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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
11.  NCCTG N0821 (Alliance): A phase II first-line study of pemetrexed, carboplatin and bevacizumab in elderly patients with advanced nonsquamous non-small cell lung cancer with good performance status 
We hypothesized that the combination of bevacizumab, carboplatin and pemetrexed will be an effective first-line regimen in fit, elderly patients with nonsquamous NSCLC.
Treatment-naïve, stage IIIB/IV nonsquamous NSCLC patients ≥ 70 years old with good performance status (ECOG PS 0-1) and adequate organ function were eligible. Carboplatin AUC 6, pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg were administered on day 1 of each 21-day cycle (up to 6 cycles) followed by maintenance pemetrexed and bevacizumab. The primary endpoint of 6-month progression-free survival rate (PFS6) of at least 70% was assessed using a one-stage binomial design. Quality of life (QOL) questionnaires were administered. Polymorphisms in genes encoding relevant proteins (drug targets, transport and metabolism proteins) were correlated with treatment outcome.
Fifty-seven eligible patients were enrolled. Median age was 74.5 years. Median treatment cycles received was 6. The most common grade 3 or higher non-hematologic adverse events were fatigue (26%) and hypertension (11%). 16% had grade 4 neutropenia and 6.5% had grade 4 thrombocytopenia. Three patients experienced grade 3/4 hemorrhagic events (one pulmonary, two gastrointestinal). Primary endpoint of PFS6 was 60% (95% CI: 45.9–73%). Median PFS was 7.0 months (95% CI: 5.9–10.1), median overall survival was 13.7 months (95% CI: 9.4–16.8). Polymorphic KDR and VEGFA variants correlated with survival and toxicity, respectively. There was no significant change in overall QOL scores over time.
This regimen is feasible and did not decrease the QOL in this study population. However, it did not meet the primary efficacy endpoint.
PMCID: PMC4145612  PMID: 25157767
Non-small cell lung cancer; Elderly; Nonsquamous histology; Bevacizumab; Survival
12.  Comparison of younger and older breast cancer survivors and age-matched controls on specific and overall QoL domains 
Cancer  2014;120(15):2237-2246.
Younger survivors (YS) of breast cancer often report more survivorship symptoms such as fatigue, depression, sexual difficulty, and cognitive problems than older survivors (OS). We sought to determine the effect of breast cancer and age at diagnosis on Quality of Life (QoL) by comparing 3 groups: 1) YS diagnosed at age 45 or before, 2) OS diagnosed between 55 and 70, and, 3) for the YS, age-matched controls (AC) of women not diagnosed with breast cancer.
Using a large Eastern Cooperative Oncology Group (ECOG) data base, we recruited 505 YS who were ages 45 or younger when diagnosed and 622 OS diagnosed at 55 to 70. YS, OS, and AC were compared on physical, psychological, social, spiritual, and overall QoL variables.
Compared to both AC and to OS, YS reported more depressive symptoms (p=.005) and fatigue (p<.001), poorer self-reported attention function (p<.001), and poorer sexual function (p<.001) than either comparison group. However, YS also reported a greater sense of personal growth (p<.001) and perceived less social constraint (p<.001) from their partner than AC.
YS reported worse functioning than AC relative to depression, fatigue, attention, sexual function, and spirituality. Perhaps even more important, YS fared worse than both AC and OS on body image, anxiety, sleep, marital satisfaction, and fear of recurrence, indicating that YS are at greater risk for long term QoL problems than survivors diagnosed at a later age.
PMCID: PMC4158315  PMID: 24891116
Young survivors; Quality of Life; Breast Cancer; Comparison of Younger; Comparison of Older Survivors
13.  Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence 
Human mutation  2014;35(8):1011-1020.
Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions and duplications within a ~2 Mb region upstream of SOX9 can recapitulate the CD-DSD phenotype fully or partially, suggesting the existence of an unusually large cis-regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ~1.2-1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harbouring candidate craniofacial regulatory elements. In parallel, ChIP-Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple non-coding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS.
PMCID: PMC4389788  PMID: 24934569
SOX9; craniofacial; enhancer; Pierre Robin; long-range regulation; campomelic dysplasia
14.  Kidney Biomarkers and Differential Diagnosis of Patients With Cirrhosis and Acute Kidney Injury 
Hepatology (Baltimore, Md.)  2014;60(2):622-632.
