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1.  Potentially avoidable hospitalisation for constipation in Victoria, Australia in 2010–11 
BMC Gastroenterology  2014;14:125.
When primary care of constipation fails, the patient may need emergency hospitalisation for disimpaction. This study aimed to provide population-based data on the number of unplanned admissions and the cost to the healthcare system for constipation in Victoria, Australia in financial year 2010–11.
The Victorian Admitted Episodes Dataset was examined to find the number of emergency hospital separations coded as constipation (ICD-10-AM Code K390). An estimate of costs was determined from the number of weighted inlier equivalent separations (WIES) multiplied by the WEIS price, used by the Victorian Government for funding purposes.
There were 3978 emergency separations for constipation in Victoria in 2010–2011, 92% in public hospitals. Fifty-five percent were female and 38% > 75 years old. One third stayed overnight and 1/3 more than 1 day. The emergency bed day rate was 7.1 per 10,000 of population. The estimate of cost, based on WEIS, was approximately $8.3 million. Potential savings could be made by reducing the number of separations in 6 Local Government Areas (LGAs).
This study shows that the burden (in number of admissions, emergency bed days and overall direct costs) in managing emergency admissions for constipation in Victoria, Australia, is very significant and likely to be similar in other developed countries. Improved primary healthcare and alternative ways to achieve faecal disimpaction without emergency admission could save the public health system a proportion of this $8.3 million.
PMCID: PMC4105390  PMID: 25015386
2.  Critical appraisal of axitinib in the treatment of advanced renal cell carcinoma 
A growing understanding of the biology of renal cell carcinoma (RCC) has led to the development and US Food and Drug Administration approval of seven new molecular targeted agents over the past 7 years. Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors and the latest to join the armamentarium of drugs available for the treatment of metastatic RCC. Despite recent advances in the development of molecular targeted agents for metastatic RCC, the ideal sequencing of these agents remains unclear.
PMCID: PMC3588609  PMID: 23467578
metastatic RCC; vascular endothelial growth factor receptor inhibitor; molecular targeted agent; clear-cell carcinoma
3.  Patient characteristics associated with hospitalisations for ambulatory care sensitive conditions in Victoria, Australia 
Ambulatory Care Sensitive Conditions (ACSCs) are those for which hospitalisation is thought to be avoidable with the application of preventive care and early disease management, usually delivered in a primary care setting. ACSCs are used extensively as indicators of accessibility and effectiveness of primary health care. We examined the association between patient characteristics and hospitalisation for ACSCs in the adult and paediatric population in Victoria, Australia, 2003/04.
Hospital admissions data were merged with two area-level socioeconomic indexes: Index of Socio-Economic Disadvantage (IRSED) and Accessibility/Remoteness Index of Australia (ARIA). Univariate and multiple logistic regressions were performed for both adult (age 18+ years) and paediatric (age <18 years) groups, reporting odds ratios (OR) and 95% confidence intervals (CI) for a number of predictors of ACSCs admissions compared to non-ACSCs admissions.
Predictors were much more strongly associated with ACSCs admissions compared to non-ACSCs admissions in the adult group than for the paediatric group with the exception of rurality. Significant adjusted ORs in the adult group were 1.06, 1.15, 1.13, 1.06 and 1.11 for sex, rurality, age, IRSED and ARIA variables, and 1.34, 1.04 and 1.09 in the paediatric group for rurality, IRSED and ARIA, respectively.
Disadvantaged paediatric and adult population experience more need of hospital care for ACSCs. Access barriers to primary care are plausible causes for the observed disparities. Understanding the characteristics of individuals experiencing access barriers to primary care will be useful for developing targeted interventions meeting the unique ambulatory needs of the population.
PMCID: PMC3549737  PMID: 23259969
Ambulatory care; Primary care; Socio-demographic; Access barriers
4.  Molecular epidemiology of β-thalassemia in Pakistan: Far reaching implications 
Indian Journal of Human Genetics  2012;18(2):193-197.
β -Thalassaemia, an autosomal recessive hemoglobinopathy, is one of the commonest genetically transmitted disorders throughout the world. Collective measures including carrier identification, genetic counseling and prenatal diagnosis are required for preventing β-thalassemia.
To achieve this objective, Identification of the spectrum of genetic mutations, especially for various ethnic backgrounds in Pakistan. Therefore, we designed a cross sectional prospective study to identify the frequency of various gene mutations in different ethnic groups of Pakistan.
Over a 5-year period, DNA from 648 blood samples {including specimens of chorionic villus sampling (CVS)} were analyzed for the twelve most common β-thalassemia mutations found in the Pakistani population by a Multiplex amplification refractory mutation system (ARMS). Each sample was analyzed for the mutation as well as the normal gene, appropriate with negative and positive controls, and reagent blanks.
