India-discovered levonadifloxacin & alalevonadifloxacin: A review on susceptibility testing methods, CLSI quality control and breakpoints along with a brief account of their emerging therapeutic profile as a novel standard-of-care.

BACKGROUND: Levonadifloxacin (intravenous) and alalevonadifloxacin (oral prodrug) are novel antibiotics based on benzoquinolizine subclass of fluoroquinolone, licensed for clinical use in India in 2019. The active moiety, levonadifloxacin, is a broad-spectrum antibiotic with a high potency against methicillin-resistant Staphylococcus. aureus, multi-drug resistant pneumococci and anaerobes. OBJECTIVE: This review, for the first time, critically analyses the antimicrobial susceptibility testing methods, Clinical Laboratory & Standards Institute (CLSI)-quality control of susceptibility testing and breakpoints of levonadifloxacin. Further, the genesis, discovery and developmental aspects as well as therapeutic profile of levonadifloxacin and alalevonadifloxacin are briefly described. CONTENTS: In order to aid the scientific and clinician communities with a single comprehensive overview on all the key aspects of levonadifloxacin and alalevonadifloxacin, the present article covers the reference MIC and disk diffusion methods for levonadifloxacin susceptibility testing that were approved by CLSI and the reference ranges for quality control strains published in the CLSI M100 document. The breakpoints of levonadifloxacin were derived in concordance to US FDA, European Committee on Antibiotic Susceptibility Testing (EUCAST) and CLSI approaches. Further, the article provides a brief account of challenges encountered during the discovery stages of levonadifloxacin and alalevonadifloxacin, activity spectrum and safety benefits accruing from structural novelty-linked mechanism of action. Further, the review also covers in vitro and in vivo activities, registrational clinical studies and patient-friendly features of levonadifloxacin/alalevonadifloxacin. Cumulatively, levonadifloxacin has a potential to offer a long awaited new standard-of-care treatment for the resistant Gram-positive bacterial infections.

Association of Baseline Patient-reported Health-related Quality of Life Metrics with Outcome in Localised Prostate Cancer.

AIMS: Although health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localised prostate cancer. We report the association of baseline HR-QoL metrics with overall survival and toxicity in localised prostate cancer. MATERIALS AND METHODS: This was a secondary analysis of a phase III randomised controlled study conducted in a single-payer health system. Patients with Gleason score ≤7, clinical stage T1b-T3a and prostate-specific antigen <30 ng/ml were randomised to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiotherapy or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate radiotherapy. HR-QoL scores were estimated using the European Organisation for Research and Treatment of Cancer QoL questionnaire. A multistate Markov model was used to determine the association of baseline HR-QoL metrics with overall survival and a multilevel multivariable Cox regression was used to determine the association with the incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P < 0.025 was considered as statistically significant. RESULTS: Overall, 393 patients with baseline HR-QoL data were included in this analysis: 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio 1.020, 95% confidence interval 1.010-1.030, P = 0.02) and dyspnoea (hazard ratio 1.020, 95% confidence interval 1.003-1.030, P = 0.01) were associated with inferior overall survival. Baseline dyspnoea was associated with a higher incidence of grade ≥3 toxicity (hazard ratio 1.020, 95% confidence interval 1.010-1.030, P = 0.023). CONCLUSION: In a cohort of localised prostate cancer patients treated with radiotherapy and short-term ADT, a 10-point higher baseline financial difficulty or dyspnoea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnoea, we noted a 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity.

Multiplexed bio-imaging using cadmium telluride quantum dots synthesized by mathematically derived process parameters in a continuous flow active microreactor.

Quantum dots (QDs) are semiconductor nanocrystals with unique size-tunable emissions. To obtain a precise emission spectrum, monodispersity in size is imperative, which is achieved by controlling the reaction kinetics in a continuous flow of active microreactors. Further, a multivariate approach (dimensional analysis) is employed to impose stringent control on the reaction process resulting in monodispersed preparation of cadmium telluride (CdTe) quantum dots. Dimensional analysis knits multiple variables into a dimensionless mathematical form which not only predicts parameters precisely to obtain narrow size tunability but also guarantees reproducibility in synthesis. Analytical, structural, and optical characterization of the microreactor synthesized polydimethylsiloxane (PDMS) coated CdTe QDs reveal quantum efficient (61.5%), photostable (44%), and biocompatible nanocrystals of 5-15 nm. Further, PDMS-coated QDs (P-QDs) are conjugated with organelle-specific antibodies/biomarkers for in-vitro imaging in NIH 3T3 cells. Likewise, proliferating cell nuclear antigen (PCNA) and anti-myosin (MF20), cardiomyocytes antibodies are conjugated with P-QDs (red and green, respectively) to image the zebrafish's cardiac tissue. Antibodies tagged with quantum dots are imaged simultaneously using confocal microscopy. Thus, multiplexed bio-imaging of in-vitro and zebrafish tissue is demonstrated successfully. The results indicate the suitability of continuous flow active microreactor in conjunction with the mathematical prediction of process parameters to synthesize reproducibly monodispersed and quantum efficient QDs.