Acute kidney injury (AKI) is common in patients with cirrhosis and associated with significant mortality. The most common etiologies of AKI in this setting are pre-renal azotemia (PRA), acute tubular necrosis (ATN) and hepatorenal syndrome (HRS). Accurately distinguishing the etiology of AKI is critical as treatments differ markedly. However, establishing an accurate differential diagnosis is extremely challenging. Urinary biomarkers of kidney injury distinguish structural from functional causes of AKI and may facilitate more accurate and rapid diagnoses. We conducted a multi-center, prospective cohort study of patients with cirrhosis and AKI assessing multiple biomarkers for differential diagnosis of clinically adjudicated AKI. Patients (n=36) whose creatinine returned to within 25% of their baseline within 48 hours were diagnosed with PRA. 76 patients with progressive AKI were diagnosed via blinded retrospective adjudication. Of these progressors, thirty-nine (53%) patients were diagnosed with ATN, 19 (26%) with PRA and 16 (22%) with HRS. Median values for neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP) and albumin differed between etiologies and were significantly higher in patients adjudicated with ATN. The fractional excretion of sodium (FENa) was lowest in patients with HRS, 0.10%, but did not differ between those with PRA, 0.27%, or ATN, 0.31%, p=0.54. The likelihood of being diagnosed with ATN increased step-wise with number of biomarkers above optimal diagnostic cutoffs.
Urinary biomarkers of kidney injury are elevated in patients with cirrhosis and AKI due to ATN. Incorporating biomarkers into clinical decision making has the potential to more accurately guide treatment by establishing which patients have structural injury underlying their AKI. Further research is required to document biomarkers specific to HRS.
PMCID: PMC4065642  PMID: 24375576
AKI; etiology; adjudication; urinary markers; ATN
15.  Intramucosal nevus of buccal mucosa in a male child 
BMJ Case Reports  2013;2013:bcr2013010191.
Nevus (mole or birthmark) is a benign tumour of skin and mucosa characterised by the presence of melanin-producing, neuroectodermally derived cells, which can be light to dark brown, reddish brown, blue or flesh coloured. It varies in shape from oval to round. Oral melanotic nevi are uncommon oral lesions causing focal pigmentation. They were found only in 0.1% of population in a large survey. Nevi can be acquired over time or congenital. Acquired nevi are considered benign neoplasms whereas congenital nevi are hamartomas. They are located usually on the palate but less commonly on buccal mucosa, gingiva and lips. This article presents a case report of an intramucosal nevus of buccal mucosa in a 5-year-old boy with its surgical removal.
PMCID: PMC3736153  PMID: 23887988
16.  Chromerid genomes reveal the evolutionary path from photosynthetic algae to obligate intracellular parasites 
eLife  null;4:e06974.
The eukaryotic phylum Apicomplexa encompasses thousands of obligate intracellular parasites of humans and animals with immense socio-economic and health impacts. We sequenced nuclear genomes of Chromera velia and Vitrella brassicaformis, free-living non-parasitic photosynthetic algae closely related to apicomplexans. Proteins from key metabolic pathways and from the endomembrane trafficking systems associated with a free-living lifestyle have been progressively and non-randomly lost during adaptation to parasitism. The free-living ancestor contained a broad repertoire of genes many of which were repurposed for parasitic processes, such as extracellular proteins, components of a motility apparatus, and DNA- and RNA-binding protein families. Based on transcriptome analyses across 36 environmental conditions, Chromera orthologs of apicomplexan invasion-related motility genes were co-regulated with genes encoding the flagellar apparatus, supporting the functional contribution of flagella to the evolution of invasion machinery. This study provides insights into how obligate parasites with diverse life strategies arose from a once free-living phototrophic marine alga.
eLife digest
Single-celled parasites cause many severe diseases in humans and animals. The apicomplexans form probably the most successful group of these parasites and include the parasites that cause malaria. Apicomplexans infect a broad range of hosts, including humans, reptiles, birds, and insects, and often have complicated life cycles. For example, the malaria-causing parasites spread by moving from humans to female mosquitoes and then back to humans.
Despite significant differences amongst apicomplexans, these single-celled parasites also share a number of features that are not seen in other living species. How and when these features arose remains unclear. It is known from previous work that apicomplexans are closely related to single-celled algae. But unlike apicomplexans, which depend on a host animal to survive, these algae live freely in their environment, often in close association with corals.
Woo et al. have now sequenced the genomes of two photosynthetic algae that are thought to be close living relatives of the apicomplexans. These genomes were then compared to each other and to the genomes of other algae and apicomplexans. These comparisons reconfirmed that the two algae that were studied were close relatives of the apicomplexans.
