Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Universal Measure for the Impact of Adiabaticity on Quantum Transitions.

Adiabaticity is crucial for our understanding of complex quantum dynamics and thus for advancing fundamental physics and technology, but its impact cannot yet be quantified in complex but common cases where dynamics is only partially adiabatic, several eigenstates are simultaneously populated and transitions between noneigenstates are of key interest. We construct a universally applicable measure that can quantify the adiabaticity of quantum transitions in an arbitrary basis. Our measure distinguishes transitions that occur due to the adiabatic change of populated system eigenstates from transitions that occur due to beating between several eigenstates and can handle nonadiabatic events. While all quantum dynamics fall within the scope of the measure, we demonstrate its usage and utility through two important material science problems-energy and charge transfer-where adiabaticity could be effected by nuclear motion and its quantification will aid not only in unraveling mechanisms but also in system design, for example, of light harvesting systems.

Land suitability analysis for turmeric crop for humid tropical Kerala, India, under current and future climate scenarios using advanced geospatial techniques.

BACKGROUND: Turmeric cultivation primarily thrives in India, followed by Bangladesh, Cambodia, Thailand, China, Malaysia, Indonesia and the Philippines. India leads globally in both area and production of turmeric. Despite this, there is a recognized gap in research regarding the impact of climate change on site suitability of turmeric. The primary objective of the present study was to evaluate both the present and future suitability of turmeric cultivation within the humid tropical region of Kerala, India, by employing advanced geospatial techniques. The research utilized meteorological data from the Indian Meteorological Department for the period of 1986-2020 as historical data and projected future data from the Coupled Model Intercomparison Project Phase 6 (CMIP6). Four climatic scenarios of shared socioeconomic pathway (SSP) from the Intergovernmental Panel on Climate Change AR6 model of MIROC6 for the year 2050 (SSP 1-2.6, SSP 2-4.5, SSP 3-7.0 and SSP 5-8.5) were used. RESULTS: The results showed that suitable area for turmeric cultivation is declining in future scenario and this decline can be primarily attributed to fluctuations in temperature and an anticipated increase in rainfall in the year 2050. Notable changes in the spatial distribution of suitable areas over time were observed through the application of geographic information system (GIS) techniques. Importantly, as per the suitability criteria provided by ICAR-National Bureau of Soil Survey and Land Use Planning (ICAR-NBSS & LUP), all the districts in Kerala exhibited moderately suitable conditions for turmeric cultivation. With the GIS tools, the study identified highly suitable, moderately suitable, marginally suitable and not suitable areas of turmeric cultivation in Kerala. Presently 28% of area falls under highly suitable, 41% of area falls under moderately suitable and 11% falls under not suitable for turmeric cultivation. However, considering the projected scenarios for 2050 under the SSP framework, there will be a significant decrease in highly suitable area by 19% under SSP 5-8.5. This reduction in area will have an impact on the productivity of the crop as a result of changes in temperature and rainfall patterns. CONCLUSION: The outcome of the present research suggests that the state of Kerala needs to implement suitable climate change adaptation and management strategies for sustaining the turmeric cultivation. Additionally, the present study includes a discussion on potential management strategies to address the challenges posed by changing climatic conditions for optimizing turmeric production in the region. © 2024 Society of Chemical Industry.

Clinical Presentation of Cases with Upper Gastro - Intestinal Bleeding.

