We have previously described strong associations between frailty, a measure of physiologic reserve initially described and validated in geriatrics, and early hospital readmission as well as delayed graft function. The goal of this study was to estimate its association with postkidney transplantation (post-KT) mortality. Frailty was prospectively measured in 537 KT recipients at the time of transplantation between November 2008 and August 2013. Cox proportional hazards models were adjusted for confounders using a novel approach to substantially improve model efficiency and generalizability in single-center studies. We precisely estimated the confounder coefficients using the large sample size of the Scientific Registry of Transplantation Recipients (n = 37 858) and introduced these into the single-center model, which then estimated the adjusted frailty coefficient. At 5 years, the survivals were 91.5%, 86.0% and 77.5% for nonfrail, intermediately frail and frail KT recipients, respectively. Frailty was independently associated with a 2.17-fold (95% CI: 1.01–4.65, p = 0.047) higher risk of death. In conclusion, regardless of age, frailty is a strong, independent risk factor for post-KT mortality, even after carefully adjusting for many confounders using a novel, efficient statistical approach.
The aim of study was to develop self-nanoemulsifying pellets (SNEP) for oral delivery of poorly water soluble drug, repaglinide (RPG). Solubility of RPG in oily phases and surfactants was determined to identify components of self-nanoemulsifying drug delivery system (SNEDDS). The surfactants and cosurfactants were screened for their ability to emulsify oily phase. Ternary phase diagrams were constructed to identify nanoemulsification area for the selected systems. SNEDDS formulations with globule size less than 100 nm were evaluated for in vivo anti-hyperglycemic activity in neonatal streptozotocin rat model. A significant reduction in glucose levels was produced by optimized SNEDDS formulation in comparison to the control group. The optimized SNEDDS formulations were pelletized via extrusion/spheronization technique using microcrystalline cellulose and lactose. SNEP were characterized by X-ray powder diffraction and scanning electron microscopy. X-ray diffraction study indicated loss of crystallinity of RPG in SNEP. The SNEP exhibited good flow properties, mechanical strength and formed nanoemulsion with globule size less than 200 nm. SNEP showed in vitro release of more than 80% RPG in 10 min which was significantly higher than RPG containing reference pellets. In conclusion, our studies illustrated that RPG, a poorly water soluble drug can be successfully formulated into SNEP which can serve as a promising system for the delivery of poorly water soluble drugs.
anti-hyperglycemic activity; extrusion/spheronization; repaglinide; self-nanoemulsifying pellets
We sought to describe the epidemiology and risk factors for Clostridium difficile infection (CDI) among kidney transplant recipients (KTR) between 1 January 2008 and 31 December 2010.
A single-institution retrospective study was conducted among all adgbult KTR with CDI, defined as a positive test for C. difficile, by a cell cytotoxic assay for C. difficile toxin A or B or polymerase chain reaction test for toxigenic C. difficile.
Among 603 kidney transplants performed between 1 January 2008 and 31 December 2010, 37 (6.1%) patients developed CDI: 12 (of 128; 9.4%) high-risk (blood group incompatible and/or anti-human leukocyte antigen donor-specific antibodies) vs. 25 (of 475; 5.3%, P=0.08) standard-risk patients. The overall rate of CDI increased from 3.7% in 2008 to 9.4% in 2010 (P = 0.05). The median time to CDI diagnosis was 9 days, with 27 (73.0%) patients developing CDI within the first 30 days after their transplant, and 14 (51.8%) developing CDI within 7 days. A case-control analysis of 37 CDI cases and 74 matched controls demonstrated the following predictors for CDI among KTR: vancomycin-resistant Enterococcus colonization before transplant (odds ratio [OR]: 3.6, P=0.03), receipt of an organ from a Centers for Disease Control high-risk donor (OR: 5.9, P =0.006), and administration of high-risk antibiotics within 30 days post transplant (OR: 6.6, P=0.001).