Further analyses suggested that thousands of genes were lost as an ancient free-living algae evolved into the apicomplexan ancestor, and further losses occurred as these early parasites evolved into modern species. The lost genes were typically those that are important for free-living organisms, but are either a hindrance to, or not needed in, a parasitic lifestyle. Some of the ancestor's genes, especially those that coded for the building blocks of flagella (structures which free-living algae use to move around), were repurposed in ways that helped the apicomplexans to invade their hosts. Understanding this repurposing process in greater detail will help to identify key molecules in these deadly parasites that could be targeted by drug treatments. It will also offer answers to one of the most fascinating questions in evolutionary biology: how parasites have evolved from free-living organisms.
PMCID: PMC4501334  PMID: 26175406
Chromera velia; Vitrella brassicaformis; evolution of parasitism; malaria; toxoplasmosis; other
17.  Early lymphoid responses and germinal center formation correlates with lower viral load set points and better prognosis of SIV infection 
We have investigated the dynamics of germinal center (GC) formation in lymphoid tissues following acute SIV infection. SIV induces a marked follicular hyperplasia, associated with an aberrant accumulation of non-proliferating TFH cells within GCs, but with an abundance of cells producing IL-21, demonstrating that the mechanisms involved for these 2 events appear independent. IL-21 stimulated TFH cells are considered a critical element for GC formation, a physiological process that seems dysregulated and excessive during HIV/SIV infection, contributing to lymphoid pathogenesis. However, the data suggest that the kinetics by which such GC are formed may be an important predictor of the host-pathogen equilibrium, as early GC hyperplasia was associated with better control of viral replication. In contrast, monkeys undergoing fast disease progression upon infection exhibited an involution of GCs without local IL-21 production in GCs. These results provide important clues regarding GC-related hyper immune responses in the context of disease progression within various individuals during HIV/SIV infection and may open novel therapeutic avenues to limit lymphoid dysfunction, post infection.
PMCID: PMC4084862  PMID: 24907346
Germinal center; Ki67; IL-21; Follicular hyperplasia
18.  Optimizing Cellular Networks Enabled with Renewal Energy via Strategic Learning 
PLoS ONE  2015;10(7):e0132997.
An important issue in the cellular industry is the rising energy cost and carbon footprint due to the rapid expansion of the cellular infrastructure. Greening cellular networks has thus attracted attention. Among the promising green cellular network techniques, the renewable energy-powered cellular network has drawn increasing attention as a critical element towards reducing carbon emissions due to massive energy consumption in the base stations deployed in cellular networks. Game theory is a branch of mathematics that is used to evaluate and optimize systems with multiple players with conflicting objectives and has been successfully used to solve various problems in cellular networks. In this paper, we model the green energy utilization and power consumption optimization problem of a green cellular network as a pilot power selection strategic game and propose a novel distributed algorithm based on a strategic learning method. The simulation results indicate that the proposed algorithm achieves correlated equilibrium of the pilot power selection game, resulting in optimum green energy utilization and power consumption reduction.
PMCID: PMC4500544  PMID: 26167934
19.  Lack of “obesity paradox” in patients presenting with ST-segment elevation myocardial infarction including cardiogenic shock: a multicenter German network registry analysis 
Studies have associated obesity with better outcomes in comparison to non-obese patients after elective and emergency coronary revascularization. However, these findings might have been influenced by patient selection. Therefore we thought to look into the obesity paradox in a consecutive network STEMI population.
The database of two German myocardial infarction network registries were combined and data from a total of 890 consecutive patients admitted and treated for acute STEMI including cardiogenic shock and cardiopulmonary resuscitation according to standardized protocols were analyzed. Patients were categorized in normal weight (≤24.9 kg/m2), overweight (25-30 kg/m2) and obese (>30 kg/m2) according to BMI.
Baseline clinical parameters revealed a higher comorbidity index for overweight and obese patients; 1-year follow-up comparison between varying groups revealed similar rates of all-cause death (9.1 % vs. 8.3 % vs. 6.2 %; p = 0.50), major adverse cardiac and cerebrovascular [MACCE (15.1 % vs. 13.4 % vs. 10.2 %; p = 0.53)] and target vessel revascularization in survivors [TVR (7.0 % vs. 5.0 % vs. 4.0 %; p = 0.47)] with normal weight when compared to overweight or obese patients. These results persisted after risk-adjustment for heterogeneous baseline characteristics of groups. An analysis of patients suffering from cardiogenic shock showed no impact of BMI on clinical endpoints.