Out of 648 samples mutations were identified in 640 (98.75%) samples by multiplex ARMS. 8 common β-thalassemia mutations were identified in 8 different ethnic groups accounting for 93.9% of the β-thalasemia alleles.
Based on the outcome of this study a cost effective proposal is formulated for detection of β-thalassemia mutations.
PMCID: PMC3491293  PMID: 23162295
Gene frequency; genetic epidemiology; prenatal diagnosis; thalassaemia prevention
5.  Devolution and public perceptions and experience of health services in Pakistan: linked cross sectional surveys in 2002 and 2004 
BMC Health Services Research  2011;11(Suppl 2):S4.
The government of Pakistan introduced devolution in 2001. Responsibility for delivery of most health services passed from provincial to district governments. Two national surveys examined public opinions, use, and experience of health services in 2001 and 2004, to assess the impact of devolution on these services from the point of view of the public.
A stratified random cluster sample drawn in 2001 and revisited in 2004 included households in all districts. Field teams administered a questionnaire covering views about available health services, use of government and private health services, and experience and satisfaction with the service. Focus groups in each community discussed reasons behind the findings, and district nazims (elected mayors) and administrators commented about implementation of devolution. Multivariate analysis, with an adjustment for clustering, examined changes over time, and associations with use and satisfaction with services in 2004.
Few of 57,321 households interviewed in 2002 were satisfied with available government health services (23%), with a similar satisfaction (27%) among 53,960 households in 2004. Less households used government health services in 2004 (24%) than in 2002 (29%); the decrease was significant in the most populous province. In 2004, households were more likely to use government services if they were satisfied with the services, poorer, or less educated. The majority of users of government health services were satisfied; the increase from 63% to 67% between 2002 and 2004 was significant in two provinces. Satisfaction in 2004 was higher among users of private services (87%) or private unqualified practitioners (78%). Users of government services who received all medicines from the facility or who were given an explanation of their condition were more likely to be satisfied. Focus groups explained that people avoid government health services particularly because of bad treatment from staff, and unavailable or poor quality medicines. District nazims and administrators cited problems with implementation of devolution, especially with transfer of funds.
Under devolution, the public did not experience improved government health services, but devolution was not fully implemented as intended. An ongoing social audit process could provide a basis for local and national accountability of health services.
PMCID: PMC3332563  PMID: 22375682
6.  Male responsibility and maternal morbidity: a cross-sectional study in two Nigerian states 
BMC Health Services Research  2011;11(Suppl 2):S7.
Nigeria continues to have high rates of maternal morbidity and mortality. This is partly associated with lack of adequate obstetric care, partly with high risks in pregnancy, including heavy work. We examined actionable risk factors and underlying determinants at community level in Bauchi and Cross River States of Nigeria, including several related to male responsibility in pregnancy.
In 2009, field teams visited a stratified (urban/rural) last stage random sample of 180 enumeration areas drawn from the most recent censuses in each of Bauchi and Cross River states. A structured questionnaire administered in face-to-face interviews with women aged 15-49 years documented education, income, recent birth history, knowledge and attitudes related to safe birth, and deliveries in the last three years. Closed questions covered female genital mutilation, intimate partner violence (IPV) in the last year, IPV during the last pregnancy, work during the last pregnancy, and support during pregnancy. The outcome was complications in pregnancy and delivery (eclampsia, sepsis, bleeding) among survivors of childbirth in the last three years. We adjusted bivariate and multivariate analysis for clustering.
The most consistent and prominent of 28 candidate risk factors and underlying determinants for non-fatal maternal morbidity was intimate partner violence (IPV) during pregnancy (ORa 2.15, 95%CIca 1.43-3.24 in Bauchi and ORa 1.5, 95%CI 1.20-2.03 in Cross River). Other spouse-related factors in the multivariate model included not discussing pregnancy with the spouse and, independently, IPV in the last year. Shortage of food in the last week was a factor in both Bauchi (ORa 1.66, 95%CIca 1.22-2.26) and Cross River (ORa 1.32, 95%CIca 1.15-1.53). Female genital mutilation was a factor among less well to do Bauchi women (ORa 2.1, 95%CIca 1.39-3.17) and all Cross River women (ORa 1.23, 95%CIca 1.1-1.5).
Enhancing clinical protocols and skills can only benefit women in Nigeria and elsewhere. But the violence women experience throughout their lives – genital mutilation, domestic violence, and steep power gradients – is accentuated through pregnancy and childbirth, when women are most vulnerable. IPV especially in pregnancy, women's fear of husbands or partners and not discussing pregnancy are all within men's capacity to change.