Acute upper gastrointestinal bleeding (UGIB) is a common emergency and can be a serious condition that requires hospitalization, rapid evaluation and management. The usual presentation is hematemesis (vomiting of blood or coffee ground-like material) and/or melena (black, tarry stools) 1. UGIB occurs more commonly in men and older subjects. PUD is the most common cause of UGIB in the US accounting for about 50% of the cases, whereas in tropical country like India, esophageal varices attribute to half the cases. Esophago-Gastro-Duodenoscopy [EGD] is a primary diagnostic and therapeutic modality in the setting of UGIB. MATERIAL: Prospective study. Forty patients who have presented with frank blood or coffee ground color vomitus and/or melena were considered for this study. All patients greater than 18 years of age were included. Their clinical presentation, hemogram and endoscopic findings were analyzed. Descriptive statistical analysis has been applied. OBSERVATION: In our study, the age distribution was between 23 and 87 years. There is a male preponderance with 65 % males and 35%females. Among 40 patients,42.5%had varices, 17.5% had Peptic Ulcer Disease and12.5% had Erosive Gastritis. The other causes of UGIB include Pangastritis(10%), Mallory Weiss Tear(7.5%), Polyp(5%), Esophagitis(2.5%), Coagulopathy induced bleed(2.5%) and Carcinoma stomach(2.5%). Of the 40 cases admitted, only 3 patients (7.5%) had massive Upper GI Bleed.10 patients (25%) had moderate bleed and 27 patients (67.5%) had mild bleed. Amongst the patients with massive bleed, an important cause is esophageal varices(66.7%). A total of 21 (52.5%) patients have recovered. There was one death(2.5%) amongst the cases which was not attributed to UGIB. 14 patients(45%) has residual disease of which 42.5% were of variceal bleed. Patients with variceal bleed have undergone banding and have been asked to regularly follow up for check endoscopy and banding till their eradication. There was 1 patient of residual disease with Carcinoma stomach(2.5%) who has been initiated on chemotherapy. CONCLUSION: Hematemesis is much commoner than melena in the presentation of upper GI bleed. EGD has a diagnostic as well as therapeutic role in UGIB .In this study endoscopy provided diagnosis in 97.5% of patients. In this cross sectional study, the most common cause of upper GI bleed was esophageal varices, with alcoholic cirrhosis being the main cause of portal hypertension. Varices remain to be the most common cause of UGIB in both males and females, however, the percentage is more in males as compared to females. Varices are an important cause of massive variceal bleed.

Changes in Bacterial Diversity and Composition in Response to Co-inoculation of Arbuscular Mycorrhizae and Zinc-Solubilizing Bacteria in Turmeric Rhizosphere.

In the present study, the impact of co-inoculation of arbuscular mycorrhizal fungi (AM Rhizophagus sp., NCBI-MN710507) and Zinc solubilizing bacteria (ZSB2- Bacillus megaterium, NCBI-KY687496) on plant growth, soil dehydrogenase activity, soil respiration and the changes in bacterial diversity in rhizosphere of turmeric (Curcuma longa) were examined. Our results showed that higher plant height and dry biomass were observed in treatments co-inoculated with AM and ZSB2. Likewise, dehydrogenase activity and soil respiration were more significant in the co-inoculation treatment, indicating abundance of introduced as well as inherent microflora. Bacterial community analysis using 16S rRNA revealed changes in the structure and diversity of various taxa due to co-inoculation of AM and ZSB2. Alpha diversity indexes (Shannon and Chao1) and beta diversity indexes obtained through unweighted unifrac approach also showed variation among the treated samples. Chloroflexi was the dominant phylum followed by Proteobacteria, Actinobacteria and Acidobacteria which accounted for 80% of all treated samples. The composition of bacterial communities at genus level revealed that co-inoculation caused distinct bacterial profiles. The Linear discriminant analysis effect size revealed the dominance of ecologically significant genera such as Bradyrhizobium, Candidatus, Pedomicrbium, Thermoporothrix, Acinetobacter and Nitrospira in treatments co-inoculated with AM and ZSB2. On the whole, co-inoculated treatments revealed enhanced microbial activities and caused significant positive shifts in the bacterial diversity and abundance compared to treatments with sole application of ZSB2 or AM.

Isolation and analysis of the molecular epidemiology and zoonotic significance of Mycobacterium tuberculosis in domestic and wildlife ruminants from three states in India.