CDI remains a common early complication in KTR, with rates steadily increasing during the study period. Host and transplant-related factors and exposure to antibiotics appeared to significantly impact the risk for CDI among KTR.
Clostridium difficile; kidney transplant
The field of metagenomics is transforming our ability to study the enormous biomass and diversity of microbial life around us. Understanding this microbial world will lead to advances and practical applications in a broad range of fields. Metagenomic sequencing, provides unprecedented access to the thousands (or even millions) of microbes in an environment. Unlike 16S SSU rRNA amplicon sequencing, metagenomic sequencing (whole shotgun sequencing) provides information on not only who is in a community but what they are doing, extending understanding of community structure towards interactions within an environment. This talk will discuss the MG-RAST analysis pipeline starting from quality control assessment to annotation and an overview the interactive tools for comparative analysis. MG-RAST has analyzed over 60,000 WGS and amplicon datasets equaling approximately 20 Tbp.
Sudden cardiac death (SCD) is the most lethal manifestation of heart disease. In an Indian study the SCDs contribute about 10% of the total mortality and SCD post ST elevation myocardial infarction (MI) constitutes for about half of total deaths.
Given the limitations of existing therapy there is a need for an effective, easy to use, broadly applicable and affordable intervention to prevent SCD post MI. Leading cardiologists from all over India came together to discuss the potential role of n-3 acid ethyl esters (90%) of eicosapentaenoic acid (EPA) 460 mg & docosahexaenoic acid (DHA) 380 mg in the management of post MI patients and those with hypertriglyceridemia.
Highly purified & concentrated omega-3 ethyl esters (90%) of EPA (460 mg) & DHA (380 mg) has clinically proven benefits in improving post MI outcomes (significant 15% risk reduction for all-cause mortality, 20% risk reduction for CVD and 45% risk reduction in SCD in GISSI-Prevenzione trial) and in reducing hypertriglyceridemia, and hence, represent an interesting option adding to the treatment armamentarium in the secondary prevention after MI based on its anti-arrhythmogenic effects and also in reducing hypertriglyceridemia.
Sudden cardiac death; Myocardial infarction; Hypertriglyceridemia; Omega-3-acid ethyl esters; Eicosapentaenoic acid & docosahexaenoic acid
To improve the quality of prosthetic vision, it is desirable to understand how targeted retinal neurons respond to stimulation. Unfortunately, the factors that shape the response of a single neuron to stimulation are not well understood. A dense band of voltage gated sodium channels within the proximal axon of retinal ganglion cells is the site most sensitive to electric stimulation, suggesting that band properties are likely to influence the response to stimulation. Here, we examined how three band properties influence sensitivity using a morphologically realistic ganglion cell model in NEURON. Longer bands were more sensitive to short-duration pulses than shorter bands and increasing the distance between band and soma also increased sensitivity. Simulations using the known limits of band length and location resulted in a sensitivity difference of approximately two. Additional simulations tested how changes to sodium channel conductance within the band influenced threshold and found that the sensitivity difference increased to a factor of nearly three. This is close to the factor of 5 difference measured in physiological studies suggesting that band properties contribute significantly to the sensitivity differences found between different types of retinal neurons.
Certain patient groups are predicted to derive significant survival benefit from transplantation with expanded criteria donor (ECD) kidneys. An algorithm published in 2005 by Merion and colleagues characterizes this group: older adults, diabetics and registrants at centers with long waiting times. Our goal was to evaluate ECD listing practice patterns in the United States in terms of these characteristics. We reviewed 142 907 first-time deceased donor kidney registrants reported to United Network for Organ Sharing (UNOS) between 2003 and 2008. Of registrants predicted to benefit from ECD transplantation according to the Merion algorithm (’ECD-benefit’), 49.8% were listed for ECD offers (’ECD-willing’), with proportions ranging from 0% to 100% by transplant center. In contrast, 67.6% of adults over the age of 65 years were ECD-willing, also ranging from 0% to 100% by center. In multivariate models, neither diabetes nor center waiting time was significantly associated with ECD-willingness in any subgroup. From the time of initial registration, irrespective of eventual transplantation, ECD-willingness was associated with a significant adjusted survival advantage in the ECD-benefit group (HR for death 0.88, p < 0.001) and in older adults (HR 0.89, p < 0.001), but an increased mortality in non-ECD-benefit registrants (HR 1.11, p < 0.001). In conclusion, ECD listing practices are widely varied and not consistent with published recommendations, a pattern that may disenfranchise certain transplant registrants.