PMCID: PMC3332566  PMID: 22375828
7.  Molecular epidemiology of β-thalassemia in Pakistan: far reaching implications 
β-thalassaemia, an autosomal recessive hemoglobinopathy, is one of the commonest genetically transmitted disorders throughout the world. Collective measures including carrier identification, genetic counseling and prenatal diagnosis are required for preventing β-thalassemia. To achieve this objective, Identification of the spectrum of genetic mutations, especially for various ethnic backgrounds in Pakistan is necessary. Therefore, we designed a cross sectional prospective study to identify the frequency of various gene mutations in different ethnic groups of Pakistan. Over a 5-year period, DNA from 648 blood samples [including specimens of chorionic villus sampling (CVS)] were analyzed for the twelve most common β-thalassemia mutations found in the Pakistani population by a Multiplex amplification refractory mutation system (ARMS). The most common mutation identified was Intervening Sequence 1-5 (IVS 1-5 (G-C)); accounting for 40.89% mutated alleles, and was represented in all ethnic groups. 15.7 % of the β-thalassemia alleles were found to have Frameshift 8-9 (Fr 8-9) as the second most common mutation Other common genetic defects responsible for β-thalassemia: IVS 1-1 (G-T) was found in 8.17%, Codon-30 (Cd-30 (G-C)) 8.02%, Codon-5(Cd-5 (-CT)) contributed 2.16% and Deletion 619 base pair (Del 619bp) affected 11.11% were found in Pakistan. This large study adds to the pre-existing data in Pakistan. Knowledge of the predominant mutation in a given ethnic group will not only help in developing a short panel of (population-specific) primers of mutations thereby providing a cost-effective method for prenatal diagnosis and also help the clinicians to counsel regarding blood transfusion regimen/ pregnancy termination.
PMCID: PMC3243455  PMID: 22200002
β-thalassemia; genetic mutations; molecular epidemiology; Pakistan
8.  Image-guided fine-needle aspiration cytology of ovarian tumors: An assessment of diagnostic efficacy 
Image-guided fine-needle aspiration cytology (FNAC) of ovarian lumps is being increasingly used for the successful diagnosis of ovarian tumors, although borderline cases may be difficult to diagnose by this method.
To demonstrate the efficacy of image-guided FNAC in diagnosing ovarian tumors (benign and malignant) and to evaluate the usefulness of cytology as a mode of easy and rapid diagnosis of ovarian lumps.
Materials and Methods:
The study was conducted on 42 female patients. Clinical evaluation and relevant investigations were carried out. Diagnosis was established by FNAC performed under image guidance (ultrasonography/computed tomography). The cytological diagnosis was confirmed by histopathological examination.
Cytological diagnosis was rendered on all the 42 ovarian lesions, with a correct diagnosis in 34 cases, resulting in a diagnostic accuracy of 80.9%. Most of the cases with discordant diagnoses were surface epithelial tumors of low malignant potential and required histopathological examination for a final diagnosis.
Image-guided FNAC is an inexpensive, rapid and fairly accurate procedure for the diagnosis of ovarian lesions. It provides a safe alternative to the more expensive, time consuming and cumbersome surgical route to diagnosis.
PMCID: PMC2983081  PMID: 21187883
Image-guided FNAC; ovarian tumors; histopathology; diagnostic accuracy
9.  One size does not fit all: local determinants of measles vaccination in four districts of Pakistan 
Rates of childhood vaccination in Pakistan remain low.There is continuing debate about the role of consumer and service factors in determining levels of vaccination in developing countries.
In a stratified random cluster sample of census enumeration areas across four districts in Pakistan, household interviews about vaccination of children and potentially related factors with 10,423 mothers of 14,542 children preceded discussion of findings in separate male and female focus groups. Logistic regression analyses helped to clarify local determinants of measles vaccination.
Across the four districts, from 17% to 61% of mothers had formal education and 50% to 86% of children aged 12-23 months had received measles vaccination. Children were more likely to receive measles vaccination if the household was less vulnerable, if their mother had any formal education, if she knew at least one vaccine preventable disease, and if she had not heard of any bad effects of vaccination. Discussing vaccinations in the family was strongly associated with vaccination. In rural areas, living within 5 km of a vaccination facility or in a community visited by a vaccination team were associated with vaccination, as was the mother receiving information about vaccinations from a visiting lady health worker. Focus groups confirmed personal and service delivery obstacles to vaccination, in particular cost and poor access to vaccination services. Despite common factors, the pattern of variables related to measles vaccination differed between and within districts.
Vaccination coverage varies from district to district in Pakistan and between urban and rural areas in any district. Common factors are associated with vaccination, but their relative importance varies between locations. Good local information about vaccination rates and associated variables is important to allow effective and equitable planning of services.
