Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Culturally adapted psychosocial interventions (CaPSI) for early psychosis in a low-resource setting: study protocol for a large multi-center RCT.

BACKGROUND: Psychosis treatment guidelines recommend cognitive behaviour therapy (CBT) and family intervention (FI), for all patients with first episode psychosis (FEP), though guidance borrows heavily from literature in adults from high income countries. To our knowledge, there are few randomized controlled trials (RCTs) examining the comparative effect of these commonly endorsed psychosocial interventions in individuals with early psychosis from high-income countries and no such trials from low and middle-income countries (LMICs). The present study aims to confirm the clinical-efficacy and cost-effectiveness of delivering culturally adapted CBT (CaCBT) and culturally adapted FI (CulFI) to individuals with FEP in Pakistan. METHOD: A multi-centre, three-arm RCT of CaCBT, CulFI, and treatment as usual (TAU) for individuals with FEP (n = 390), recruited from major centres across Pakistan. Reducing overall symptoms of FEP will be the primary outcome. Additional aims will include improving patient and carer outcomes and estimating the economic impact of delivering culturally appropriate psychosocial interventions in low-resource settings. This trial will assess the clinical-efficacy and cost-effectiveness of CaCBT and CulFI compared with TAU in improving patient (positive and negative symptoms of psychosis, general psychopathology, depressive symptoms, quality of life, cognition, general functioning, and insight) and carer related outcomes (carer experience, wellbeing, illness attitudes and symptoms of depression and anxiety). CONCLUSIONS: A successful trial may inform the rapid scale up of these interventions not only in Pakistan but other low-resource settings, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority groups with FEP. TRIAL REGISTRATION: NCT05814913.

Single TRAM domain RNA-binding proteins in Archaea: functional insight from Ctr3 from the Antarctic methanogen Methanococcoides burtonii.

TRAM domain proteins present in Archaea and Bacteria have a ß-barrel shape with anti-parallel ß-sheets that form a nucleic acid binding surface; a structure also present in cold shock proteins (Csps). Aside from protein structures, experimental data defining the function of TRAM domains is lacking. Here, we explore the possible functional properties of a single TRAM domain protein, Ctr3 (cold-responsive TRAM domain protein 3) from the Antarctic archaeon Methanococcoides burtonii that has increased abundance during low temperature growth. Ribonucleic acid (RNA) bound by Ctr3 in vitro was determined using RNA-seq. Ctr3-bound M. burtonii RNA with a preference for transfer (t)RNA and 5S ribosomal RNA, and a potential binding motif was identified. In tRNA, the motif represented the C loop; a region that is conserved in tRNA from all domains of life and appears to be solvent exposed, potentially providing access for Ctr3 to bind. Ctr3 and Csps are structurally similar and are both inferred to function in low temperature translation. The broad representation of single TRAM domain proteins within Archaea compared with their apparent absence in Bacteria, and scarcity of Csps in Archaea but prevalence in Bacteria, suggests they represent distinct evolutionary lineages of functionally equivalent RNA-binding proteins.

Prime-boost vaccination strategy with bacillus Calmette-Guérin (BCG) and liposomized alpha-crystalline protein 1 reinvigorates BCG potency.

Bacillus Calmette-Guérin (BCG) remains the only available and most widely administered vaccine against Mycobacterium tuberculosis (Mtb), yet it fails to protect vaccinated individuals either from primary infection or reactivation of latent tuberculosis (TB). Despite BCG's variable efficacy against TB, the fact remains that BCG imparts protection in children against the disease, indicating that BCG possesses a wide protective antigenic repertoire. However, its failure to impart protection in adulthood can be linked to its failure to generate long-lived memory response and elicitation of an inadequate immune response against latency-associated antigens. Therefore, to improve the protective efficacy of BCG, a novel vaccination strategy is required. Consequently, in the present study, we have exploited the vaccination potential of liposomized α-crystalline 1 (Acr1L), a latency-associated antigen to induce enduring protective immunity against Mtb in BCG-primed animals. It is noteworthy that an increase in the multi-functional [interferon (IFN)-γ(hi) /tumour necrosis factor (TNF)-α(hi) ] CD4 and CD8 T cells were observed in BCG-primed and Acr1L-boosted (BCG-Acr1L) animals, compared to BCG alone. Further, substantial expansion of both central memory (CD44(hi) /CD62L(hi) ) and effector memory (CD44(hi) /CD62L(lo) ) populations of CD4 and CD8 T cells was noted. Importantly, BCG-Acr1L exhibited significantly better protection than BCG, as evidenced by a reduction in the bacterial burden and histopathological data of the lungs. In essence, BCG-Acr1L could be a potent future vaccination strategy to reinvigorate BCG potency.