Deceased donor transplantation; expanded criteria donor; older adults; organ utilization
Relationships between plasma morphine concentrations and neonatal responses to endotracheal tube (ETT) suctioning are unknown in preterm neonates.
Ventilated preterm neonates (n=898) from 16 centres were randomly assigned to placebo (n=449) or morphine (n=449). After an i.v. loading dose (100 µg kg−1), morphine infusions [23–26 weeks postmenstrual age (PMA) 10 µg kg−1 h−1; 27–29 weeks 20 µg kg−1 h−1; and 30–32 weeks 30 µg kg−1 h−1] were established for a maximum of 14 days. Open-label morphine (20–100 µg kg−1) was given for pain or agitation. Morphine assay and neonatal response to ETT suctioning was measured at 20–28 and 70–76 h after starting the drug infusion and at 10–14 h after discontinuation of the study drug. The concentration–effect response was investigated using non-linear mixed effects models.
A total of 5119 data points (1598 measured morphine concentrations and 3521 effect measures) were available from 875 neonates for analysis. Clearance was 50% that of the mature value at 54.2 weeks PMA (CLmat50) and increased from 2.05 litre h−1 70 kg−1 at 24 weeks PMA to 6.04 litre h−1 70 kg−1 at 32 weeks PMA. The volume of distribution in preterm neonates was 190 litre 70 kg−1 (CV 51%) and did not change with age. There was no relationship between morphine concentrations (range 0–440 µg litre−1) and heart rate changes associated with ETT suctioning or with the Premature Infant Pain Profile.
A sigmoid curve describing maturation of morphine clearance is moved to the right in preterm neonates and volume of distribution is increased compared with term neonates. Morphine does not alter the neonatal response to ETT suctioning.
anaesthesia, paediatric; anaesthetic–analgesic regimens; analgesics opioid, morphine; model, pharmacodynamic; model, pharmacokinetic
Several 4-arylidene-2-phenyl-1-(2,4,5-trichlorophenyl)-1H-imidazol-5(4H)-ones (4a-q), N-(4-benzylidene-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-4-chlorobenzamides (5a-o) and N-(4-benzylidene-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)-2,4-dichlorobenzamides (6a-m) were prepared. All newly synthesized compounds have been tested for their antibacterial activity against gram (+)ve and gram (−)ve bacteria and also on different strains of fungi. Introduction of OH, OCH3, NO2, Cl and Br groups to the heterocyclic frame work enhanced antibacterial and antifungal activities.
5-Imidazolinone; antibacterial activity; antifungal activity
Objectives: To report the unexpected absence of HIV-1 antibodies and provirus in the peripheral blood of a 4 year old with previously diagnosed perinatal HIV infection.
Methods: Case study including review of clinic and laboratory records and confirmation of results of HIV-1 enzyme linked immunosorbent assay (ELISA), western blot, and HIV-1 DNA PCR from reference laboratory.
Results: This child had high plasma viral load at the initiation of highly active antiretroviral therapy (HAART) at 10 months of age. Following undetectable HIV viraemia continuously for a 3 year period, he had normal CD4 and immunoglobulin levels. When retested at the request of the parent, HIV-1 ELISA, western blot, and HIV DNA PCR were all negative, raising the question of misdiagnosis and the parental misperception of a "cure." A rebound increase in viral load on cessation of therapy led to these diagnostic tests becoming positive again, with better parental acceptance of the diagnosis and treatment plan.
