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author:("prima, S.")
1.  Apoptosis Induction of Centella Asiatica on Human Breast Cancer Cells 
The present study evaluated the ability of methanolic extract of Centella asiatica (Linn) Urban (Umbelliferae) to induce apoptosis in different cancer cell lines. MCF-7 cells emerged as the most sensitive cell line for in vitro growth inhibitory activity. C. asiatica extract induced apoptosis in MCF-7 cells as indicated by nuclear condensation, increased annexin staining, loss of mitochondrial membrane potential and induction of DNA breaks identified by TUNEL reactivity. It is possible that the use of C. asiatica extract as a component in herbal medicines could be justifiable.
PMCID: PMC2816528  PMID: 20162036
Apoptosis; Cancer; Centella asiatica
2.  Novel Association of Rectal Evacuation Disorder and Rumination Syndrome: Diagnosis, Co-morbidities and Treatment 
Patients with disorders of gastrointestinal function may undergo unnecessary treatment if misdiagnosed as motility disorders.
To report on clinical features, medical, surgical and psychiatric co-morbidities, and prior treatments of a patient cohort diagnosed concurrently with non-psychogenic rumination syndrome and pelvic floor dysfunction (also termed rectal evacuation disorder).
From a consecutive series (1994-2013) of 438 outpatients with rectal evacuation disorders in the practice of a single gastroenterologist at a tertiary care center, 57 adolescents or adults were diagnosed with concomitant rumination syndrome. All underwent formal psychological assessment or completed validated questionnaires.
All 57 patients (95% female) fulfilled Rome III criteria for rumination syndrome; rectal evacuation disorder was confirmed by testing of anal sphincter pressures and rectal balloon evacuation. Prior to diagnosis, most patients underwent multiple medical and surgical treatments (gastrostomy, gastric fundoplication, other gastric surgery, ileostomy, colectomy) for their symptoms. Psychological co-morbidity was identified in 93% of patients. Patients were managed predominantly with psychological and behavioral approaches: diaphragmatic breathing for rumination and biofeedback retraining for pelvic floor dysfunction.
Awareness of concomitant rectal evacuation disorder and rumination syndrome and prompt identification of psychological co-morbidity are keys to instituting behavioral and psychological methods to avoid unnecessary treatment.
PMCID: PMC3979495  PMID: 24724013
rectal evacuation disorder; rumination syndrome; psychological co-morbidities
3.  Design of a Simple Model of Candida albicans Biofilms Formed under Conditions of Flow: Development, Architecture and Drug Resistance 
Mycopathologia  2009;168(3):101-109.
Candida albicans biofilms on most medical devices are exposed to a flow of body fluids that provide water and nutrients to the fungal cells. While C. albicans biofilms grown in vitro under static conditions have been exhaustively studied, the same is not true for biofilms developed under continuous flow of replenishing nutrients. Here, we describe a simple flow biofilm (FB) model that can be built easily with materials commonly available in most microbiological laboratories. We demonstrate that C. albicans biofilms formed using this flow system show increased architectural complexity compared to biofilms grown under static conditions. C. albicans biofilms under continuous medium flow grow rapidly, and by 8 h show characteristics similar to 24 h statically grown biofilms. Biomass measurements and microscopic observations further revealed that after 24 h of incubation, FB were more than 2 fold thicker than biofilms grown under static conditions. Microscopic analyses revealed that the surface of these biofilms was extremely compact and wrinkled, unlike the open hyphal layer typically seen in 24 h static biofilms. Results of antifungal drug susceptibility tests showed that C. albicans cells in FB exhibited increased resistance to most clinically used antifungal agents.
PMCID: PMC3972753  PMID: 19370400
Candida albicans; biofilm; flow; shear stress
4.  Presence of extracellular DNA in the Candida albicans biofilm matrix and its contribution to biofilms 
Mycopathologia  2009;169(5):323-331.