PMCID: PMC3226236  PMID: 19828062
10.  Development of Novel Tumor-Targeted Theranostic Nanoparticles Activated by Membrane-Type Matrix Metalloproteinases for Combined Cancer Magnetic Resonance Imaging and Therapy 
A major drawback with current cancer therapy is the prevalence of unrequired dose-limiting toxicity to non-cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, we describe the design and characterization of novel multifunctional “theranostic” nanoparticles (TNPs) for enzyme-specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery.
TNPs were synthesized by conjugation of FDA-approved iron oxide nanoparticles ferumoxytol to an MMP-activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIO-ICTs (TNPs). Significant cell death was observed in TNP-treated MMP-14 positive MMTV-PyMT breast cancer cells in vitro, but not MMP-14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrated significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO-ICTs induced a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death was observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol.
Our findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme-activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.
PMCID: PMC3946335  PMID: 24038954
nanoparticles; iron oxide; cancer therapy; MR imaging; theranostic; MMP-14
11.  Serum bicarbonate may independently predict acute kidney injury in critically ill patients: An observational study 
AIM: To explore whether serum bicarbonate at admission to intensive care unit (ICU) predicted development of acute kidney injury (AKI).
METHODS: We studied all patients admitted to our ICU over a 2 year period (February 2010 to 2012). The ICU has a case mix of medical and surgical patients excluding cardiac surgical, trauma and neurosurgical patients. We analysed 2035 consecutive patients admitted to ICU during the study period. Data were collected by two investigators independently and in duplicate using a standardised spread sheet to ensure accuracy. Ambiguous data were checked for accuracy where indicated. AKI was defined using the Kidney Disease Improving Global Outcomes criteria. Patients were divided into two groups; patients who developed AKI or those who did not, in order to compare the baseline characteristics, and laboratory and physiologic data of the two cohorts. Regression analysis was used to identify if serum bicarbonate on admission predicted the development of AKI.
RESULTS: Of 2036 patients 152 (7.5%) were excluded due to missing data. AKI developed in 43.1% of the patients. The AKI group, compared to the non-AKI group, was sicker based on their lower systolic, diastolic and mean arterial pressures and a higher acute physiology and chronic health evaluation (APACHE) III and SAPS II scores. Moreover, patients who developed AKI had more co-morbidities and a higher proportion of patients who developed AKI required mechanical ventilation. The multi-regression analysis of independent variables showed that serum bicarbonate on admission (OR = 0.821; 95%CI: 0.796-0.846; P < 0.0001), APACHE III (OR = 1.011; 95%CI: 1.007-1.015; P < 0.0001), age (OR = 1.016; 95%CI: 1.008-1.024; P < 0.0001) and presence of sepsis at ICU admission (OR = 2.819; 95%CI: 2.122-23.744; P = 0.004) were each significant independent predictors of AKI. The area under the ROC curve was 0.8 (95%CI: 0.78-0.83), thereby demonstrating that the predictive model has relatively good discriminating power for predicting AKI.
CONCLUSION: Serum bicarbonate on admission may independently be used to make a diagnosis of AKI.
PMCID: PMC4326766
Acute kidney injury; Bicarbonate; Mortality; Sepsis
12.  Assessing post-abortion care in health facilities in Afghanistan: a cross-sectional study 
Complications of abortion are one of the leading causes of maternal mortality worldwide, along with hemorrhage, sepsis, and hypertensive diseases of pregnancy. In Afghanistan little data exist on the capacity of the health system to provide post-abortion care (PAC). This paper presents findings from a national emergency obstetric and neonatal care needs assessment related to PAC, with the aim of providing insight into the current situation and recommendations for improvement of PAC services.
A national Emergency Obstetric and Neonatal Care Needs Assessment was conducted from December 2009 through February 2010 at 78 of the 127 facilities designated to provide emergency obstetric and neonatal care services in Afghanistan. Research tools were adapted from the Averting Maternal Death and Disability Program Needs Assessment Toolkit and national midwifery education assessment tools. Descriptive statistics were used to summarize facility characteristics, and linear regression models were used to assess the factors associated with providers’ PAC knowledge and skills.
The average number of women receiving PAC in the past year in each facility was 244, with no significant difference across facility types. All facilities had at least one staff member who provided PAC services. Overall, 70% of providers reported having been trained in PAC and 68% felt confident in their ability to perform these services. On average, providers were able to identify 66% of the most common complications of unsafe or incomplete abortion and 57% of the steps to take in examining and managing women with these complications. Providers correctly demonstrated an average of 31% of the tasks required for PAC during a simulated procedure. Training was significantly associated with PAC knowledge and skills in multivariate regression models, but other provider and facility characteristics were not.