Conclusions: Patients and providers should exercise caution in interpreting negative serological tests in children on HAART.
Background/aim: Retinoblastoma is the commonest primary intraocular tumour in children. Chemotherapy now plays a big part in the treatment of these tumours. There is not much information about the role of the multidrug resistance proteins (MDR)—P-glycoprotein (P-gp) and vault protein lung resistance protein (LRP)—in retinoblastoma. The authors investigated the expression of P-gp and LRP in retinoblastoma and correlated them clinicopathologically.
Methods: Among 60 retinoblastomas, 40 tumours were not subjected to preoperative or postoperative chemotherapy and 20 tumours were subjected to postoperative chemotherapy. In this cohort 27 tumours had no invasion and 33 tumours had invasion of choroid, optic nerve, and orbit. P-gp and LRP expression were studied by immunohistochemistry. Immunoanalysis was done semiquantitatively.
Results: Among the 60 tumours P-gp was expressed in 23 (38%) tumours and LRP was expressed in 35 (58%). P-gp was expressed in 11/27 (40%) tumours with no invasion and in 12/33 (36%) tumours with invasion. LRP was expressed in 15/27 (55%) tumours with no invasion and in 20/33 (60%) tumours with invasion. Both P-gp and LRP were negative in three tumours with invasion, which had later developed bone marrow metastasis. There was no correlation between P-gp and LRP expression with invasion, differentiation and laterality of the tumours and response to treatment.
Conclusion: Retinoblastoma expresses P-gp and LRP intrinsically before chemotherapy and none of these proteins predicted the response to chemotherapy. Thus, further studies are needed to understand the significance of the expression of the P-gp and LRP proteins in retinoblastoma.
lung resistance protein; P-glycoprtein; multidrug resistance; retinoblastoma; immunohistochemistry; chemotherapy
Methods: Case study including review of clinic records, adherence information, laboratory data, and HIV genotyping results in mother and infant.
Results: Poor maternal adherence to clinic visits and antiretroviral therapy contributed to detectable viraemia antenatally. When tested for the first time at age 6 months, the infant was found to have virus with resistance to multiple drugs. In this case, prophylaxis with zidovudine (AZT) failed to prevent the transmission of the MDR strain.
Conclusions: Perinatal transmission of MDR HIV can occur despite standard peripartum prophylaxis with AZT. Perinatal prophylaxis should be tailored to the mother's treatment history and resistance profile. Paediatric HIV specialists should be prepared to deal with a small, but slowly increasing number of babies with a "nightmare" multidrug resistant virus with limited treatment options.
OBJECTIVES: Changes to the polio vaccination schedule, first to a sequential inactivated poliovirus/oral poliovirus (IPV/OPV) schedule in 1996 and most recently to an all-IPV schedule, require infants to receive additional injections. Some surveys show parental hesitation concerning extra injections, whereas others show that parents prefer multiple simultaneous injections over extra immunization visits. This study describes parental behavior and attitudes about the poliovirus vaccine recommendations and additional injections at the 2- and 4-month immunization visits. METHODS: Beginning July 1, 1996, providers in eight public health clinics in Cobb and Douglas Counties, Georgia, informed parents of polio vaccination options and recommended the IPV/OPV sequential schedule. A cross-sectional clinic exit survey was conducted from July 15, 1996, to January 31, 1997, with parents whose infants (younger than 6 months) were eligible for a first poliovirus vaccination. RESULTS: Of approximately 405 eligible infants, parents of 293 infants were approached for an interview, and 227 agreed to participate. Of those 227 participants, 210 (92%) parents chose IPV for their infant and 17 (8%) chose OPV. Of greatest concern to most parents was vaccine-associated paralytic polio (VAPP) (155, or 68.3%); the next greatest concern was an extra injection (22, or 9.7%). These parental concerns were unrelated to the number of injections the infant actually received. CONCLUSIONS: After receiving information on polio vaccination options and a provider recommendation, parents overwhelmingly chose IPV over OPV. Concern about VAPP was more common than objection to an extra injection. The additional injection that results from using IPV for an infant's first poliovirus vaccination appears to be acceptable to most parents.