Introduction of vincristine mini-bags and an assessment of the subsequent risk of extravasation.

INTRODUCTION: Numerous international organisations have advocated the preparation of vincristine in small volume intravenous bags in order to eliminate inadvertent intrathecal administration. However, the risk of extravasation is a significant deterrent, and adoption of this practice has been variable and only hesitantly accepted in the clinical setting. PURPOSE: We carried out a study with the aims of establishing the incidence of reported extravasation of vincristine administration to paediatric and adult patients in mini-bags; here we describe motivating factors and barriers faced by clinical staff. The secondary aim was to support the need for change and implementation of the international recommendations. METHODS: Chemotherapy-certified nurses completed a survey spanning August 2009 to August 2011, to ascertain the incidence of extravasation associated with the administration of vincristine in mini-bags. RESULTS: This period captured 421 occasions of vincristine administration in 25-ml or 50-ml mini-bags (in 0.9% sodium chloride). The median age of patients was 13 years (range 2.5 months to 99 years). Vincristine was administered through peripheral lines (26.4%), portacath (52.0%), PICC line (15.9%) and Hickman line (5.7%). The majority of infusions were over at least 10 minutes (50.1%). There were no cases of extravasation reported. CONCLUSIONS: The administration of vincristine in small volume intravenous bags was safe, practical, and feasible in all patient groups. The successful implementation of the international recommendations for vincristine administration in mini-bags to eliminate potential inadvertent intrathecal administration was dependent on stakeholder buy-in.

Comparative Efficacy of Levosalbutamol and Racemic Salbutamol in the Treatment of Acute Exacerbation of Asthma.

Asthma is a major noncommunicable disease (NCD), affecting both children and adults, and is the most common chronic disease among children. It is common in all ages and the prevalence is increasing in most countries, especially among children as because of urbanization. Multiple therapeutic modalities are available for management of acute asthma. The commonly used formulation is Racemic Salbutamol which contains equal amounts of both R and S isomers. Levosalbutamol contains only R isomer. The aim of the study was to compare the efficacy of levosalbutamol and racemic salbutamol for the treatment of acute exacerbation of asthma in children (5 to 15 years). A randomized double blind clinical trial was conducted in the Department of Paediatrics, Sylhet MAG Osmani Medical College Hospital, Sylhet, Bangladesh from October 2013 to March 2014. In this study randomization was done in two groups. Group A received nebulized levosalbutamol (LEV) and Group B received nebulized racemic salbutamol (RAC). The study parameters were respiratory rate (RR), heart rate (HR), oxygen saturation in room air (SpO2), PEFR, asthma score and serum K+ level. The results of treatment outcome were compared between two groups. After treatment the respiratory rate was 24.4±5.6 per minute versus 27.6±5.3 per minute (p<0.05); heart rate was 115.5±16.4 per minute versus 124.5±12.0 per minute (p<0.05); SpO2 was 97.2±1.8% vs 95.0±1.6% (p<0.05); PEFR was found 159.6±30.7L/min versus 143.8±27.1L/min (p<0.05) in the LEV and RAC group respectively. LEV is more effective than RAC in respect to significant improvement of asthma score. Regarding adverse events racemic salbutamol causes significant tachycardia. The study concluded that nebulized levosalbutamol is superior to racemic salbutamol in children in the treatment of acute exacerbation of asthma.

Relativistic ultrafast electron diffraction at high repetition rates.

The ability to resolve the dynamics of matter on its native temporal and spatial scales constitutes a key challenge and convergent theme across chemistry, biology, and materials science. The last couple of decades have witnessed ultrafast electron diffraction (UED) emerge as one of the forefront techniques with the sensitivity to resolve atomic motions. Increasingly sophisticated UED instruments are being developed that are aimed at increasing the beam brightness in order to observe structural signatures, but so far they have been limited to low average current beams. Here, we present the technical design and capabilities of the HiRES (High Repetition-rate Electron Scattering) instrument, which blends relativistic electrons and high repetition rates to achieve orders of magnitude improvement in average beam current compared to the existing state-of-the-art instruments. The setup utilizes a novel electron source to deliver femtosecond duration electron pulses at up to MHz repetition rates for UED experiments. Instrument response function of sub-500 fs is demonstrated with < 100 fs time resolution targeted in future. We provide example cases of diffraction measurements on solid-state and gas-phase samples, including both micro- and nanodiffraction (featuring 100 nm beam size) modes, which showcase the potential of the instrument for novel UED experiments.