While designated emergency obstetric facilities in Afghanistan generally have most supplies and equipment for PAC, the capacity of healthcare providers to deliver PAC is limited. Therefore, we strongly recommend training all skilled birth attendants in PAC services. In addition, a PAC training package should be integrated into pre-service medical education.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-015-0439-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4320442  PMID: 25645657
Post-abortion care; Emergency obstetric and neonatal care; Afghanistan
13.  A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma 
Nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase; NOX) is a complex enzyme responsible for increased levels of reactive oxygen species (ROS), superoxide (O2.−). NOX derived O2.− is a key player in oxidative stress and inflammation mediated multiple secondary injury cascades (SIC) following traumatic brain injury (TBI). The O2.− reacts with nitric oxide (NO), produces various reactive nitrogen species (RNS), and contributes to apoptotic cell death. Following a unilateral cortical contusion, young adult rats were killed at various times post injury (1, 3, 6, 12, 24, 48, 72, and 96 h). Fresh tissue from the hippocampus was analyzed for NOX activity, and level of O2.−. In addition we evaluated the translocation of cytosolic NOX proteins (p67Phox, p47Phox and p40Phox) to the membrane, along with total NO and the activation (phosphorylation) of endothelial nitric oxide synthase (p-eNOS). Results show that both enzymes and levels of O2.− and NO have time dependent injury effects in the hippocampus. Translocation of cytosolic NOX proteins into membrane, NOX activity and O2.− were also increased in a time dependent fashion. Both, NOX activity and O2.− were increased at 6 h. Levels of p-eNOS increased within 1 h, with significant elevation of NO at 12 h post TBI. Levels of NO failed to show a significant association with p-eNOS, but did associate with O2.−. NOX up-regulation strongly associated with both the levels of O2.− and also total NO. The initial 12 hours post TBI are very important as a possible window of opportunity to interrupt SIC. It may be important to selectively target the translocation of cytosolic subunits for the modulation of NOX function.
PMCID: PMC4313124  PMID: 25224032
NADPH-oxidase; free radicals; secondary injury cascades; traumatic brain injury
14.  Choroid, Haller's, and Sattler's Layer Thickness in Intermediate Age-Related Macular Degeneration With and Without Fellow Neovascular Eyes 
To analyze choroidal, Sattler's, and Haller's layer thickness maps in age-related macular degeneration (AMD) patients having eyes with bilateral large drusen and pigment changes (intermediate AMD), in patients having intermediate AMD eyes with neovascular fellow eyes (nAMD), and in healthy subjects using three-dimensional (3D) 1060-nm optical coherence tomography (OCT).
Automatically generated choroidal thickness (ChT), retinal thickness, and Sattler's and Haller's layer thickness maps were statistically analyzed in 67 subjects consisting of intermediate AMD (n = 21), intermediate AMD (n = 22) with fellow nAMD eyes (n = 22), and healthy eyes (n = 24) with no age and axial eye length difference between groups of eyes (P > 0.05, ANOVA). Eyes were imaged by a prototype high-speed (60,000 A-scans/s) spectral-domain 3D 1060-nm OCT over a 36° × 36° field of view.
The mean ± SD (μm) subfoveal ChT for healthy subjects and for bilateral intermediate AMD, unilateral intermediate AMD, and their nAMD fellow eyes was 259 ± 95 and 222 ± 98, 149 ± 60, and 171 ± 78, respectively. Choroidal thickness maps demonstrated significant submacular thinning in unilateral intermediate AMD in comparison to healthy and bilateral intermediate AMD eyes (P < 0.001, ANOVA, post hoc P < 0.001 and P < 0.05, respectively). Sattler's and Haller's layers were thinnest in intermediate AMDs that presented with nAMD fellow eyes (Kruskal-Wallis test P < 0.01). For the choroid and its sublayers, there was no difference between the intermediate AMD eyes and their fellow nAMD eyes (paired testing, P < 0.05).
The 3D 1060-nm OCT choroidal imaging visualized significant changes in choroidal, Sattler's, and Haller's layer thickness in relation to the progression of AMD. This may be important for understanding the choroidopathy in the pathophysiology of AMD.
3D 1060-nm OCT mapping visualized significant choroidal, Sattler's, and Haller's layer differences in intermediate age-related macular degeneration (AMD) with and without fellow neovascular AMD that may mark the choroidopathy in the progression of AMD.