Fifty three patients of alcohol dependence were studied for lipid profile at Drug Dependence Treatment Centre, A.I.I.M.S. Statistically significant differences were observed on most of lipid profile indicators when compared to control group. Ratio of Apo A-I & Apo B appeared to be better indicator than Apo A1 or Apo B. The findings of the study are discussed in context of other studies from India and other countries.
lipid; alcohol dependence; specialised setting
During Epstein-Barr virus (EBV) latent infection of B lymphocytes in vitro, six EBV nuclear antigens (EBNAs) are expressed from one of two promoters, Cp and Wp, whose activities are mutually exclusive. Upon infection, Wp is initially active, followed by a switch to Cp for the duration of latency. In this study, the impact on Cp and Wp activity of sequences downstream of the distal EBNA gene promoter, Cp, was assessed in two lymphoblastoid cell lines. Cp activity was detected in constructs extending from just upstream of oriP to the first W1 exon. In contrast, Wp activity required the presence of the next downstream exon, W2. Viral sequences from -2199 to +2680 bp, relative to the Cp transcription start site, were dispensable for Wp activity. Sequences from +155 to +2680 bp, relative to the Cp transcription start site, were dispensable for Cp activity. Deletion of a 200-bp region from +2680 to +2880 bp downstream of Cp decreased both Cp and Wp activity two- to fivefold. Wp activity was also significantly diminished by deletion of the sequences from +2880 to +3000 bp downstream of the Cp transcription initiation site, which encompassed the Wp CCATT box. Based on deletion analyses of 10.3 kb of viral genomic sequence extending from just upstream of oriP to the first Wp, the only deletions which significantly upregulated Wp activity were those which abrogated Cp activity. However, reporter constructs in which the orientation of Cp was reversed displayed Wp activity comparable to that of reporter constructs in which Cp was deleted, even though the steady-state level of Cp-initiated transcripts from the inverted promoter was indistinguishable from that observed with Cp in normal orientation. This is the first direct evidence to support transcriptional interference as the mechanism for the mutually exclusive behavior of Cp and Wp.
Ninety two patients of alcohol dependence were studied for liver function at a specialised drug dependence treatment centre. Biochemical laboratory evidence of liver dysfunction was found in a very large number of patients, including the patients who had no clinical signs or symptoms. The findings from this retrospective study are discussed in the context of the earlier studies from other settings in India.
Liver Dysfunction; Alochol Dependence; Specialised Settings
Percutaneous Transhepatic Biliary Drainage (PTBD) is performed in surgical jaundice to
decompress the biliary tree and improve hepatic functions. However, the risk of sepsis is high
in these patients due to immunosuppression and surgical outcome remains poor. This raises a
question—can we do away with PTBD? To answer this query a study was carried out in 4
groups of patients bearing in mind the high incidence of sepsis and our earlier studies, which
have demonstrated immunotherapeutic potential of Tinospora cordifolia (TC): (A) those
undergoing surgery without PTBD (n = 14), (B) those undergoing surgery after PTBD
(n = 13). The mortality was 57.14% in Group A as compared to 61.54% in Group B. Serial
estimations of bilirubin levels carried out during the course of drainage (3 Wks) revealed a
gradual and significant decrease from 12.52 ± 8.3 mg% to 5.85 ± 3.0 mg%. Antipyrine half-life
did not change significantly (18.35 ± 4.2 hrs compared to basal values 21.96 ± 3.78 hrs). The
phagocytic and intracellular killing (ICK) capacities of PMN remained suppressed (Basal:
22.13 ± 3.68% phago, and 19.1 ± 4.49% ICK; Post drainage: 20 ± 8.48% Phago and 11.15 ± 3.05% ICK). Thus PTBD did not improve the metabolic capacity ofthe liver and mortality was
higher due to sepsis. Group (C) patientg received TC during PTBD (n = 16) and Group (D)
patients received TC without PTBD (n = 14). A significant improvement in PMN functions
occurred by 3 weeks in both groups (30.29 ± 4.68% phago, 30 ± 4.84% ICK in Group C and
30.4 ± 2.99% phago, 27.15 ± 6.19% ICK in Group D). The mortality in Groups C and D was
25% and 14.2% respectively during the preoperative period. There was no mortality after
surgery. It appears from this study that host defenses as reflected by PMN functions play an
important role in influencing prognosis. Further decompression of the biliary tree by PTBD
A method of treatment for cleft lip in children in the first 48 h of life is described and the rationale discussed. My experience over 18 years of the treatment of 300 newborn babies with this deformity is reported.