DNA has been described as a structural component of the extracellular matrix (ECM) in bacterial biofilms. In Candida albicans there is a scarce knowledge concerning the contribution of extracellular DNA (eDNA) to biofilm matrix and overall structure.
This work examined the presence and quantified the amount of eDNA in C.albicans biofilm ECM and the effect of DNase treatment and the addition of exogenous DNA on C. albicans biofilm development as indicators of a role for eDNA in biofilm development. We were able to detect the accumulation of eDNA in biofilm ECM extracted from C. albicans biofilms formed under conditions of flow, although the quantity of eDNA detected differed according to growth conditions, in particular with regards to the medium used to grow the biofilms. Experiments with C. albicans biofilms formed statically using a microtiter plate model indicated that the addition of exogenous DNA (>160 ng/ml) increases biofilm biomass and, conversely, DNase treatment (>0.03 mg/ml) decreases biofilm biomass at later time points of biofilm development. We present evidence for the role of eDNA in C. albicans biofilm structure and formation, consistent with eDNA being a key element of the ECM in mature C. albicans biofilms and playing a predominant role in biofilm structural integrity and maintenance.
PMCID: PMC3973130  PMID: 20012895
C. albicans; biofilm; extracellular matrix; extracellular DNA; DNase
5.  Mapping creatinine and cystatin C related white matter brain deficits in the elderly 
Neurobiology of aging  2012;34(4):1221-1230.
Poor kidney function is associated with increased risk of cognitive decline and generalized brain atrophy. Chronic kidney disease impairs glomerular filtration rate (eGFR), and this deterioration is indicated by elevated blood levels of kidney biomarkers such as creatinine (SCr) and cystatin C (CysC). Here we hypothesized that impaired renal function would be associated with brain deficits in regions vulnerable to neurodegeneration.
Using tensor-based morphometry, we related patterns of brain volumetric differences to SCr, CysC levels, and eGFR in a large cohort of 738 (mean age: 75.5±6·8 years; 438 men/300 women) elderly Caucasian subjects scanned as part of the Alzheimer’s Disease Neuroimaging Initiative.
Elevated kidney biomarkers were associated with volume deficits in the white matter region of the brain. All the three renal parameters in our study showed significant associations consistently with a region that corresponds with the anterior limb of internal capsule, bilaterally.
This is the first study to report a marked profile of structural alterations in the brain associated with elevated kidney biomarkers; helping us explain the cognitive deficits.
PMCID: PMC3603573  PMID: 23182131
creatinine; cystatin C; GFR; kidney function; brain volumes; brain structure; brain atrophy; neuroimaging; cognitive deficits
6.  Caloric Restriction Reverses Obesity Induced Mammary Gland Inflammation in Mice 
Obesity is a risk factor for the development of hormone receptor-positive breast cancer in post-menopausal women. Estrogen synthesis is catalyzed by aromatase. Recently, we identified an obesity-inflammation-aromatase axis in mouse models and women. In mouse models of obesity, inflammatory foci characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages were found in the mammary gland (MG). CLS of the breast were found in most overweight and obese women. CLS were associated with adipocyte hypertrophy, activation of NF-κB, elevated levels of proinflammatory mediators and aromatase, and increased expression of the progesterone receptor (PR). Collectively, these findings provide a plausible explanation for the link between obesity, chronic inflammation, and post-menopausal breast cancer. Here we investigated whether caloric restriction (CR) reversed the inflammatory state and related molecular changes in the MG of obese mice. Obese ovariectomized C57BL/6J mice were subjected to 30% CR for 7 or 14 weeks. Findings in CR mice were compared with results in mice fed a high fat diet ad libitum or with control mice fed a low fat diet. CR was associated with more than a 75% decrease in mammary CLS/cm2. Reduced histological inflammation following CR was associated with decreased adipocyte diameter and MCP-1 levels, reduced NF-κB binding activity, and normalization of levels of proinflammatory mediators, aromatase and PR. In summary, obesity-related inflammation of the MG and elevated aromatase and PR levels were reversed with CR. Our results provide a rationale for determining whether weight loss can reverse breast inflammation associated with obesity in women.