The majority of tuberculosis cases in ruminants are caused by Mycobacterium bovis (MB). However, in this study, the authors reported the isolation of Mycobacterium tuberculosis (MT) from bovine milk, nasal swabs and post-mortem tissue samples (n = 841) collected from cattle and buffaloes in the states of Telangana, Maharashtra and Gujarat in India in the period from 2010 to 2015. The isolates (n = 7) were confirmed as Mycobacterium due to their growth characteristics and colony morphology in a commercial liquid medium Mycobacterial Growth Indicator Tube (MGIT)™ employing the BD BACTEC™ MGIT™ 960 system and the Löwenstein-Jensen (LJ) medium supplemented with glycerol but not with sodium pyruvate, and BD-DIFCO™ Middlebrook 7H10 agar containing oleic albumin dextrose catalase (OADC). These isolates were initially identified as members of the M. tuberculosis complex (MTC) using a commercial nested polymerase chain reaction (PCR) kit based on the IS6110 MTC specific nucleotide sequence. The isolates were confirmed as MT using three commercial line probe assay kits, were further genotyped, and the spoligotypes identified were of East African Indian (EAI) 3_IND, EAI5, Central-Asian (CAS) 1_DELHI, U and T1 lineages. Two MT isolates from one antelope (Antilope cervipara) andone gazelle (Gazella bennettii) from Gujarat, which were identified previously, were spoligotyped during this study and identified as belonging to EAI3_IND and EAI5 lineages, respectively. The epidemiological significance and zoonotic implications of regional presence and documentation of the same or two differents poligotypes in different species within the family Bovidae as well as humans is discussed.

La majorité des cas de tuberculose chez les ruminants sont dus à Mycobacterium bovis. Néanmoins, les auteurs rapportent les résultats d'une étude réalisée de 2010 à 2015 en Inde (états de Telangana, Maharashtra et Gujarat), au cours de laquelle Mycobacterium tuberculosis a été isolé à partir de lait de vache ainsi que d'écouvillons nasaux et de prélèvements tissulaires postmortem (n = 841) collectés sur des bovins et des buffles. L'appartenance des isolats au genre Mycobacterium a été confirmée par l'observation des caractéristiques de croissance des colonies et de leur morphologie dans un milieu de culture liquide du commerce (Mycobacterial Growth Indicator Tube [MGIT]™ : tube avec indicateur de croissance mycobactérienne) en utilisant l'automate BD BACTEC™MGIT™ 960 et un milieu de Lowenstein-Jensen additionné de glycérol mais sanspyruvate de sodium, ainsi qu'une gélose BD-DIFCO™ Middlebrook enrichie en acide oléique, albumine, dextrose et catalase (OADC). Dans un premier temps, les isolats ont été identifiés comme étant des membres du complexe M. tuberculosisau moyen d'une amplification en chaîne par polymérase nichée ciblant la séquence nucléotidique spécifique IS6110 du complexe M. tuberculosis. Trois kits commerciaux d'analyse de souches ont permis d'identifier les isolats comme étant M. tuberculosis ; il a ensuite été procédé à l'analyse des génotypes des souches de spoligotypes, lesquelles appartenaient aux lignées East African Indian (EAI) 3_IND,EAI5, Central-Asian (CAS) 1_DELHI, U et T1. Les spoligotypes de deux isolats de M. tuberculosis obtenus précédemment, provenant respectivement d'une antilope(Antilope cervipara) et d'une gazelle (Gazella bennettii) de l'état de Gujarat ont été analysés lors de la présente étude et identifiés comme étant respectivement de lignée EAI3_IND et EAI5. Les auteurs analysent l'importance épidémiologique et la portée zoonotique de la présence rapportée dans la région du même spoligotype ou de deux spoligotypes différents chez des espèces différentes de la famille des Bovidés ainsi que chez l'homme.