Factors Associated with Delayed Hospital Arrival of Patients Presenting with Acute Myocardial Infarction: A Cross-Sectional Study in Bangladesh.

Delay in seeking medical care of the patients with acute myocardial infarction (AMI) could affect the outcome. Therefore, it is important to recognize and reduce pre-hospital in initiating treatment of these patients. The objective of the study was to evaluate the factors associated with delayed hospital arrival of patients with AMI. This cross-sectional study was carried out among 385 patients with AMI attended in the Department of Cardiology, Dhaka Medical College Hospital (DMCH), Dhaka, Bangladesh. The delay in arrival to the hospital was recorded along with socio-demographic data, conditions of the patients during onset and other relevant data. The mean age of the patients 59.7±9.9 years with a male-female ratio of 2.4:1. About 22% of patients with AMI arrived at the hospital within 6 hours of symptoms onset and only around 13% arrived within 2 hours of onset of symptoms. Comparatively younger (p=0.037), unmarried (p=0.008) and Muslim (p=0.008) patients were more likely to present for hospital care sooner (p=0.037). Patients coming from upper middle class of socioeconomic status (p<0.001) and those with college or post college level of education (p<0.001) were more likely to present earlier for hospital care. Prehospital delay was larger in non-manual worker patients (p<0.001) as well as in patients with onset of chest pain during rest period (p<0.001) and while at home (p<0.001). Pre-hospital delay was shorter in patients with onset of chest pain from 12am to 6am and 6am to 12pm (p<0.001). Lack of awareness of AMI symptoms and benefits of its early treatment, long distance and mode of transport were shown as the most common causes of delayed arrival of patients at hospital (p<0.001). This study has identified the factors associated with AMI in context of Bangladesh. Effective measures including increasing awareness of AMI symptoms should be taken for better outcome of the patients.

Percuteneous mitral balloon valvuloplasty in patients with post surgical mitral restenosis: result of 70 cases.

OBJECTIVE: To evaluate the immediate results of balloon mitral valvulplasty in mitral restenosis patients with previous surgical mitral commissurotomy. METHODS: Percuteneous balloon mitral valvuloplasty (BMV) was done in 145 cases of which 70patients had the history of previous surgical commissurotomy (Group I) and 75 patients were the new cases for the BMV (Group II). RESULTS: In group I the age range was 35-65 years. In group I the duration of surgical commissurotomy (SC) was of 2-18 years past. In this group the result of balloon mitral valvuloplasty (BMV) was successful in 69 cases. Mitral valve area (MVA) before the procedure was 0.5-0.9 sq cm with mean 0.7 +/- 0.2 sq cm. Following procedure the MVA was 1.2-2.0 cm2 with a mean of 1.6 +/- 0.4 cm2. Mean gradient across mitral valve (MV) before the procedure was 15-25 mm of Hg with a mean 20 +/- 5 mm of Hg and after the procedure was 3-5 mm Hg with a mean of 4 +/- 1 mm Hg. In Group I, MVA > 1.8 cm2 was achieved in 25 cases & > 1.2-1.8 cm2 in 44 cases. Mitral regurgitation > or = grade 1 occurred in 8 cases (compared to previous echocardiography). In group II the age range was between 35-60 years. The result of BMV was successful in 74 cases. MVA before the procedure was 0.4-1.2 cm2 with a mean of 0.8 +/- 0.4 cm2. Following the procedure MVA was 1.3-2.1 cm2 with a mean of 1.7 +/- 0.4 cm2. Mean gradient across the mitral valve before the procedure was 15-29 mm of Hg with a mean of 22 +/- 7 mm of Hg. Mean gradient across the mitral valve after the procedure was 2-4 mm of Hg with a mean of 3 +/- 1 mm of Hg. MVA more than 1.8 cm2 was achieved in 29 cases and between 1.3-1.8 in 45 cases. CONCLUSION: BMVin patients with mitral restenosis following Surgical mitral commissurtomy can be performed with almost similar success rate like that of BMV for the first time with low risk of major cardiac complication.

Hematopoietic stem cell transplantation in children with Griscelli syndrome type 2: a single-center report on 35 patients.