Our data from two network systems in Germany revealed no evidence of an “obesity paradox”in an all-comer STEMI population including patients with cardiogenic shock.
PMCID: PMC4498506  PMID: 26162888
Coronary stent; Obesity paradox; Mortality; Cardiogenic shock
20.  Herpesvirus Genome Recognition Induced Acetylation of Nuclear IFI16 Is Essential for Its Cytoplasmic Translocation, Inflammasome and IFN-β Responses 
PLoS Pathogens  2015;11(7):e1005019.
The IL-1β and type I interferon-β (IFN-β) molecules are important inflammatory cytokines elicited by the eukaryotic host as innate immune responses against invading pathogens and danger signals. Recently, a predominantly nuclear gamma-interferon-inducible protein 16 (IFI16) involved in transcriptional regulation has emerged as an innate DNA sensor which induced IL-1β and IFN-β production through inflammasome and STING activation, respectively. Herpesvirus (KSHV, EBV, and HSV-1) episomal dsDNA genome recognition by IFI16 leads to IFI16-ASC-procaspase-1 inflammasome association, cytoplasmic translocation and IL-1β production. Independent of ASC, HSV-1 genome recognition results in IFI16 interaction with STING in the cytoplasm to induce interferon-β production. However, the mechanisms of IFI16-inflammasome formation, cytoplasmic redistribution and STING activation are not known. Our studies here demonstrate that recognition of herpesvirus genomes in the nucleus by IFI16 leads into its interaction with histone acetyltransferase p300 and IFI16 acetylation resulting in IFI16-ASC interaction, inflammasome assembly, increased interaction with Ran-GTPase, cytoplasmic redistribution, caspase-1 activation, IL-1β production, and interaction with STING which results in IRF-3 phosphorylation, nuclear pIRF-3 localization and interferon-β production. ASC and STING knockdowns did not affect IFI16 acetylation indicating that this modification is upstream of inflammasome-assembly and STING-activation. Vaccinia virus replicating in the cytoplasm did not induce nuclear IFI16 acetylation and cytoplasmic translocation. IFI16 physically associates with KSHV and HSV-1 genomes as revealed by proximity ligation microscopy and chromatin-immunoprecipitation studies which is not hampered by the inhibition of acetylation, thus suggesting that acetylation of IFI16 is not required for its innate sensing of nuclear viral genomes. Collectively, these studies identify the increased nuclear acetylation of IFI16 as a dynamic essential post-genome recognition event in the nucleus that is common to the IFI16-mediated innate responses of inflammasome induction and IFN-β production during herpesvirus (KSHV, EBV, HSV-1) infections.
Author Summary
Herpesviruses establish a latent infection in the nucleus of specific cells and reactivation results in the nuclear viral dsDNA replication and infectious virus production. Host innate responses are initiated by the presence of viral genomes and their products, and nucleus associated IFI16 protein has recently emerged as an innate DNA sensor regulating inflammatory cytokines and type I interferon (IFN) production. IFI16 recognizes the herpesvirus genomes (KSHV, EBV, and HSV-1) in the nucleus resulting in the formation of the IFI16-ASC-Caspase-1 inflammasome complex and IL-1β production. HSV-1 genome recognition by IFI16 in the nucleus also leads to STING activation in the cytoplasm and IFN-β production. However, how IFI16 initiates inflammasome assembly and activates STING in the cytoplasm after nuclear recognition of viral genome are not known. We show that herpesvirus genome recognition in the nucleus by IFI16 leads to interaction with histone acetyltransferase-p300 and IFI16 acetylation which is essential for inflammasome assembly in the nucleus and cytoplasmic translocation, activation of STING in the cytoplasm and IFN-β production. These studies provide insight into a common molecular mechanism for the innate inflammasome assembly and STING activation response pathways that result in IL-1β and IFN-β production, respectively.
PMCID: PMC4489722  PMID: 26134128
21.  The Essentiality of Reporting Hardy-Weinberg Equilibrium Calculations in Population-Based Genetic Association Studies 
Cell Journal (Yakhteh)  2015;17(2):187-192.