La mayoría de los casos de tuberculosis que afectan a los rumiantes son causados por Mycobacterium bovis (MB). En este estudio, sin embargo, los autores dan cuenta del aislamiento de Mycobacterium tuberculosis (MT) en muestras de leche, frotis nasales y tejidos obtenidos post-mortem (n = 841) de ganado vacuno y búfalos de los estados de Telangana, Maharashtra y Gujarat (India) entre 2010 y 2015. Se confirmó que los microorganismos aislados(n = 7) eran micobacterias por sus características de crecimiento y la morfología de las colonias cultivadas en medio líquido comercial Mycobacterial Growth Indicator Tube (MGIT)™ empleando el sistema BD BACTEC™ MGIT™ 960 y el medio Löwenstein-Jensen (LJ) suplementado con glicerol, pero no con piruvato sódico, y agar BD-DIFCO™ Middlebrook 7H10 con ácido oleico, albúmina, dextrosa y catalasa (OADC). Mediante una PCR (reacción en cadena de la polimerasa) anidada comercial basada en la secuencia nucleotídica IS6110 específica del complejo, se empezó por determinar que esos microorganismos pertenecían al complejo M. tuberculosis (MTC). Tras confirmar que se trataba de M. tuberculosis empleando tres ensayos comerciales con sondas en línea, se procedió a caracterizar su genotipo, lo que sirvió para identificar espoligotipos correspondientes a los siguientes linajes: East African Indian (EAI) 3_IND, EAI5, Central-Asian (CAS) 1_DELHI, U y T1. Durante el estudio se caracterizaron asimismo los espoligotipos de dos M. tuberculosis aislados previamente a partir de un antílope (Antilope cervipara) y una gacela (Gazella bennettii) de Gujarat, lo que permitió adscribirlos respectivamente a los linajes EAI3_IND y EAI5. Los autores exponen la importancia desde el punto de vista epidemiológico que tiene la presencia comprobada en la región del mismo espoligotipo o de dos espoligotipos diferentes en distintas especies de la familia Bovidae, así como en el ser humano, y las consecuencias que de ahí se siguen por lo que respecta a posibles zoonosis.

Resveratrol Preconditioning Protects Against Cerebral Ischemic Injury via Nuclear Erythroid 2-Related Factor 2.

BACKGROUND AND PURPOSE: Nuclear erythroid 2 related factor 2 (Nrf2) is an astrocyte-enriched transcription factor that has previously been shown to upregulate cellular antioxidant systems in response to ischemia. Although resveratrol preconditioning (RPC) has emerged as a potential neuroprotective therapy, the involvement of Nrf2 in RPC-induced neuroprotection and mitochondrial reactive oxygen species production after cerebral ischemia remains unclear. The goal of our study was to study the contribution of Nrf2 to RPC and its effects on mitochondrial function. METHODS: We used rodent astrocyte cultures and an in vivo stroke model with RPC. An Nrf2 DNA binding ELISA and protein analysis via Western blotting of downstream Nrf2 targets were performed to determine RPC-induced activation of Nrf2 in rat and mouse astrocytes. After RPC, mitochondrial function was determined by measuring reactive oxygen species production and mitochondrial respiration in both wild-type and Nrf2-/- mice. Infarct volume was measured to determine neuroprotection, whereas protein levels were measured by immunoblotting. RESULTS: We report that Nrf2 is activated by RPC in rodent astrocyte cultures, and that loss of Nrf2 reduced RPC-mediated neuroprotection in a mouse model of focal cerebral ischemia. In addition, we observed that wild-type and Nrf2-/- cortical mitochondria exhibited increased uncoupling and reactive oxygen species production after RPC treatments. Finally, Nrf2-/- astrocytes exhibited decreased mitochondrial antioxidant expression and were unable to upregulate cellular antioxidants after RPC treatment. CONCLUSIONS: Nrf2 contributes to RPC-induced neuroprotection through maintaining mitochondrial coupling and antioxidant protein expression.

Signaling pathways leading to ischemic mitochondrial neuroprotection.

There is extensive evidence that ischemic/reperfusion mediated mitochondrial dysfunction is a major contributor to ischemic damage. However data also indicates that mild ischemic stress induces mitochondrial dependent activation of ischemic preconditioning. Ischemic preconditioning is a neuroprotective mechanism which is activated upon a brief sub-injurious ischemic exposure and is sufficient to provide protection against a subsequent lethal ischemic insult. Current research demonstrates that mitochondria are not only the inducers of but are also an important target of ischemic preconditioning mediated protection. Numerous proteins and signaling pathways are activated by ischemic preconditioning which protect the mitochondria against ischemic damage. In this review we examine some of the proteins activated by ischemic precondition which counteracts the deleterious effects of ischemia/reperfusion thereby maintaining normal mitochondrial activity and lead to ischemic tolerance.