Regulation of STAT3 signaling in IFNγ and IL10 pathways and in their cross-talk.

The pro-inflammatory IFNγ-STAT1 pathway and anti-inflammatory IL10-STAT3 pathway elicit cellular responses primarily utilizing their canonical STATs. However IL10 mediated STAT1 and IFNγ mediated STAT3 activation is also observed, suggesting crosstalk of these functionally opposing signaling pathways can potentially reshape the canonical dynamics both STATs and alter the expression of their target genes. Herein, we measured the dynamics of STATs in response to different doses of IL10 or IFNγ and in their co-stimulation and employed quantitative modeling to understand the regulatory mechanisms controlling signal responses in individual and co-simulation scenarios. Our experiments show, STAT3 in particular, exhibits a bell-shaped dose-response while treated with IFNγ or IL10 and our model quantiatively captured the dose-dependent dynamics of both the STATs in both pathways. The model next predicted and subsequent experiments validated that STAT3 dynamics would robustly remain IL10 specific when subjected to a co-stimulation of both IFNγ and IL10. Genes common to both pathways also exhibited IL10 specific expression during the co-stimulation. The findings thus uncover anovel feature of the IL10-STAT3 signaling axis during pathway crosstalk. Finally, parameter sampling coupled to information theory based analysis showed that bell-shaped signal-response of STAT3 in both pathways is primarily dependent on receptor concentration whereas robustness of IL10-STAT3 signaling axis in co-stimulation results from the negative regulation of the IFNγ pathway.

Antibiofilm and anti-quorum sensing activities of eugenol and linalool from Ocimum tenuiflorum against Pseudomonas aeruginosa biofilm.

AIMS: The aim of this study is to determine the ability of two bioactive compounds, namely, eugenol and linalool, purified from leaves of Ocimum tenuiflorum for eradication of biofilm produced by Pseudomonas aeruginosa. METHODS AND RESULTS: The phytoextract of O. tenuiflorum (KT), a common ethno-botanical plant of India, was purified through high-performance liquid chromatography and was analysed using ultraviolet (UV) spectroscopy and gas chromatography-mass spectrometry (GC-MS). Eugenol and linalool were found to be the most active amongst all phytocompounds present in phytoextract and showed a significant reduction in the viability of sessile cells of P. aeruginosa and the minimum revival after withdrawal of phyto-challenge. They could bring about notable reduction in the protein and carbohydrate content of exopolysaccharide of biofilm. Eugenol and linalool could affect the synthesis of quorum sensing (QS) proteins like LasA and LasB as well as virulence factors such as pyocyanin, and rhamnolipids, which seriously hamper the formation of biofilm. The biofilm framework was extremely affected by the phytocompounds through the reduction of protein and carbohydrate content of extracellular polymeric substance (EPS). Another interesting found out was that they brought about maximum inhibition to the genomic DNA and RNA content. The studies were supported by in silico interaction between eugenol and linalool with the QS proteins. The antibiofilm efficacies of eugenol, linalool and phytoextract (KT) were further confirmed by microscopic studies with scanning electron microscopy (SEM), atomic force microscopy and fluorescence confocal microscopy microscopic studies. CONCLUSIONS: The phytocompounds are proved to be more effective than conventional antibiotics in inhibiting the biofilm forming sessile cells and can be used as a replacement for antibiotic. SIGNIFICANCE AND IMPACT OF THE STUDY: Pure eugenol extracted from common basil leaves can be used as a safe substitute for common antibiotic for treatment of chronic infections caused by P. aeruginosa. It will be cost effective, devoid of notable side effects and will not generate antibiotic resistance in host body.

Use of immunoadsorption columns in ABO-incompatible renal transplantation: A prospective study at a tertiary care center in India.