Population-based genetic association studies have proven to be a powerful tool in identifying genes implicated in many complex human diseases that have a huge impact on public health. An essential quality control step in such studies is to undertake Hardy-Weinberg equilibrium (HWE) calculations. Deviations from HWE in the control group may reflect important problems including selection bias, population stratification and genotyping errors. If HWE is violated, the inferences of these studies may thus be biased. We therefore aimed to examine the extent to which HWE calculations are reported in genetic association studies published in Cell Journal(Yakhteh)(Cell J). Using keywords pertaining to genetic association studies, eleven relevant articles were identified of which ten provided full genotypic data. The genotype distribution of 16 single nucleotide polymorphisms (SNPs) was re-analyzed for HWE by using three different methods where appropriate. HWE was not reported in 60% of all articles investigated. Among those reporting, only one article provided calculations correctly and in detail. Therefore, 90% of articles analyzed failed to provide sufficient HWE data. Interestingly, three articles had significant HWE deviation in their control groups of which one highly deviated from HWE expectations (P= 9.8×10-12). We thus show that HWE calculations are under-reported in genetic association studies published in this journal. Furthermore, the conclusions of the three studies showing significant HWE in their control groups should be treated cautiously as they may be potentially misleading. We therefore recommend that reporting of detailed HWE calculations should become mandatory for such studies in the future.
PMCID: PMC4503832  PMID: 26199897
Genetic Association; Hardy-Weinberg Equilibrium; Population Stratification; Polymorphism; Bias
22.  Lifetime and 5 years risk of breast cancer and attributable risk factor according to Gail model in Iranian women 
Breast cancer is the most commonly diagnosed cancers in women worldwide and in Iran. It is expected to account for 29% of all new cancers in women at 2015. This study aimed to assess the 5 years and lifetime risk of breast cancer according to Gail model, and to evaluate the effect of other additional risk factors on the Gail risk.
Materials and Methods:
A cross sectional study conducted on 296 women aged more than 34-year-old in Qom, Center of Iran. Breast Cancer Risk Assessment Tool calculated the Gail risk for each subject. Data were analyzed by paired t-test, independent t-test, and analysis of variance in bivariate approach to evaluate the effect of each factor on Gail risk. Multiple linear regression models with stepwise method were used to predict the effect of each variable on the Gail risk.
The mean age of the participants was 47.8 ± 8.8-year-old and 47% have Fars ethnicity. The 5 years and lifetime risk was 0.37 ± 0.18 and 4.48 ± 0.925%, respectively. It was lower than the average risk in same race and age women (P < 0.001). Being single, positive family history of breast cancer, positive history of biopsy, and radiotherapy as well as using nonhormonal contraceptives were related to higher lifetime risk (P < 0.05). Moreover, a significant direct correlation observed between lifetime risk and body mass index, age of first live birth, and menarche age. While an inversely correlation observed between lifetimes risk of breast cancer and total month of breast feeding duration and age.
Based on our results, the 5 years and lifetime risk of breast cancer according to Gail model was lower than the same race and age. Moreover, by comparison with national epidemiologic indicators about morbidity and mortality of breast cancer, it seems that the Gail model overestimate the risk of breast cancer in Iranian women.
PMCID: PMC4517323
Breast cancer; Gail model; Iran; malignancy; predictor; risk factors
23.  Antiproliferative effects of curcumin analog L49H37 in pancreatic stellate cells: a comparative study 
Pancreatic cancer is a devastating disease with poor prognosis. It is characterized by a pronounced stromal reaction, which resists chemotherapeutics and effective tumor treatment. Pancreatic stellate cells (PSCs) are mainly responsible for this stromal reaction. Moreover, the cancer and stromal interaction seems to promote tumor proliferation. In this study, L49H37, a newly synthesized curcumin analog, was used as intervention to target the stromal compartment of pancreatic cancer.
In vitro cultures of human PSCs were exposed to curcumin and L49H37. Cell viability as well as growth promoting and survival signaling pathways were monitored by MTT, flow cytometry and western blotting.
Curcumin and L49H37 effectively inhibited proliferation and induced apoptosis in PSCs. L49H37 was found to be more potent at a lower concentration than curcumin in the induction of apoptosis, as evidenced by cleaved poly (ADP-ribose) polymerase (PARP). The cells were retained in the G0/G1 phase of the cell cycle through the downregulation of p21WAF1/Cip1. L49H37 significantly decreased the phosphorylation of extracellular signal regulated kinase ½ (ERK½).
The results indicate that curcumin analog L49H37 exhibits more potent inhibitory effects than curcumin itself at a lower concentration, which suggests that it may have a potential for further evaluation of its use against pancreatic adenocarcinoma, either as a single agent but, more probable, as part of a combination regimen.