Zinc solubilization and organic acid production by the entomopathogenic fungus, Metarhizium pingshaense sheds light on its key ecological role in the environment.

We report for the first-time higher zinc (Zn) solubilization efficiency and plant growth promotion by an entomopathogenic fungus (EPF), Metarhizium pingshaense IISR-EPF-14, which was earlier isolated from Conogethes punctiferalis, a pest of global importance. The Zn solubilizing efficiency of the fungus varied depending on the type of insoluble source of Zn used, which was observed to be 1.6 times higher in Zn3(PO4)2-amended media compared to ZnO media. In liquid media, there was a 6.2-fold increase in available Zn in ZnO-amended media, whereas a 20.2-fold increase in available Zn was recorded in Zn3(PO4)2 medium. We ascribe the production of various organic acids such as gluconic, keto-gluconic, oxalic, tartaric, malonic, succinic and formic acids, which in general, interact with insoluble Zn sources and make them soluble by forming metal cations and displacing anions as the major mechanism for Zn solubilization by M. pingshaense. However, the type and amount of organic acid produced in the media varied depending on the source of Zn used and the incubation period. Application of the fungus alone and in combination with insoluble Zn sources enhanced various plant growth parameters in rice and cardamom plants. Moreover, the uptake of Zn in rice plants was enhanced up to ~2.5-fold by fungal application. The fungus also exhibited various other plant growth-promoting traits, such as production of Indole-3-acetic acid, ammonia, siderophores, solubilization of mineral phosphate, and production of hydrolytic enzymes such as α-amylase, protease, and pectinase. Hence, apart from its use as a biological control agent, M. pingshaense has the potential to be used as a bio-fortifier to enhance the solubilization and uptake of Zn from nutrient poor soils under field conditions. Our findings shed light on the broader ecological role played by this fungus and widen its scope for utilization in sustainable agriculture.

Ischemic preconditioning and clinical scenarios.

PURPOSE OF REVIEW: Ischemic preconditioning (IPC) is gaining attention as a novel neuroprotective therapy and could provide an improved mechanistic understanding of tolerance to cerebral ischemia. The purpose of this article is to review the recent work in the field of IPC and its applications to clinical scenarios. RECENT FINDINGS: The cellular signaling pathways that are activated following IPC are now better understood and have enabled investigators to identify several IPC mimetics. Most of these studies were performed in rodents, and efficacy of these mimetics remains to be evaluated in human patients. Additionally, remote ischemic preconditioning (RIPC) may have higher translational value than IPC. Repeated cycles of temporary ischemia in a remote organ can activate protective pathways in the target organ, including the heart and brain. Clinical trials are underway to test the efficacy of RIPC in protecting brain against subarachnoid hemorrhage. SUMMARY: IPC, RIPC, and IPC mimetics have the potential to be therapeutic in various clinical scenarios. Further understanding of IPC-induced neuroprotection pathways and utilization of clinically relevant animal models are necessary to increase the translational potential of IPC in the near future.

Is there a role for agomelatine in the treatment of anxiety disorders?A review of published data.

Anxiety disorders (Ads) are the most common type of psychiatric disorders, Pharmacologic options studied for treating ADs may include benzodiazepines, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), noradrenergic and specific serotonergic antidepressants (NaSSA) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Agomelatine, a new melatonergic antidepressant, has been shown effective in various types of mood disorders. Moreover, some evidence points towards a possible efficacy of such a drug in the treatment of ADs. Therefore, the aim of this review was to elucidate current (facts and views) data on the role of agomelatine in the treatment of ADs. The trials evaluating agomelatine in the treatment of generalized anxiety disorder are few but, overall, encouraging in regards to its efficacy. However, further randomized, placebo-controlled studies on larger samples use are needed. Apart from some interesting case reports, no large studies are, to date, present in literature regarding agomelatine in the treatment of other ADs, such as panic disorder, social anxiety disorder, obsessive-compulsive disorder and post-traumatic stress disorder. Therefore, the clinical efficacy and the relative good tolerability of agomelatine in generalized anxiety (GAD) warrants further investigation in ADs.