Eighty three patients with alcoholism were evaluated on several biochemical parameters against seventy five healthy controls. Linear discriminant analysis of three laboratory tests (GGT, GOT and GPT) yielded accurate diagnosis among 63% of the total sample. Sensitivity of these tests was 47% and specificity 80%. Repeat analysis of these three test among 50 alcoholics following thirty days of abstinence showed significant decline of values. Preliminary observation suggests improvement of liver function following cessation of drinking habit.
Formal training programmes in psychiatry for general practitioners (GPs) by Psychiatrists so far reported have involved MBBS graduates. But, a considerable proportion of registered medical practitioners who serve the community are non-MBBS about whose training needs, no experience is yet available. This paper describes a training programme in which an attempt was made to know the training needs of the non-MBBS GPs and also to assess the potential of the previously trained GPs to complementarily assist the psychiatrists in such training programmes.
Aggression is psychological and social menace. The safety of the patient as well as other members of the society is jeopardised due to severe acts of aggression. Hence control of aggressive behaviour gets a priority over various other symptoms. Various treatment modalities have been tried to control the act of aggression. We carried out this study to find out antiaggressive effect of lithium carbonate. Twenty resistant patients of varied psychiatric diagnosis showing aggressive behaviour completed this six weeks outdoor trial. They were started on lithium after initial assessment and were called once a week for evaluation with their relatives for total period of six weeks. Their lithium dose was adjusted and they were assessed on an aggression scale. We found clinical improvement in seventy percent of our cases. Our conclusion was that lithium has a definite role in controlling aggression.
Twenty newborn infants with clinically apparent intraventricular haemorrhage were studied in order to determine the factors associated with mortality and morbidity. Ten survived, 4 without handicap and 2 with only moderate handicap. Maturity and not size of haemorrhage appeared to be the main factor affecting mortality and morbidity at 1 year. Coma longer than 24 hours after intraventricular haemorrhage distinguished survivors with handicap from those without and may be a useful prognostic sign.
Compensatory mutations have been constructed which demonstrate that P8 and P6, two of nine proposed base-pairing interactions characteristic of group I introns, exist within the folded structure of the Tetrahymena thermophila rRNA intervening sequence, and that these secondary structure elements are important for splicing in E. coli and self-splicing in vitro. Two-base mutations in the 5' and 3' segments of P8 are predicted to disrupt P8 and a strong splicing-defective phenotype is observed in each case. A compensatory four-base mutation in P8 is predicted to restore pairing, and results in the restoration of splicing activity to nearly wild type levels. Thus, we conclude that P8 exists and is essential for splicing. In contrast to the strong phenotypes generally exhibited by mutations which disrupt RNA secondary structure, a two-base mutation in L8, the loop between P8[5'] and P8[3'], results in only a slight decrease in splicing activity. We also tested P6, a pairing which is proposed to consist of only two base-pairs in this intron. A two-base mutation in P6[3'] reduces splicing activity to a greater extent than does a two-base mutation in P6[5']. Comparison of the activities of these mutants and a compensatory P6 four-base mutant support the existence of P6, and suggest that the P6 pairing may be particularly important in the exon ligation step of splicing.