BACKGROUND: We present our experience of ABO-incompatible renal transplant using immunoadsorption (IA) columns. We have compared efficacy of two commercially available columns. METHODS: This single-center prospective study was conducted at Army Hospital Research and Referral, Delhi. All consecutive ABO-incompatible renal transplants from January 2014 to February 2018 were analyzed. Of 30 patients who underwent transplantations, 28 underwent antibody depletion with immunoadsorption columns. Of them, 14 cases were in the "Glycosorb group," while 14 in the "Adsopak group." RESULTS: The donors in the Adsopak group were older than those in the Glycosorb group (p < 0.05). Both groups had spousal donors in majority. The cutoff for the antibody titer was 1:8. The median titer in the Adsopak group was 128 (range, 1:4 to 1:2048), while that in the Glycosorb group was 24 (range, 1:8 to 1:128). All patients in the Glycosorb group had baseline titers ≤1:128, while 13 patients in the Adsopak group had baseline titers ≤1:512. Nil titer was achievable with Glycosorb® (50%,7/14) but not with Adsopak® (P < 0.01). Around 4 sessions were required for the Glycosorb group, while around 8 sessions were required for the Adsopak group before transplantation (p < 0.001). The Glycosorb group was advantageous in terms of graft failure because no rejection was noticed in these patients in their follow-up period. Three patients in the Adsopak group developed rejection (two had mixed rejection, and one had antibody-mediated rejection). Four patients died of sepsis (three in the Glycosorb and one in the Adsopak group). Lower baseline serum creatinine level was achieved in the Glycosorb group. CONCLUSIONS: Results of ABO-incompatible renal transplantation were satisfactory, and the use of immunoadsorption columns could effectively deplete antibody titers. Glycosorb columns were more efficient than Adsopak columns. Graft survival was better with Glycosorb. Posttransplant infections were a major cause of mortality.

Assessment of antibacterial activity of levonadifloxacin against contemporary gram-positive clinical isolates collected from various Indian hospitals using disk-diffusion assay.

Objectives: Levonadifloxacin is a novel benzoquinolizine subclass of quinolone with broad-spectrum activities against problematic pathogens such as methicillin-resistant Staphylococcus aureus, quinolone-resistant S. aureus, vancomycin intermediate S. aureus, and vancomycin-resistant S. aureus. Levonadifloxacin and its oral prodrug, alalevonadifloxacin, have been recently approved in India for the treatment of acute bacterial skin and skin structure infections, including concurrent bacteraemia and diabetic foot infections. The aim of the study is to assess the activity of levonadifloxacin against Gram-positive clinical isolates collected from various Indian hospitals using the disc-diffusion method. Materials and Methods: Nonduplicate isolates of S. aureus and other Gram-positive isolates collected from June 2019 to March 2020 were subjected to levonadifloxacin susceptibility testing (disk diffusion method) as per the Clinical and Laboratory Standards Institute guidelines (Year 2019). Levonadifloxacin 10 µg impregnated disks were used during the testing. Results: A total of 664 diverse Gram-positive clinical isolates collected from six different hospitals in India were analyzed. Majority (65.5%) of the isolates were S. aureus. All the S. aureus and other Gram-positive isolates were found to be susceptible to levonadifloxacin as per the prespecified interpretive criteria identified based on population pharmacokinetic model and Monte Carlo simulation enabled probability of pharmacodynamic target attainment analysis. Conclusions: The present study showed that levonadifloxacin was highly active against contemporary Gram-positive pathogens and furthermore demonstrated that levonadifloxacin susceptibilities can be reliably determined using the disc-diffusion method.

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.

Fulminant Neisseria meningitidis septicaemia with purpura fulminans requiring limb amputation.