In 2010, we reported the outcome of hematopoietic stem cell transplantation (HSCT) in 11 children with Griscelli syndrome type 2 (GS2). We report here the update on this cohort to include 35 patients. Twenty-seven (77%) patients received conditioning regimen including busulfan, cyclophosphamide with etoposide. Eight (23%) were given busulfan, fludarabine. Thiotepa was added to busulfan and fludarabine regimen in two patients; one received haploidentical marrow and one unrelated cord blood. Posttransplant clinical events included veno-occlusive disease (n = 7), acute (n = 8), or chronic (n = 1) graft-versus-host disease II-IV. With a mortality rate of 37.1% (n = 13) and a median follow-up of 87.7 months of the survivors, 5-year cumulative probability of overall survival (OS) for our cohort of patients was 62.7% (±8.2%). Cumulative probability of 5-year OS was significantly better in those who did not have hemophagocytic lymphohistiocytosis (HLH) prior to HSCT (100% vs. 53.3 ± 9.5%, P value: 0.042). Of the 16 patients with neurologic involvement before HSCT, 8 survived and 3 presented sequelae. OS at 5-year was 50 ± 12.5% and 73.3 ± 10.2% (P value: 0.320) in patients with and without CNS involvement, respectively. In conclusion, HSCT in patients with GS2 is potentially curative with long-term disease-free survival. Early HSCT before the development of the accelerated phase is associated with a better outcome.

RAD52 polymorphisms contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population.

Genetic polymorphisms of DNA repair genes seem to determine the DNA repair capacity. We hypothesized that polymorphisms of genes responsible for DNA repair may be associated with risk of thyroid cancer. To evaluate the role of genetic polymorphisms of DNA repair genes in thyroid cancer, we conducted a hospital-based case-control study in Saudi population. Two hundred and twenty-three incident papillary thyroid cancer cases and 229 controls recruited from Saudi Arabian population were analyzed for 21 loci in 8 selected DNA repair genes by PCR-restriction fragment length polymorphism including non-homologous end joining pathway genes LIGIV (LIGlV ASP62HIS, PRO231SER, TRP46TER), XRCC4 Splice 33243301G>A and XRCC7 ILE3434THR; homologous recombination pathway genes XRCC3 ARG94HIS and THR241MET, RAD51 UTR 15452658T>C, 15455419A>G, RAD52 2259 and GLN221GLU, conserved DNA damage response gene Tp53 PRO47SER, PRO72ARG, Tp53 UTR 7178189A>C and base excision repair gene XRCC1 ARG194TRP, ARG280HIS, ARG399GLN, ARG559GLN. RAD52 GLN221GLU genotypes CG and variants carrying G allele showed statistical significance and very high risk of developing thyroid cancer compared to wild type [CG vs CC; p<0.001, odds ratio (OR)=15.57, 95% confidence interval (CI)=6.56-36.98, CG+GG vs CC; p<0.001, OR=17.58, 95% CI=7.44-41.58]. Similarly, RAD52 2259 genotypes CT and variant allele T showed a significant difference in terms of risk estimation (CT vs CC; p<0.05, OR=1.53, 95% CI=1.03-2.28, CT+TT vs CC; p<0.001, OR=1.922, 95% CI=1.31-2.82). Remaining loci demonstrated no significance with risk. Of the 21 loci screened, RAD52 2259 and RAD52 GLN221GLU may be of importance to disease process and may be associated with papillary thyroid cancer risk in Saudi Arabian population.

Role of pneumonectomy for lung cancer in current scenario: An Indian perspective.

BACKGROUND: Surgical treatment for lung cancer has evolved from pneumonectomy to lobectomy/sleeve resection around the world. Although condemned for poor outcomes, pneumonectomy may still be required in a select group of patients in developing countries. With the better patient selection, optimization of medical comorbidities, better perioperative care; pneumonectomy may show better results. Thus, there is a need to reconsider the role of pneumonectomy in patients with locally advanced lung cancer in the current scenario. PATIENTS AND METHODS: The aim of this study was to analyze the demographic and clinicopathologic profile of lung cancer patients and the role of pneumonectomy at a tertiary cancer center in India. The records of patients, who underwent surgery for lung cancer at our institute from January 2011 to April 2014, were analyzed retrospectively, and various parameters in pneumonectomy were compared to lobectomy patients. RESULTS: Out of 48 patients undergoing major lung resections, nearly 80% patients were symptomatic at presentation and were mostly in advanced stages, thus requiring neoadjuvant chemotherapy in 45.8% cases and pneumonectomy in 41.6% patients. There was no difference in morbidity and mortality in pneumonectomy (25%, 5%) versus lobectomy (21.2%, 3.5%). Disease-free survival at 1, 2, and 3 years after pneumonectomy (71.8%, 51.4%, and 42.8%) was comparable to lobectomy (73.3%, 66.1%, and 55.6%). After neoadjuvant therapy, survival was not affected by the type of surgery. CONCLUSIONS: In the Indian scenario, as the majority of lung cancer patients present at an advanced stage, pneumonectomy still plays a major role, and the acceptable postoperative outcome can be achieved with aggressive perioperative management.