PMCID: PMC4132555  PMID: 25052997
age-related macular degeneration; optical coherence tomography; choroidal thickness maps; retina; choroid; retina
15.  Selective Pharmacologic Inhibition of a PASTA Kinase Increases Listeria monocytogenes Susceptibility to β-Lactam Antibiotics 
While β-lactam antibiotics are a critical part of the antimicrobial arsenal, they are frequently compromised by various resistance mechanisms, including changes in penicillin binding proteins of the bacterial cell wall. Genetic deletion of the penicillin binding protein and serine/threonine kinase-associated protein (PASTA) kinase in methicillin-resistant Staphylococcus aureus (MRSA) has been shown to restore β-lactam susceptibility. However, the mechanism remains unclear, and whether pharmacologic inhibition would have the same effect is unknown. In this study, we found that deletion or pharmacologic inhibition of the PASTA kinase in Listeria monocytogenes by the nonselective kinase inhibitor staurosporine results in enhanced susceptibility to both aminopenicillin and cephalosporin antibiotics. Resistance to vancomycin, another class of cell wall synthesis inhibitors, or antibiotics that inhibit protein synthesis was unaffected by staurosporine treatment. Phosphorylation assays with purified kinases revealed that staurosporine selectively inhibited the PASTA kinase of L. monocytogenes (PrkA). Importantly, staurosporine did not inhibit a L. monocytogenes kinase without a PASTA domain (Lmo0618) or the PASTA kinase from MRSA (Stk1). Finally, inhibition of PrkA with a more selective kinase inhibitor, AZD5438, similarly led to sensitization of L. monocytogenes to β-lactam antibiotics. Overall, these results suggest that pharmacologic targeting of PASTA kinases can increase the efficacy of β-lactam antibiotics.
PMCID: PMC4135996  PMID: 24867981
16.  Novel hemostatic patch achieves sutureless epicardial wound closure during complex cardiac surgery, a case report 
Treatment of damaged cardiac tissue in patients with high bleeding tendency can be very challenging, damaged myocardial tissue has a high rupture risk when being sutured subsequently on-going bleeding is a major risk factor for poor clinical outcome. We present a case demonstrating the feasibility in using a novel haemostatic collagen sponge for the management of a myocardial wound. This report is the first description in cardiac surgery where Hemopatch® sponges are used to successfully seal a left ventricle wound. Our patient was diagnosed with endocarditis, had a low pre-operative haemoglobin count and underwent cardiac surgery for multiple valve repairs. The procedure was performed on cardiopulmonary bypass, which meant our patient had to be heparinized. Despite these major risk factors for bleeding Hemopatch® managed to contain bleeding and seal the wound, no sutures were needed.
PMCID: PMC4311444  PMID: 25622592
Hemostasis; Epicardial wound closure; Sutureless repair
17.  Surgical Treatment of Primary Intracardiac Myxoma: 20-Year Experience in “Shahid Modarres Hospital”—A Tertiary University Hospital—Tehran, Iran 
The Scientific World Journal  2015;2015:303629.
Although cardiac tumors are not common they may vary in terms of race and surgical approach in different countries. Method. Patients data of 20 years was collected and evaluated in the “Shahid Modarres Hospital”—a tertiary university hospital—Tehran, Iran. Results. 42 patients with cardiac myxoma (all cases in 20 years) were included in study, 17 males and 25 females, age difference: 13 to 76 years (mean 50.6). Most of patients were in functional classes I, II. 35 patients complained of dyspnea and 3 patients had embolic events. 97.6% of tumors were primary (41 patients) and one tumor was recurrent (2.4%), 85.7% of tumors (36 cases) were located in LA, and 88.1% of tumors (37 cases) were pediculated. 40 patients (95%) had one tumor. In 22 patients (52.3%) after tumor resection septal defects were repaired primarily while in 18 patients (42.8%) the defects were repaired with pericardial patch and In one patient, tumor resected without any septal defect. Mean tumor size was about 5.22 cm (range of 2.2 to 8.2 cm). Postoperatively, 33 patients discharged from hospital without any complication. Discussion. The research reveals that patients' age and gender were similar to that of other studies in other countries while tumor's incidence seems to be higher. 3 patients were diagnosed after remote embolic event and one patient was diagnosed after MI reflecting relatively high tumor complications and late diagnosis. Conclusion. In our study mean time from diagnosis to operation was too long. The patients had more preoperative embolic events and complication. However, size of myxoma and location of that was as same as its rate in the other literature. As recommendation we suggested that in all patients with vague chest pain or remote embolic events cardiac myxomas should be ruled out.
PMCID: PMC4321676
18.  The role of epigenetics in personalized medicine: challenges and opportunities 
BMC Medical Genomics  2015;8(Suppl 1):S5.
Epigenetic alterations are considered to be very influential in both the normal and disease states of an organism. These alterations include methylation, acetylation, phosphorylation, and ubiquitylation of DNA and histone proteins (nucleosomes) as well as chromatin remodeling. Many diseases, such as cancers and neurodegenerative disorders, are often associated with epigenetic alterations. DNA methylation is one important modification that leads to disease. Standard therapies are given to patients; however, few patients respond to these drugs, because of various molecular alterations in their cells, which may be partially due to genetic heterogeneity and epigenetic alterations. To realize the promise of personalized medicine, both genetic and epigenetic diagnostic testing will be required. This review will discuss the advances that have been made as well as the challenges for the future.