Despite the isolation of Neisseria meningitidis over 200 years ago, meningococcal disease remains a feared cause of bacterial sepsis, with significant morbidity and mortality, despite prompt antibiotic use and modern critical care support. Neisseria meningitides is a Gram-negative encapsulated diplococcus, which exists only in the human host (Kvalsvig and Unsworth, 2003). The bacterium can cause life-threatening septic shock and coagulopathy, which may rapidly manifest within a matter of hours from preceding mild symptoms (Kvalsvig and Unsworth, 2003). Whilst N. meningitidis is recognised as a common commensal organism in the nasopharynx, associated with asymptomatic carriage in up to 10 %, manifestation of life-threatening disease is rare (Rappuoli and Pizza, 2015). We report the case of 31-year-old male presenting with devastating meningococcal septicaemia with disseminated intravascular coagulopathy (DIC) and purpura fulminans, requiring surgical debridement and a right above-knee amputation for sepsis-driven skin necrosis. The patient suffered extensive tissue loss secondary to a type 3 immune hypersensitivity reaction involving immune-complex mediated inflammation and tissue necrosis. Due to a strong immune component driving the patient's failure to convalesce pulsed intravenous methylprednisolone was used alongside antimicrobial therapy. The use of steroids was associated with fever subsidence and significant clinical improvement, highlighting the benefit of corticosteroid use in immune-complex mediated pathology.

In vitro activity of a novel antibacterial agent, levonadifloxacin, against clinical isolates collected in a prospective, multicentre surveillance study in India during 2016-18.

BACKGROUND: Levonadifloxacin is a novel antibiotic belonging to the benzoquinolizine subclass of fluoroquinolones with potent activity against MRSA and quinolone-resistant Staphylococcus aureus. IV levonadifloxacin and its oral prodrug alalevonadifloxacin have recently been approved in India for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) including diabetic foot infections. OBJECTIVES: To investigate the in vitro activity of levonadifloxacin against contemporary clinical isolates collected from multiple tertiary care hospitals across India in the Antimicrobial Susceptibility Profiling of Indian Resistotypes (ASPIRE) surveillance study. METHODS: A total of 1376 clinical isolates, consisting of staphylococci (n = 677), streptococci (n = 178), Enterobacterales (n = 320), Pseudomonas aeruginosa (n = 140) and Acinetobacter baumannii (n = 61), collected (2016-18) from 16 tertiary hospitals located across 12 states in India, were included in the study. The MICs of levonadifloxacin and comparator antibiotics were determined using the reference agar dilution method and broth microdilution method. RESULTS: Levonadifloxacin exhibited potent activity against MSSA (MIC50/90: 0.5/1 mg/L), MRSA (MIC50/90: 0.5/1 mg/L) and levofloxacin-resistant S. aureus (MIC50/90: 1/1 mg/L) isolates. Similarly, potent activity of levonadifloxacin was also observed against CoNS including MDR isolates (MIC50/90: 1/2 mg/L). Against Streptococcus pneumoniae, levonadifloxacin (MIC50/90: 0.5/0.5 mg/L) showed superior activity compared with levofloxacin (MIC50/90: 1/2 mg/L). Among levofloxacin-susceptible Enterobacterales, 80.6% of isolates were inhibited at ≤2 mg/L levonadifloxacin. CONCLUSIONS: Levonadifloxacin displayed potent activity against contemporary MRSA and fluoroquinolone-resistant staphylococcal isolates, thus offering a valuable IV as well as an oral therapeutic option for the treatment of ABSSSIs. Furthermore, levonadifloxacin exhibited a broad-spectrum activity profile as evident from its activity against streptococci and levofloxacin-susceptible Gram-negative isolates.

Acute kidney injury due to acute cortical necrosis following vivax malaria.

Malaria is a parasitic infection of global importance but has a high prevalence in the developing countries. Renal failure is a common complication of severe Plasmodium falciparum malaria and has been reported in up to 40% of all cases. Acute kidney injury (AKI), however, is not commonly associated with Plasmodium vivax infection. In those patients who develop AKI following P. vivax infection, the cause is commonly attributed to mixed undiagnosed falciparum infection or coexistent sepsis, dehydration, or hypotension. Infrequently, an association of P. vivax infection with thrombotic microangiopathy (TMA) has been reported. The purpose of this report is to describe renal failure due to TMA following malaria caused by P. vivax. A 24-year-old female presented with a history of fever and jaundice of two weeks duration followed by progressive oliguria and swelling of the face and feet five days after the onset of fever. The evaluation revealed normal blood pressure, anemia, thrombocytopenia, azotemia, unconjugated hyperbilirubinemia with mildly elevated transaminases, and elevated lactate dehydrogenase. Peripheral smear was positive for P. vivax, and schistocytes were seen. She was given intravenous artesunate followed by oral primaquine for 14 days. Urine examination showed proteinuria and microscopic hematuria. She remained oliguric and dialysis dependent, and her kidney biopsy revealed patchy cortical necrosis involving 40% of sampled cortex with widespread fibrinoid necrosis of the vessel wall, red blood cell fragmentation, and luminal thrombotic occlusion. Hemodialysis was discontinued after three weeks when there was the improvement of renal function over time, and her serum creatinine decreased to 2.2 mg/dL by six weeks. Patients with P. vivax malaria developing renal failure may have TMA. Renal biopsy, if performed early in the course of the disease, may identify TMA and institution of plasma exchange in such patients could help in early recovery.

