parameters in a linear unsupervised principal component analysis (PCA) pattern recognition technique. We have demonstrated that FFT combined with PCA is an excellent tool for the differentiation of these reducing gases.

Arsenic(III) sorption on nanostructured cerium incorporated manganese oxide (NCMO): a physical insight into the mechanistic pathway.

Arsenic(III) sorption was investigated with nanostructured cerium incorporated manganese oxide (NCMO). The pH between 6.0 and 8.0 was optimized for the arsenic(III) sorption. Kinetics and equilibrium data (pH=7.0±0.2, T=303±1.6 K, and I=0.01 M) of arsenic(III) sorption by NCMO described, respectively, the pseudo-second order and the Freundlich isotherm equations well. The sorption process was somewhat complicated in nature and divided into two different segments, initially very fast sorption followed by slow intraparticle diffusion process. Sorption reaction of arsenic(III) on NCMO was endothermic (ΔH°=+13.46 kJ mol(-1)) and spontaneous (ΔG°=-24.75 to -30.15 kJ mol(-1) at T=283-323 K), which took place with increasing entropy (ΔS°=+0.14 kJ mol(-1)K(-1)) at solid-liquid interface. Energy of arsenic(III) sorption estimated by analyzing the equilibrium data using the D-R isotherm model was 15.4 kJ mol(-1), indicating the ion-exchange type mechanism. Raman, FT-IR, pH effect, desorption, etc. studies indicated that arsenic(III) was oxidized to arsenic(V) during the sorption process.

Increasing sensitivity to radiotherapy and chemotherapy by using novel biological agents that alter the tumor microenvironment.

Sensitivity to radiation and chemotherapy can be influenced by factors extrinsic to the cancer cell. For example, severely hypoxic cells require 2-3 times the radiation dose as do well-oxygenated cells to achieve similar cell killing. Apart from the tumor cells, neighboring cells such as endothelial cells may influence radiosensitivity. Irradiation can lead to expression of molecules that may increase radio/chemoresistance, for example vascular endothelial growth factor (VEGF), a secreted protein that regulates angiogenesis, or hypoxia inducible factor-1 alpha (HIF-1 alpha), a master transcription factor that regulates gene expression in hypoxia. Hence, response to cytotoxic therapy may be improved by modulating the tumor microenvironment (TME). Several agents in clinical use may do this. Some of these target vasculature, either directly or indirectly by disrupting VEGF and/or HIF-1 signaling. Many of these agents have been shown to increase radio/chemosensitivity in preclinical models. A confounding factor in terms of radiosensitization is the variable effect of these drugs on tumor oxygenation. Some of these agents ablate the vasculature, thereby increasing hypoxia. Others may normalize tumor vasculature, leading to increased blood flow and oxygenation, thereby potentially increasing radiosensitivity and the delivery of chemotherapy. Inhibitors of EGFR signaling and the PI3K/Akt pathway can also cause similar vascular changes in preclinical models, perhaps by indirectly inhibiting VEGF secretion. In summary, agents are currently available in the clinic that might modulate the TME in a way that could improve radio/chemosensitivity. The challenge is to show that this occurs in human patients and then use this information to optimize cancer therapy.

Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data.

BACKGROUND: India has the highest burden of acute coronary syndromes in the world, yet little is known about the treatments and outcomes of these diseases. We aimed to document the characteristics, treatments, and outcomes of patients with acute coronary syndromes who were admitted to hospitals in India. METHODS: We did a prospective registry study in 89 centres from 10 regions and 50 cities in India. Eligible patients had suspected acute myocardial infarction with definite electrocardiograph changes (whether elevated ST [STEMI] or non-STEMI or unstable angina), or had suspected myocardial infarction without ECG changes but with prior evidence of ischaemic heart disease. We recorded a range of clinical outcomes, and all-cause mortality at 30 days. FINDINGS: We enrolled 20,937 patients. Of the 20,468 patients who were given a definite diagnosis, 12,405 (60.6%) had STEMI. The mean age of these patients was 57.5 (SD 12.1) years; patients with STEMI were younger (56.3 [12.1] years) than were those with non-STEMI or unstable angina (59.3 [11.8] years). Most patients were from lower middle 10,737 (52.5%) and poor 3999 (19.6%) social classes. The median time from symptoms to hospital was 360 (IQR 123-1317) min, with 50 (25-68) min from hospital to thrombolysis. 6226 (30.4%) patients had diabetes; 7720 (37.7%) had hypertension; and 8242 (40.2%) were smokers. Treatments for STEMI differed from those for non-STEMI or unstable angina. More patients with STEMI than with non-STEMI were given anti-platelet drugs (98.2%vs 97.4%); angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) (60.5%vs 51.2%); and percutaneous coronary interventions (8.0%vs 6.7%, p<0.0001 for all comparisons). Thrombolytics (96.3% streptokinase) were used for 58.5% of patients with STEMI. Conversely, fewer patients with STEMI than those with non-STEMI or unstable angina were given beta blockers (57.5%vs 61.9%); lipid-lowering drugs (50.8%vs 53.9%); and coronary bypass graft surgery (1.9%vs 4.4%, p<0.0001 for all comparisons). The 30-day outcomes for patients with STEMI were death (8.6%), reinfarction (2.3%), and stroke (0.7%). Outcomes for those with non-STEMI or unstable angina were better: death (3.7%), reinfarction (1.2%), and stroke (0.3%, p<0.0001 for all comparisons). Use of key treatments also differed by socioeconomic status: more rich patients than poor patients were given thrombolytics (60.6%vs 52.3%), beta blockers (58.8%vs 49.6%), lipid-lowering drugs (61.2%vs 36.0%), ACE inhibitors or ARB (63.2%vs 54.1%), percutaneous coronary intervention (15.3%vs 2.0%), and coronary artery bypass graft surgery (7.5%vs 0.7%, p<0.0001 for all comparisons). Mortality was higher for poor patients than for rich patients (8.2%vs 5.5%, p<0.0001). Adjustment for treatments (but not risk factors and baseline characteristics) eliminated this difference in mortality. INTERPRETATION: Patients in India who have acute coronary syndromes have a higher rate of STEMI than do patients in developed countries. Since most of these patients were poor, less likely to get evidence-based treatments, and had greater 30-day mortality, reduction of delays in access to hospital and provision of affordable treatments could reduce morbidity and mortality.