PMCID: PMC4315318
19.  Phylogenetic Groups of Escherichia coli Strains from Patients with Urinary Tract Infection in Iran Based on the New Clermont Phylotyping Method 
BioMed Research International  2015;2015:846219.
Objectives. In 2013, Clermont classified E. coli strains into eight phylogenetic groups using a new quadruplex PCR method. The aims of this study were to identify the phylogenetic groups of E. coli based on this method and to assess their antibiotic resistance patterns in Bushehr, Iran. Methods. In this cross-sectional study, 140 E. coli isolates were subjected to phylogenetic typing by a quadruplex PCR method. Antimicrobial susceptibility testing was performed by disk diffusion method. Results. Phylogenetic group B2 was most predominant (39.3%), followed by unknown (27.1%), E (9.3%), C and clade I (each 6.4%), B1 (5%), F and D (each 2.9%), and A (0.7%). The most common antibiotic resistance was related to amoxicillin (82.1%) and the least to meropenem (0.7%). 82.14% of isolates were multiple drug resistant (MDR). Antibiotic resistance was mainly detected in group B2 (50%). Conclusions. Our findings showed the high prevalence of MDR E. coli isolates with dominance of group B2. About 25% of E. coli isolates belong to the newly described phylogroups C, E, F, and clade I. Such studies need to be done also in other regions to provide greater understanding of the antibiotic resistance pattern and the prevalences of different phylogenetic groups.
PMCID: PMC4322292
20.  4-hydroxynonenal in the pathogenesis and progression of human diseases 
Current medicinal chemistry  2014;21(2):230-237.
Metastable aldehydes produced by lipid peroxidation act as 'toxic second messengers' that extend the injurious potential of free radicals. 4-hydroxy 2-nonenal (HNE), a highly toxic and most abundant stable end product of lipid peroxidation, has been implicated in the tissue damage, dysfunction, injury associated with aging and other pathological states such as cancer, Alzheimer, diabetes, cardiovascular and inflammatory complications. Further, HNE has been considered as a oxidative stress marker and it act as a secondary signaling molecule to regulates a number of cell signaling pathways. Biological activity of HNE depends on its intracellular concentration, which can differentially modulate cell death, growth and differentiation. Therefore, the mechanisms responsible for maintaining the intracellular levels of HNE are most important, not only in the defense against oxidative stress but also in the pathophysiology of a number of disease processes. In this review, we discusse the significance of HNE in mediating various disease processes and how regulation of its metabolism could be therapeutically effective.
PMCID: PMC3964795  PMID: 23848536
4-hydroxy 2-nonenal; oxidative stress; cancer; cataract; Alzheimer
21.  3D Hemodynamics in Intracranial Aneurysms: Influence of Size and Morphology 
Journal of magnetic resonance imaging : JMRI  2013;39(1):10.1002/jmri.24110.
To employ 4D-flow MRI for the comprehensive in-vivo analysis of hemodynamics and its relationship to size and morphology of different intracranial aneurysms (IA). We hypothesize that different IA groups, defined by size and morphology, exhibit different velocity fields, wall shear stress and vorticity.
Materials and Methods
4D-flow MRI (spatial resolution=0.99–1.8×0.78–1.46×1.2–1.4mm3, temporal resolution=44–48ms) was performed in 19 IAs (18 patients, age=55.4 ± 13.8 years) with saccular (n=16) and fusiform (n=3) morphology and different sizes ranging from small (n=8, largest dimension=6.2 ± 0.4mm) to large and giant (n=11, 25 ± 7mm). Analysis included quantification of volumetric spatial-temporal velocity distribution, vorticity, and wall shear stress (WSS) along the aneurysms 3D surface.
4D-flow MRI revealed distinct hemodynamic patterns for large/giant saccular aneurysms (Group 1), small saccular aneurysms (Group 2) and large/giant fusiform aneurysms (Group 3). Saccular IA (Groups 1, 2) demonstrated significantly higher peak velocities (p<0.002) and WSS (p<0.001) compared to fusiform aneurysms. Although intra-aneurysmal 3D velocity distributions were similar for Group 1 and 2, vorticity and WSS was significantly (p<0.001) different (increased in Group 1 by 54%) indicating a relationship between IA size and hemodynamics. Group 3 showed reduced velocities (p<0.001) and WSS (p<0.001).
4D flow MRI demonstrated the influence of lesion size and morphology on aneurysm hemodynamics suggesting the potential of 4D-flow MRI to assist in the classification of individual aneurysms.