Pre-clinical toxicity & immunobiological evaluation of DNA rabies vaccine & combination rabies vaccine in rhesus monkeys (Macaca mulatta).

BACKGROUND & OBJECTIVES: Pre-clinical toxicology evaluation of biotechnology products is a challenge to the toxicologist. The present investigation is an attempt to evaluate the safety profile of the first indigenously developed recombinant DNA anti-rabies vaccine [DRV (100 µg)] and combination rabies vaccine [CRV (100 µg DRV and 1.25 IU of cell culture-derived inactivated rabies virus vaccine)], which are intended for clinical use by intramuscular route in Rhesus monkeys. METHODS: As per the regulatory requirements, the study was designed for acute (single dose - 14 days), sub-chronic (repeat dose - 28 days) and chronic (intended clinical dose - 120 days) toxicity tests using three dose levels, viz. therapeutic, average (2x therapeutic dose) and highest dose (10 x therapeutic dose) exposure in monkeys. The selection of the model i.e. monkey was based on affinity and rapid higher antibody response during the efficacy studies. An attempt was made to evaluate all parameters which included physical, physiological, clinical, haematological and histopathological profiles of all target organs, as well as Tiers I, II, III immunotoxicity parameters. RESULTS: In acute toxicity there was no mortality in spite of exposing the monkeys to 10XDRV. In sub chronic and chronic toxicity studies there were no abnormalities in physical, physiological, neurological, clinical parameters, after administration of test compound in intended and 10 times of clinical dosage schedule of DRV and CRV under the experimental conditions. Clinical chemistry, haematology, organ weights and histopathology studies were essentially unremarkable except the presence of residual DNA in femtogram level at site of injection in animal which received 10X DRV in chronic toxicity study. No Observational Adverse Effects Level (NOAEL) of DRV is 1000 ug/dose (10 times of therapeutic dose) if administered on 0, 4, 7, 14, 28 th day. INTERPRETATION & CONCLUSIONS: The information generated by this study not only draws attention to the need for national and international regulatory agencies in formulating guidelines for pre-clinical safety evaluation of biotech products but also facilitates the development of biopharmaceuticals as safe potential therapeutic agents.

Metagenomics indicates abundance of biofilm related genes and horizontal transfer of multidrug resistant genes among bacterial communities in nano zinc oxide polluted soil.

The unsafe and reckless disposal of metal oxide nanoparticles like ZnO (nZnO) into the soil could seriously impact bacterial behavioural responses and functions. Under such stress, biofilm formation is considered to be a robust mechanism for bacterial survival in soil. We examined the response of bacterial metagenomes in soils exposed to varying levels of Zn (50, 200, 500 and 1000 mg kg-1) as nano Zn oxide (nZnO) in terms of biofilm genesis and regulation and their co-occurrences with multidrug resistance genes (MDRGs) and mobile genetic elements (MGEs). The size-specific effects of nZnO were verified using its bulk counterpart (bZnO). Both nZnO and bZnO facilitated profusion of biofilm related genes (BGs) especially at higher Zn levels (500 and 1000 mg kg-1 Zn), though maximum abundance was registered at a comparatively lower level under nZnO. In general, nZnO favoured an enhancement of genes involved in exopolysaccharide biosynthesis and attachment, while bZnO favoured genes related to capsule formation, chemotaxis and biofilm dispersion. Co-occurrence network analysis revealed significant positive correlations between abundances of BGs, MDRGs and MGEs, indicating an enhanced probability for horizontal gene transfer of MDRGs in nZnO polluted soils.

Soil polluted with nano ZnO reveals unstable bacterial communities and decoupling of taxonomic and functional diversities.