The fate of chlorinated volatile organic compounds in aeration basins using recirculated aeration: a pilot-plant evaluation.

The fate of chloroform, which was chosen to represent chlorinated volatile organic compounds sometimes found in publicly owned wastewater treatment works, has been followed in a pilot aeration basin utilizing aeration recirculation. Tests were conducted using real wastewaters spiked with two different concentration levels of chloroform and operated at conditions similar to those of a large-scale aeration basin of the Mill Creek Wastewater Treatment Plant in Cincinnati, Ohio. Aeration recirculation levels of 0, 25, 50, and 75% were used to evaluate the concept that aeration recirculation can be an effective method of reducing the release of these toxic compounds to the atmosphere. Data obtained demonstrated that the concentration of chloroform in the off-gas increased as the recirculation ratio increased, but that the total mass emission rate to the atmosphere decreased due to the decreased off-gas volumetric flow rate. Biodegradation in the pilot plant increased by 183% for the 75% recirculation level compared to 0% recirculation. Mass balance analysis results indicated that 60% of chloroform emissions could be reduced with 75% recirculation ratio with little or no effect of dissolved oxygen concentration.

Characterization of a temperature-responsive two component regulatory system from the Antarctic archaeon, Methanococcoides burtonii.

Cold environments dominate the Earth's biosphere and the resident microorganisms play critical roles in fulfilling global biogeochemical cycles. However, only few studies have examined the molecular basis of thermosensing; an ability that microorganisms must possess in order to respond to environmental temperature and regulate cellular processes. Two component regulatory systems have been inferred to function in thermal regulation of gene expression, but biochemical studies assessing these systems in Bacteria are rare, and none have been performed in Archaea or psychrophiles. Here we examined the LtrK/LtrR two component regulatory system from the Antarctic archaeon, Methanococcoides burtonii, assessing kinase and phosphatase activities of wild-type and mutant proteins. LtrK was thermally unstable and had optimal phosphorylation activity at 10 °C (the lowest optimum activity for any psychrophilic enzyme), high activity at 0 °C and was rapidly thermally inactivated at 30 °C. These biochemical properties match well with normal environmental temperatures of M. burtonii (0-4 °C) and the temperature this psychrophile is capable of growing at in the laboratory (-2 to 28 °C). Our findings are consistent with a role for LtrK in performing phosphotransfer reactions with LtrR that could lead to temperature-dependent gene regulation.

Safety and efficacy of Qurse-e-istisqua in chronic hepatitis C infection: an exploratory study.

BACKGROUND: Qurse-e-istisqua (Q-e-I), an Unani medicine commonly prescribed to treat liver disorders. OBJECTIVES: To study efficacy and safety of Q-e-I in hepatitis C virus (HCV) infection. METHODS: In this randomized double-blind exploratory study, 60 naive patients of HCV infection were assigned to receive either interferonα2a (IFNα2a) (3 mIU, subcutaneous, thrice weekly), ribavirin (RBV) (1000 mg, orally, twice daily in divided doses) and placebo (n = 30) or IFNα2a, RBV and Q-e-I (5 g, orally, thrice daily in divided doses) (n = 30). HCV RNA levels, serum hyaluronic acid (SHA), ultrasound image scoring for fibrosis, liver and renal function test, prothrombin time, were done at the baseline and thereafter periodically. RESULTS: Early virologic response (EVR), end of treatment response (ETR) and sustained virologic response (SVR) were 90%, 96.6% and 90% in the control group and 86.6%, 90.0% and 83.3% in the treatment group. SHA level was lower in the treatment group at the end of the treatment as compared to the control group. Mean end of follow-up ultrasound image scoring for fibrosis in the control and the treatment group was 1.37 ± 0.07 and 1.22 ± 0.06 respectively. Aspartate aminotransferase (AST) levels were significantly lower in the treatment group than the control group at 1-month. Commonly observed adverse drug reactions included fever, hair fall, fatigue, anemia, and diarrhea. CONCLUSION: Q-e-I was well tolerated and showed anti-fibrotic activity. EVR, ETR and SVR suggested that Q-e-I do not have any anti-HCV activity. Early recovery in AST and inhibition of progress of fibrosis in Q-e-I group was probably due to the anti-inflammatory and antioxidant activity of its ingredients.