PMCID: PMC3865211  PMID: 24151067
intracranial aneurysms; 4D flow MRI; hemodynamics; WSS; vorticity; velocity
22.  The challenges and outcomes of living donor kidney transplantation in pediatric and adolescent age group in a developing country: A critical analysis from a single center of north India 
Renal transplantation is the treatment of choice for children with end-stage renal disease (ESRD). We evaluated the outcome of renal transplantation in the pediatric and adolescent age groups in the perspective of a developing country as compared with developed nations while highlighting the challenges we have faced in a pediatric transplant programme.
Materials and Methods:
Seventy live related pediatric and adolescent renal transplantations were reviewed retrospectively. Variables analyzed were etiology of ESRD, pre-transplant renal replacement modality, donor relationship, surgical complications, rejection episodes, immuno-suppression regimens, compliance to immunosuppression, graft survival and overall survival.
The cohort consisted of 13 (18%) female and 57 male (82%) recipients. The mean age was 14 ± 1.4 years. The etiology of ESRD was chronic glomerulonephritis (n = 43), chronic interstitial nephritis (n = 26) and Alport's syndrome (n = 1). Fifty-six (80%) children were on hemo-dialysis and 10 (14%) on peritoneal dialysis prior to transplantation. 80.5% and 61% patients were strictly compliant to immunosuppresant medications at 1 and 5 years. The 1, 3 and 5 year graft survival rates were 94.3%, 89.2% and 66.8%, respectively. The overall survival rates were 95.7%, 96.4% and 94.1% for 1, 3 and 5 years, respectively.
The spectrum of etiology of ESRD differs in our patients from the west, with chronic glomerulonephritis being the most common etiology. Early graft survival is comparable, but the 5-year graft survival is clearly inferior as compared with developed countries.
PMCID: PMC4300569  PMID: 25624573
Challenges; kidney transplantation; pediatric
24.  Diffuse large B-cell non-Hodgkin lymphoma of the prostate presenting with urinary outlet obstruction: A case report 
Urology Annals  2015;7(1):100-103.
Large B-cell non-Hodgkin lymphoma involving the prostate accounts for 0.09% and 0.1% of non-Hodgkin lymphoma. We report a case of prostatic large B-cell non-Hodgkin lymphoma in a 77-year-old male with symptoms of urinary retention most probably due to benign prostate hyperplasia. He underwent multiple needle core biopsies through transrectal ultrasound of the prostate. Histopathological examination of the core biopsies revealed diffuse infiltration by atypical lymphoid cells in the prostatic stroma, which was strongly positive for leukocyte common antigen and CD20. CD3, CK, PSA, BCL2, k-light chain, Cyclin D1 and synaptophysin were negative. Histopathology and immunohistochemical profile in the case was consistent with the diagnosis of diffuse large B-cell non-Hodgkin lymphoma of the prostate.
PMCID: PMC4310096  PMID: 25657557
Immunohistochemistry and urinary retention; lymphoma; prostate
25.  In vivo blockade of the PD-1 pathway using soluble rPD-1-Fc enhances CD4+ and CD8+ T cell responses but has limited clinical benefit 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(12):10.4049/jimmunol.1302044.
The PD-1/PD-Ligand pathway has been shown to limit cell mediated effector functions during chronic viral infections impeding clearance of pathogens. As a strategy to reverse this exhaustion and increase T cell poly-functionality, PD-1 ligands were blocked in vivo using a recombinant macaque PD1-Fc fusion protein (rPD-1-Fc) in SIVmac239 infected rhesus macaques during the early chronic phase of infection, either alone or in combination with ART. In vitro blockade showed improvement of antigen specific CD4+ and CD8+ T cells from monkeys chronically infected with SIV. Of note, a prolonged 5-day blockade in culture was beneficial for both gag specific CD4+ and CD8+ T cells based on proliferation and dual cytokine production. While the in vivo administration of a recombinant rhesus PD-1 Fc fusion protein (rPD-1-Fc) induced enhanced SIV specific CD4 and CD8 T cell proliferation both in the blood and gut, it failed to alter plasma viremia. However, rPD-1-Fc administration in the context of ART interruption induced a significant delay of viral load rebound. In addition, rPD-1-Fc administration in MamuA*001+ monkeys led to both an increase in the frequencies and Ki67 expression of GagCM9+ CD8+ T cells in the blood and rectal mucosa and poly-functionality of GagCM9+ CD8+ T cells in blood. In conclusion, however, our data suggest that PD-1/PD-Ligand blockade using soluble rPD-1-Fc instead of anti-PD1 Mab, while effective in rescuing the effector function of SIV-specific CD4+ and CD8+ T cells during the early chronic phase of infection, has limited clinical benefit.
PMCID: PMC3858463  PMID: 24227774
PD1 blockade; SIVmac239; soluble recombinant PD1 protein

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