PMCID: PMC4480178  PMID: 26129848
Pancreatic cancer; stroma; cleaved PARP; p21WAF1/Cip1
24.  Human T-cell leukemia virus type-I Tax induces the expression of CD83 on T cells 
Retrovirology  2015;12:56.
CD83, a cell surface glycoprotein that is stably expressed on mature dendritic cells, can be transiently induced on other hematopoietic cell lineages upon cell activation. In contrast to the membrane form of CD83, soluble CD83 appears to be immunosuppressive. In an analysis of the phenotype of leukemic CD4+ T cells from patients with adult T-cell leukemia (ATL), we found that a number of primary CD4+ T cells became positive for cell surface CD83 after short-term culture, and that most of these CD83+ CD4+ T cells were positive for human T-cell leukemia virus type-I (HTLV-I) Tax (Tax1). We hypothesized that Tax1 is involved in the induction of CD83.
We found that CD83 was expressed selectively on Tax1-expressing human CD4+ T cells in short-term cultured peripheral blood mononuclear cells (PBMCs) isolated from HTLV-I+ donors, including ATL patients and HTLV-I carriers. HTLV-I-infected T cell lines expressing Tax1 also expressed cell surface CD83 and released soluble CD83. CD83 can be expressed in the JPX-9 cell line by cadmium-mediated Tax1 induction and in Jurkat cells or PBMCs by Tax1 introduction via infection with a recombinant adenovirus carrying the Tax1 gene. The CD83 promoter was activated by Tax1 in an NF-κB-dependent manner. Based on a previous report showing soluble CD83-mediated prostaglandin E2 (PGE2) production from human monocytes in vitro, we tested if PGE2 affected HTLV-I propagation, and found that PGE2 strongly stimulated expression of Tax1 and viral structural molecules.
Our results suggest that HTLV-I induces CD83 expression on T cells via Tax1 -mediated NF-κB activation, which may promote HTLV-I infection in vivo.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-015-0185-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4487981  PMID: 26129803
CD83; HTLV; Tax; ATL; PGE2
25.  Morphometric Analysis of Axis and Its Clinical Significance -An Anatomical Study of Indian Human Axis Vertebrae 
The atlas and axis vertebra have unique shape and complex relationship with vertebral artery. Fracture of dens of axis accounts for 7-27% of all cervical spine fractures, but surgeries in these regions are highly risky because of the reported incidences of vertebral artery injury.
Aim and Objectives
The study was designed to measure morphometric data of human axis vertebra, of Indian origin. The different anatomical parameters on dry specimen of human axis vertebrae were established and the results were compared with other studies.
Materials and Methods
Thirty intact human axis vertebrae were measured with digital vernier caliper and mini-inclinometer. Various linear and angular parameters of axis were observed.
The mean distance from the midline of body to the tip of transverse process of axis was 29.32 mm on right side and 29.06mm on left side. The mean distance from the midline of body to the lateral most edge of superior articulating facet was 22.8 mm on right side and 22.6 mm on left side. The mean value of anterior and posterior height of axis was 34.33±2.69mm and 30.56±2.78mm respectively. The anterior and posterior height of body of axis was 19.67 mm and 16.67mm respectively. Mean A-P and transverse diameter of inferior surface of axis was 15.42mm and 17.7mm respectively. Mean transverse diameter and mean A-P diameter of odontoid process was 9.32 mm and 10.1 mm respectively. Mean anterior and posterior height of the odontoid process was 14.66 mm and 13.89mm respectively. Mean of dens axis sagittal angle (angle between an axis that was imagined to pass longitudinally through the dens axis and the vertical line on a sagittal plane) was 13.23 degree. The shape of superior articulating facets of C2 varies from oval to circular. In the present study, 84% of SAF were oval and 16% were circular. Inferior articulating facets were circular in shape in 90% cases, and oval in 10% vertebra. Mean pedicle width was 10.07mm on right side and 10.52mm on left side. Mean transverse diameter of vertebral canal was 22.37±1.73mm. Mean of A-P diameter of vertebral canal at inlet was 18.31±2.05mm and mean of A-P diameter of vertebral canal at outlet was 14.84±1.63mm.
These results obtained from this study may be helpful for the surgeons in avoiding and minimizing complications such as vertebral artery injury, cranial nerve damage and injury to other vital structures while doing surgery around cranio-vertebral region.
PMCID: PMC4484059  PMID: 26155467
Axis; Dens; Morphometry; Inferior articulating facet; Superior articulating facet

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