Transport phenomena and clot dissolving therapy: an experimental investigation of diffusion-controlled and permeation-enhanced fibrinolysis.

We have investigated the effects of diffusive and convective transport on fibrinolysis. Using a constant pressure drop (delta P/L) from 0 to 3.7 mmHg/cm-clot to drive fluid permeation, various regimes of lytic agents were delivered into fine and coarse fibrin gels (3 mg/ml) and whole blood clots. Using plasmin (1 microM) delivered into pure fibrin or urokinase (1 microM) delivered into glu-plasminogen (2.2 microM)-laden fibrin, the velocity at which a lysis front moved across fibrin was greatly enhanced by increasing delta P/L. Lysis of fine and coarse fibrin clots by 1 microM plasmin at delta P/L of 3.67 and 1.835 mmHg/cm-clot, respectively, led to a 12-fold and 16-fold enhancement of the lysis front velocity compared to lysis without pressure-driven permeation. For uPA-mediated lysis of coarse fibrin at delta P/L = 3.67 mmHg/cm-clot, the velocity of the lysis front was 25-fold faster than the lysis front velocity measured in the absence of permeation. Similar permeation-enhanced phenomenon was seen for the lysis of whole blood clots. Without permeation, the placement of a lytic agent adjacent to a clot boundary led to a reaction front that moved at a velocity dependent on the concentration of plasmin or uPA used. Overall, these studies suggest that transport phenomena within the clot can play a major role in determining the time needed for reperfusion during fibrinolysis.

Phage-induced change of toxigenesis in Vibrio cholerae.

A temperate phage coding for constitutive hypertoxigenicity has been constructed in Vibrio cholerae strain 569B and used to lysogenise the low-toxin-producing strain MAK 757; 18% of lysogens showed 10-100-fold increase in toxin production. This property was also transmitted at low frequency to second generation lysogens. Thus temperate phage can increase toxin production in a low-toxin-producing strain.

Phage beta interaction with Vibrio cholerae.

The role of temperate phage beta in determining the serology and eltor-lytic phage sensitivity in Vibrio cholerae was investigated. The only serological change found in six host strains was a change to roughness. This was accompanied by failure to adsorb several of the lytic phages. Various phage-sensitivity changes were induced by phage beta in two hosts at the post-adsorption level. In strain HP47, three types of progeny were obtained of which one was universally resistant to lytic phages. These untypable lysogens were culturally stable but gave rise to segregants of the rare phage-type 6 on single colony selection.

Avirulent mutants of Macrophomina phaseolina and Aspergillus fumigatus initiate infection in Phaseolus mungo in the presence of phaseolinone; levamisole gives protection.

To evaluate the role of phaseolinone, a phytotoxin produced by Macrophomina phaseolina, in disease initiation, three nontoxigenic avirulent mutants of the fungus were generated by UV-mutagenesis. Two of them were able to initiate infection in germinating Phaseolus mungo seeds only in the presence of phaseolinone. The minimum dose of phaseoli-none required for infection in 30% seedlings was 2 5 mg/ml. A human pathogen, Aspergillus fumigatus was also able to infect germinating seeds of P. mungo in the presence of 5 mg/ml concentration of phaseolinone. Phaseolinone seemed to facilitate infection by A. fumigatus, which is not normally phytopathogenic, by reducing the immunity of germinating seedlings in a nonspecific way. Levamisole, a non-specific immunopotentiator gave protection against infection induced by A. fumigatus at an optimum dose of 50 mg/ml. Sodium malonate prevented the effects of levamisole.

Induction of sister-chromatid exchanges in L1210 leukemia cells by new antitumor 2-haloethyl(methylsulfonyl) methanesulfonate compounds.

The antitumor 2-halo(chloro, bromo, and fluoro)-ethyl(methylsulfonyl) methanesulfonates, ethyl(methylsulfonyl) methanesulfonate, and chlorozotocin, a 2-chloroethylnitrosourea, were evaluated for their potential to induce SCEs in L1210 cells. The results indicate that all the compounds induced approximately 2-fold or greater increases in SCEs in a dose-related manner. 2-Chloroethyl(methylsulfonyl) methanesulfonate, a DNA-interacting agent and a drug selected for clinical trials, exhibited the highest SCE increase in these cells.