Genotypic characterisation of Indian cattle, buffalo and sheep isolates of Echinococcus granulosus.

Twelve isolates of Echinococcus granulosus, collected from domestic animals, including cattle, buffalo and sheep were analysed for DNA nucleotide sequence variation within mitochondrial cytochrome c oxidase I (coxI), NADH dehydrogenase subunit I (nadI) and internal transcribed spacer gene I (ITS1). After analysis of sequence information this was found that the fragment size of ITS1 of buffalo isolate was more in comparison to cattle and sheep isolates. Based on the nadI genotype this was found that Indian cattle, buffalo and sheep isolates could be grouped into E. granulosus sensu stricto. Based on coxI genotype two sheep isolates and one buffalo isolate were homologous to G2 genotype. Rests of the isolates were microvariants of G2 genotype. Presence of G2 genotype in buffalo is the first report of this genotype from this host.

Evaluation of efficacy and tolerability of Losartan and Ramipril combination in the management of hypertensive patients with associated diabetes mellitus in India (LORD Trial).

AIM: The study was conducted to evaluate efficacy and tolerability of fixed dose combination (FDC) of Losartan and Ramipril in the management of mild to moderate hypertensive Native Asian Indian patients with associated diabetes mellitus. The secondary objective was to evaluate the efficacy of the combination in reducing microalbuminuria. MATERIAL AND METHODS: The study was an open, non-comparative, multicentric clinical trial conducted in seven Indian centres in 315 eligible patients. All the patients were treated with Losartan 50 mg + Ramipril 2.5 mg or Losartan 50 mg + Ramipril 5 mg once a day in 12 weeks and consisted of a total of eight visits. RESULTS: The mean age of patients was 52.93 years (range 45 - 60 years). Of the total patients, 62.86% were males and 37.14% were females. The mean prestudy systolic blood pressure was 160.56 +/- 14.44 which was significantly reduced to 126.85 +/- 9.78 at the end of 12 weeks (P < 0.001). Similarly the mean diastolic blood pressure was 98.91 +/- 8.33 at baseline (stage I) which was significantly reduced to 79.82 +/- 5.42 at the end of 12 weeks (P < 0.001). A mean fall of 33.72 mmHg in systolic blood pressure and the mean fall of 19.10 mmHg was observed in systolic and diastolic blood pressure respectively at the end of the treatment which was statistically highly significant (P < 0.001). The JNC-VII goal of blood pressure < 130/80 was achieved in 79.05% patients after the treatment which losartan and ramipril combination only. Microalbuminuria (urinary albumin excretion > 30 but < 300 mg/day) was seen in 83/250 (33.2%) patients and 135 (54%) patients had clinical proteinuria (albuminuria) at baseline. At the end of the therapy 20.8% patients achieved normoalbuminuria. Good to excellent efficacy response was reported in 98.09% patients and 98.41% patients reported good to excellent tolerability to the treatment. CONCLUSION: The fixed dose combination of Losartan and Ramipril showed good to excellent efficacy response in 98.10% patients and achieved a target blood pressure of 130/80 mmHg in 79.05% patients in 12 weeks. The combination reduced the urinary albumin excretion in majority of the patients with microalbuminuria and proteinuria (the major marker of nephropathy).

Hypoxia and VEGF mRNA expression in human tumors.

High expression of circulating plasma vascular endothelial growth factor (VEGF) in patients with cancer is an indicator of poor treatment response. Similarly, hypoxia in tumors, as measured by oxygen needle electrodes, has been found to predict for tumor-treatment failure. These two predictors may be related because hypoxia is a potent stimulator of VEGF expression in vitro. However, the demonstration of a relationship between hypoxia and VEGF in human tumors has, to date, been indirect or even negative. The purpose of this study was to test whether this unexpected result was caused by factors unique to human tumors, or whether the prior results could have been influenced by the known complexities of VEGF regulation. Therefore, we undertook a direct assessment of VEGF induction in human tumors using in situ hybridization and compared its distribution with that of hypoxia, as measured by the distribution of adducts of the hypoxia marker EF5. The distribution of both markers was assessed in relationship to the distribution of blood vessels, as measured by antibodies to CD31. Our hypothesis was that VEGF mRNA and hypoxia would colocalize, assuming that detectability of the former was not limiting. Four squamous cell carcinomas, three sarcomas and one glioblastoma multiforme were studied. When VEGF mRNA signal was detectable, its maxima colocalized with regional maxima of EF5 binding. The strongest levels of both signals were sometimes adjacent to regions of tissue necrosis. However, we were unable to predict absolute levels of EF5 binding based on absolute levels of VEGF mRNA. Conversely, for all tumors studied, regions with relatively low levels of EF5 binding had relatively low or undetectable VEGF mRNA. We found moderate EF5 binding in some keratinized cells but VEGF mRNA was not expressed by these differentiated cells. The paradigm that hypoxia and VEGF expression are linked in human tumors is supported by the data presented herein. A better understanding of the biology behind VEGF expression, including its modulation by hypoxia, is important for optimizing its use as a prognostic indicator and/or modulating its presence with biologic therapies.