AKT is indispensable for coordinating Par-4/JNK cross talk in p21 downmodulation during ER stress.

The double-edged role of p21 to command survival and apoptosis is emerging. The current investigation highlights ER stress-mediated JNK activation that plausibly triggers cell death by attenuating endogenous p21 level. Here, we demonstrated that ER stress activator 3-AWA diminishes the p21 levels in cancer cells by averting the senescent phenotype to commence G2/M arrest. In essence, the deceleration in p21 level occurs through ER stress/JNK/Caspase-3 axis via activation/induction of proapoptotic Par-4 and inhibition of AKT. The molecular dynamics studies identified important interactions, which may be responsible for the AKT inhibition and efficacy of 3-AWA towards AKT binding pocket. Interestingly, the p21 deceleration was rescued by incubating the cells with 3-AWA in the presence of an ER stress inhibitor, Salubrinal. Furthermore, we demonstrated that p21 expression decreases solitarily in Par-4+/+ MEFs; albeit, ER stress-induced JNK activation was observed in both Par-4+/+ and Par-4-/- MEFs. Par-4 knockdown or overexpression studies established that ectopic Par-4 along with ER stress are not sufficient to downregulate p21 in PC-3 cells but are adequate for DU-145 cells and that the ER stress inflicted activation of JNK, inhibition of AKT and Par-4 induction are all crucial to p21 downmodulation by 3-AWA. By using isogenic cell lines, such as HCT-116 p53+/+ and HCT-116 p53-/-, we found that deceleration in p21 expression due to ER stress is p53 independent. Moreover, in orthotopic carcinogen-induced rat colorectal carcinoma model, we found that 3-AWA inhibits colorectal tumor growth and formation of colorectal polyps at a tolerable dose, similar to the first-line drug for colorectal cancer-5-fluorouracil.

Correspondence analysis to evaluate the transmission of Staphylococcus aureus strains in two New York State maximum-security prisons.

Prisons/jails are thought to amplify the transmission of Staphylococcus aureus (SA) particularly methicillin-resistant SA infection and colonisation. Two independently pooled cross-sectional samples of detainees being admitted or discharged from two New York State maximum-security prisons were used to explore this concept. Private interviews of participants were conducted, during which the anterior nares and oropharynx were sampled and assessed for SA colonisation. Log-binomial regression and correspondence analysis (CA) were used to evaluate the prevalence of colonisation at entry as compared with discharge. Approximately 51% of admitted (N = 404) and 41% of discharged (N = 439) female detainees were colonised with SA. Among males, 59% of those admitted (N = 427) and 49% of those discharged (N = 393) were colonised. Females had a statistically significant higher prevalence (1·26: P = 0·003) whereas males showed no significant difference (1·06; P = 0·003) in SA prevalence between entry and discharge. CA demonstrated that some strains, such as spa types t571 and t002, might have an affinity for certain mucosal sites. Contrary to our hypothesis, the prison setting did not amplify SA transmission, and CA proved to be a useful tool in describing the population structure of strains according to time and/or mucosal site.

Snakebite mediated acute kidney injury, prognostic predictors, oxidative and carbonyl stress: A prospective study.