Due to relentless production and disposal of nano zinc oxide (nZnO), it has become critical to comprehend the serious risks large-scale accumulation of nZnO pose to bacterial communities in soil. The primary objective was to evaluate the changes in bacterial community structure and associated functional pathways through predictive metagenomic profiling and subsequent validation through Quantitative Realtime PCR in soil spiked with nZnO (0, 50, 200, 500 and 1000 mg Zn kg-1) and similar levels of bulk ZnO (bZnO). The results revealed that soil microbial biomass-C, -N, -P, soil respiration and enzyme activities decreased markedly at higher ZnO levels. The alpha diversity decreased with increasing ZnO level, with more impact under nZnO, while beta diversity analyses indicated a distinct dose- dependent separation of bacterial communities. The dominant taxa including Proteobacteria, Bacterioidetes, Acidobacteria and Planctomycetes significantly increased in abundance, while Firmicutes, Actinobacteria and Chloroflexi decreased in abundance with elevated nZnO and bZnO levels. Redundancy analysis indicated that changes in bacterial community structure instilled a greater dose- rather than size- specific response on key microbial parameters. Predicted key functions did not show a dose- specific response, and at 1000 mg Zn kg-1, methane metabolism as well as starch and sucrose metabolism were attenuated, while functions involving two component systems and bacterial secretion systems were enhanced under bZnO indicating better stress avoidance mechanism than under nZnO. Realtime PCR and microbial endpoint assays confirmed the metagenome derived taxonomic and functional data, respectively. Taxa and functions that varied substantially under stress were established as bioindicators to predict nZnO toxicity in soils. Taxon-function decoupling indicated that the soil bacterial communities deployed adaptive mechanisms under high ZnO, with lesser buffering capacity and resilience of communities under nZnO.

Endovascular Treatment of Cerebrovascular Lesions Using Nickel- or Nitinol-Containing Devices in Patients with Nickel Allergies.

Nickel is used in many cerebral endovascular treatment devices. However, nickel hypersensitivity is the most common metal allergy, and the relative risk of treatment in these patients is unknown. This retrospective analysis identified patients with nickel or metal allergies who underwent cerebral endovascular treatment with nickel-containing devices. Seven patients with nickel and/or other metal allergies underwent treatment with 9 nickel-containing devices. None experienced periprocedural complications. No patient received treatment with corticosteroids or antihistamines. At a mean clinical follow-up for all patients of 22.8 months (range, 10.5-38.0 months), no patients had symptoms attributable to nickel allergic reactions. The mean radiographic follow-up for all patients at 18.4 months (range, 2.5-37.5 months) showed successful treatment of the targeted vascular pathologies, with no evidence of in-stent stenosis or other allergic or hypersensitivity sequelae. The treatment of cerebrovascular lesions with a nickel-containing device resulted in no adverse outcomes among these patients and was safe and effective.

Current status and future readiness of Indian radiation oncologists to embrace prostate high-dose-rate brachytherapy: An Indian Brachytherapy Society survey.

Purpose: This survey aimed to understand the practice pattern and attitude of Indian doctors towards prostate brachytherapy. Material and methods: A 21-point questionnaire was designed in Google form and sent to radiation oncologists practicing in India, using texts, mails, and social media. Responses were collated, and descriptive statistical analysis was performed. Results: A total of 212 radiation oncologists from 136 centers responded to the survey questionnaire, with majority (66%) being post-specialty training > 6 years. We found that about 44.3% (n = 94) of respondents do not practice interstitial brachytherapy for any site, and majority (83.3%, n = 175) do not practice high-dose-rate (HDR) prostate brachytherapy. Only 2.8% (n = 6) of doctors preferred boost by brachytherapy compared with 38.1% (n = 80) of respondents, who favored stereotactic body radiation therapy (SBRT) boost. When asked about the indication of HDR prostate brachytherapy in Indian setting, 32.5% (n = 67) of respondents favored monotherapy, 46.1% (n = 95) of oncologists thought boost as a good indication, and 21.4% (n = 44) preferred re-irradiation/salvage setting. The most cited reason for prostate brachytherapy not being popularly practiced in India was lack of training (84.8%, n = 179). It was also noted that out of 80 respondents who practiced SBRT for prostate boost, 37 would prefer HDR brachytherapy boost if given adequate training and facilities. Conclusions: The present survey provided insight on practice of prostate brachytherapy in India. It is evident that majority of radiation oncologists do not practice HDR prostate brachytherapy due to lack of training and infrastructure. Indian physicians are willing to learn and start prostate brachytherapy procedures if dedicated training and workshops are organized.

Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia.

BACKGROUND: Severe early and late radiation reaction to radiotherapy is extremely rare in breast cancer patients. Such a reaction prompted an investigation into a 44-year-old mother (patient A-T213). METHODS: A neurological examination was performed and blood lymphocytes and skin fibroblasts were assessed for radiosensitivity chromosomally and by colony-forming assay. The ATM gene was sequenced and ATM mutations modelled by site-directed mutagenesis. The ATM kinase activity was also assessed. RESULTS: Patient A-T213 was normally ambulant with no ataxia and minimal other neurological features. T lymphocytes and skin fibroblasts were unusually radiosensitive, although less sensitive than in classical ataxia telangiectasia (A-T). A lymphoblastoid cell line and skin fibroblasts expressed ATM protein with some retained kinase activity. One missense ATM mutation c.8672G>A (p.Gly2891Asp) and a c.1A>G substitution were identified. In the modelling system, the p.Gly2891Asp mutant protein was expressed and shown to have residual ATM kinase activity. CONCLUSION: Patient A-T213 has a milder form of A-T with biallelic ATM mutations, which may have contributed to breast cancer development, and certainly caused the severe radiation reaction. Ataxia telangiectasia should be investigated as a potential cause of untoward severe early and late radiation reactions in breast cancer patients.

Redox signaling pathways involved in neuronal ischemic preconditioning.

There is extensive evidence that the restoration of blood flow following cerebral ischemia contributes greatly to the pathophysiology of ischemia mediated brain injury. The initiating stimulus of reperfusion injury is believed to be the excessive production of reactive oxygen (ROS) and nitrogen (RNS) species by the mitochondria. ROS and RNS generation leads to mitochondrial protein, lipid and DNA oxidation which impedes normal mitochondrial physiology and initiates cellular death pathways. However not all ROS and RNS production is detrimental. It has been demonstrated that low levels of ROS production are protective and may serve as a trigger for activation of ischemic preconditioning. Ischemic preconditioning is a neuroprotective mechanism which is activated upon a brief sublethal ischemic exposure and is sufficient to provide protection against a subsequent lethal ischemic insult. Numerous proteins and signaling pathways have been implicated in the ischemic preconditioning neuroprotective response. In this review we examine the origin and mechanisms of ROS and RNS production following ischemic/reperfusion and the role of free radicals in modulating proteins associated with ischemic preconditioning neuroprotection.

Forecasting the Incremental Value to Society Created by a Class of New Prescription Drugs: A Proposed Methodology and Its Application to Treating Chronic Hepatitis C in India.

BACKGROUND: For low- and middle-income countries, the forecasted incremental value to society created by a class of new prescription drugs would be a useful criterion to prioritize the licensing, subsidization, and provision of new drugs. OBJECTIVES: We provide a methodology to forecast the value of a new class of drugs, defined as the incremental value obtained in the scenario in which the new class of drugs is available along with existing drugs compared with the scenario of existing drugs only. We forecasted the value created by direct-acting antiviral drugs to treat chronic hepatitis C in India. METHOD: We conducted a physician survey together with an aggregate multinomial logit model to forecast for each patient type the fraction of physicians who would prescribe the new drug under different scenarios. Value was determined by the monetary equivalent of increased life expectancy, reduced disability, and decreased future infection of others, minus drug cost, all treatment-related costs, and the cost of side effects. RESULTS: We forecasted that the introduction of direct-acting antiviral drugs is likely to create USD11.5 billion of value in India over a 5-year period, based on a 'realistic' assumption about the growth rate of India's per capita GDP. Under 'pessimistic' and 'optimistic' assumptions about the growth rate, the value changes to USD6.5 and 22.5 billion, respectively. CONCLUSIONS: There is major value likely to be created by the new direct-acting antiviral drugs in treating hepatitis C in India; this is consistent with the Indian Government's decision to provide the drugs free of cost.