Snake bite is an occupational hazard in India and important preventable cause of acute kidney injury (AKI). This study was done to estimate the magnitude of snakebite-induced AKI (SAKI) who required renal replacement therapy, prognostic predictors, and final outcome, and to measure the oxidative and carbonyl stress (CS) level in SAKI patient who underwent hemodialysis (HD). All SAKI patients dialyzed between April 2010 and July 2011 in NRS Medical College were included. Demographical, clinical, and biochemical data were analyzed, and patients are followed to discharge or death. Oxidative and CS markers (advanced oxidation protein product [AOPP], advanced glycation end product, pentosidine, dityrosine, thioberbituric acid reactive substance, and methylglyoxal [MG]) were measured in 48 SAKI patient requiring HD. About 155 SAKI patients (M: F 2.2:1) received HD. Of them. The age was 36.2 (range 4-74) years. The most common site of the bite was lower limb (88.7%). Oliguria and bleeding manifestation were the common presentation. Hypotension was found in 52 (33.5%) cases, cellulitis and inflammation were found in about 63%. Mean creatinine was 4.56 ± 0.24 mg/dl. About 42 (27.1%) had disseminated intravascular coagulation (DIC). 36 (78.2%) had cellulites, 24 (52.2%) had hypotension or shock at initial presentation (P < 0.05), bleeding manifestation was found in 37 (80.4%), and 22 (47.8%) had DIC (P < 0.05). Forty-six (29.7%) patient died. DIC and hypotension/shock at initial presentation came out as an independent predictor of death. Among all markers measured for oxidative and CS (n = 48) AOPP and MG came out as an independent predictor (P < 0.05) of adverse outcome. Hypotension, DIC, AOPP, and MG were a poor prognostic marker in SAKI patients requiring dialysis.

PiSZ alpha-1 antitrypsin deficiency (AATD): pulmonary phenotype and prognosis relative to PiZZ AATD and PiMM COPD.

INTRODUCTION: The PiSZ genotype results in less severe deficiency of alpha-1 antitrypsin (AAT) than PiZZ. Less is known about phenotypic and prognostic features. METHODS: We studied 699 PiZZ, 126 PiSZ and 316 PiMM patients. All AAT deficiency (AATD) patients were augmentation naive. PiSZ were compared with PiZZ patients for clinical phenotype at baseline including CT findings, smoke exposure, progression of lung disease and survival. Similarly, PiSZ patients diagnosed as a result of investigation for possible lung disease (lung index cases) were compared with PiMM. Multivariable analytical techniques and matching (PiSZ to PiZZ) were employed to account for demographic differences. RESULTS: Pack-years smoked and FEV1 exhibited a negative correlation in PiSZ and ZZ patients (both r=-0.43), with emphysema and COPD occurring more commonly in PiZZ patients at <20 pack-year exposure. In multivariable analyses, PiSZ patients were less likely to have emphysema (p<0.01) and had better survival than PiZZ (p=0.017), but lung function decline did not differ significantly. 42% of PiSZ patients had upper-zone-dominant emphysema on CT scan. Analyses of AAT level confirmed a critical threshold at 11 µM, particularly with regard to phenotypes classical of PiZZ AATD.Significant baseline differences suggested that PiSZ had presented earlier to health services than PiMM. Once this was accounted for, risk of emphysema did not differ between PiSZ and PiMM although survival was lower in PiMM patients (p<0.01). CONCLUSIONS: PiSZ patients are less susceptible to cigarette smoke than PiZZ. The pattern of emphysema may be similar at diagnosis to usual COPD.

Pneumocystis jiroveci outbreak in a renal transplant center: Lessons learnt.

Pneumocystis jiroveci pneumonia (PJP) is an important opportunistic infection in immunosuppressed hosts. At our center, nine transplant recipients developed PJP over a 4-month period. The median time from transplant was 56 months and none of them was on cotrimoxazole prophylaxis at the time of developing the infection. Over half had been admitted to the renal transplant ward for unrelated indications and contracted the infection in-hospital. Diagnosis was based on microbiological demonstration of P. jiroveci in sputum and/or bronchoalveolar lavage in symptomatic patients. Atypical clinical and radiological signs were common with poor correlation of symptoms to computed tomography findings. Cotrimoxazole therapy was effective; however, patients with pre-existing graft dysfunction developed hyperkalemia commonly (50%). Alternative treatment with clindamycin and primaquine combination was equally effective. Early diagnosis and prompt treatment resulted in low mortality rate (11%). The outbreak was halted after universal use of cotrimoxazole prophylaxis to all patients admitted to the renal transplant ward. We report the first ever outbreak of PJP in Indian renal transplant recipients with possible inter-human transmission of infection in admitted patients.

Urinary ascites after an alcohol binge: An uncommon treatable cause of acute kidney injury.

A 38-year-old male presented after a binge of alcohol with acute onset, rapidly progressive distension of abdomen, hematuria, oligoanuria and dialysis dependent renal failure. Evaluation revealed ascitic fluid with high creatinine and computed tomography cystogram showed contrast leak into the peritoneum. Retrograde cystoscopy confirmed rupture of the bladder. He had prompt diuresis after indwelling Foley's catheter was placed. By 2 weeks, he had recovered renal function completely. A high index of suspicion can make an early diagnosis and avoid unnecessary investigations. The mechanism of spontaneous rupture of bladder after an alcohol binge is discussed.

An in vivo role for Rho kinase activation in the tumour vascular disrupting activity of combretastatin A-4 3-O-phosphate.

BACKGROUND AND PURPOSE: Combretastatin A-4 3-O-phosphate (CA4P) is in clinical trial as a tumour vascular disrupting agent (VDA) but the cause of blood flow disruption is unclear. We tested the hypothesis that activation of Rho/Rho kinase (ROCK) is fundamental to the effects of this drug in vivo. EXPERIMENTAL APPROACH: Mouse models of human colorectal carcinoma (SW1222 and LS174T) were used. Effects of the ROCK inhibitor, Y27632, alone or in combination with CA4P, on ROCK activity, vascular function, necrosis and immune cell infiltration in solid tumours were determined. Mean arterial BP (MABP) was measured to monitor systemic interactions and the vasodilator, hydralazine, was used to control for the hypotensive effects of Y27632. KEY RESULTS: Y27632 caused a rapid drop in blood flow in SW1222 tumours, with recovery by around 3 h, which was paralleled by MABP changes. Y27632 pretreatment reduced CA4P-induced ROCK activation and partially blocked CA4P-induced tumour vascular effects, in both tumour types. Y27632 also partially inhibited CA4P-induced tumour necrosis and was associated with reduced immune cell infiltration in SW1222 tumours. Hydralazine caused a similar hypotensive effect as Y27632 but had no protective effect against CA4P treatment. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that ROCK activity is critical for full manifestation of the vascular activity of CA4P in vivo, providing the evidence for pharmacological intervention to enhance the anti-tumour efficacy of CA4P and related VDAs.

Modelling system dynamics and phytoplankton diversity at Ranchi lake using the carbon and nutrient mass balance equations.

Modelling system dynamics in a hyper-eutrophic lake is quite complex especially with a constant influx of detergents and sewage material which continually changes the state variables and interferes with the assessment of the chemical rhythm occurring in polluted conditions as compared to unpolluted systems. In this paper, a carbon and nutrient mass balance model for predicting system dynamics in a complex environment was studied. Studies were conducted at Ranchi lake to understand the altered environmental dynamics in hyper-eutrophic conditions, and its impact on the plankton community. The lake was monitored regularly for five years (2007 - 2011) and the data collected on the carbon flux, nitrates, phosphates and silicates was used to design a mass balance model for evaluating and predicting the system. The model was then used to correlate the chemical rhythm with that of the phytoplankton dynamics and diversity. Nitrates and phosphates were not limiting (mean nitrate and phosphate concentrations were 1.74 and 0.83 mgl⁻¹ respectively). Free carbon dioxide was found to control the system and, interacting with other parameters determined the diversity and dynamics of the plankton community. N/P ratio determined which group of phytoplankton dominated the community, above 5 it favoured the growth of chlorophyceae while below 5 cyanobacteria dominates. TOC/TIC ratio determined the abundance. The overall system was controlled by the availability of free carbon dioxide which served as a limiting factor.

Chloroplast pigments, proteins, lipid peroxidation and activities of antioxidative enzymes during maturation and senescence of leaves and reproductive organs of Cajanus cajan L.

A comparative investigation was undertaken with pigeon pea leaves and attached flower buds/flowers/pods during their developmental stages including senescence in a natural system in experimental plots. Alterations in chloroplast pigments, total soluble proteins, lipid peroxidation, malondialdehyde (MDA) content and activities of guaiacol peroxidase (POD, EC 1.11.1.7) and superoxide dismutase (SOD, EC 1.15.1.1) were studied at 5-day interval from initial to 40-day stage. Chloroplast pigments and proteins of leaves increased upto 15 and 20-day stages respectively followed by a steady decline. Reproductive parts, however, exhibited rise in chloroplast pigments upto 25-day and protein till last stage as developing pods gain the amount from the senescing leaves which are nearest to them. Senescing leaves show very high POD activity than the developing and senescing pods and POD appears to be associated with chlorophyll degradation. Considerably higher activity and amount of LOX and MDA respectively have been noticed in senescing leaves than in flowers and pods. Increase in SOD activity during early stage of leaf growth and maturation indicates protective role that declined at senescent stages. Pods are unique in having very high SOD activity, only last stage of senescence does show a decline.