PMCID: PMC3618560  PMID: 23430756
7.  Gambling-Related Attitudes and Behaviors in Adolescents Having Received Instant (Scratch) Lottery Tickets as Gifts 
Instant (scratch) lottery ticket gambling is popular among adolescents. Prior research has not determined whether adolescents’ gambling behavior and attitudes toward gambling are influenced by the receipt of scratch lottery tickets as gifts.
Cross-sectional survey data from 2,002 Connecticut high school students with past-year gambling were analyzed using bivariate approaches and logistic regression analyses. Interactions between gambling-problem severity and lottery-gift status were examined in relation to multiple outcomes.
Adolescents who received a scratch lottery ticket as a gift compared with those who did not were more likely to report features of problem gambling, buy scratch lottery tickets for themselves, and buy and receive other types of lottery tickets; they were also less likely to report parental disapproval of gambling and to see gambling prevention efforts as important. Later (≥15 years) age-at-gambling-onset was inversely linked to gambling-problem severity in the lottery gift group (odds ratio [OR] = .38) but not in the nongift group (OR = .91), yielding a significant severity by gift status interaction. Other academic, health, and gambling-related correlates of gambling-problem severity were similar in the gift and nongift groups.
For adolescents, the receipt of scratch lottery tickets as gifts during childhood or adolescence was associated with risky/problematic gambling and with gambling-related attitudes, behaviors, and views suggesting greater gambling acceptability. The extent to which the receipt of scratch lottery tickets may promote gambling behaviors and the development of gambling problems warrants consideration. Education, prevention, and treatment strategies should incorporate findings relating to receipt of gambling products by underage individuals.
PMCID: PMC3667499  PMID: 23299004
Gambling; Adolescence; Lottery; Risk behaviors; Gifts
8.  Characterization of a 3rd Generation Lentiviral Vector Pseudotyped With Nipah Virus Envelope Proteins For Endothelial Cell Transduction 
Gene therapy  2013;20(10):10.1038/gt.2013.23.
Lentiviruses are becoming progressively more popular as gene therapy vectors due to their ability to integrate into quiescent cells and recent clinical trial successes. Directing these vectors to specific cell types and limiting off-target transduction in vivo remains a challenge. Replacing the viral envelope proteins responsible for cellular binding, or pseudotyping, remains a common method to improve lentiviral targeting. Here, we describe the development of a high titer, 3rd generation lentiviral vector pseudotyped with Nipah virus fusion protein (NiV-F) and attachment protein (NiV-G). Critical to high titers was truncation of the cytoplasmic domains of both NiV-F and NiV-G. As known targets of wild-type Nipah virus, primary endothelial cells are shown to be effectively transduced by the Nipah pseudotype. In contrast, human CD34+ hematopoietic progenitors were not significantly transduced. Additionally, the Nipah pseudotype has increased stability in human serum compared to VSV pseudotyped lentivirus. These findings suggest that the use of Nipah virus envelope proteins in 3rd generation lentiviral vectors would be a valuable tool for gene delivery targeted to endothelial cells.
PMCID: PMC3839624  PMID: 23698741
lentivirus; pseudotype; endothelial cell; Nipah virus
9.  Small Cell Neuroendocrine Carcinoma of the Cervix: A Rare Entity 
Small cell carcinoma of the cervix is a rare and a very aggressive tumour. Once being considered to be a rare type of squamous cell carcinoma, evidence has proven that most of the tumours express one or more markers of neuroendocrine differentiation. The behaviour of this rare malignancy is different from that of squamous cell carcinomas, with a high propensity for nodal and distant metastases. Hence, there is a need to highlight this histopathological entity.
PMCID: PMC3972537
Small cell; Neuroendocrine; Cervix
10.  Neuroendocrine Carcinoma of the Stomach-A Case Report 
Neuroendocrine carcinomas of stomach have been considered a rare neoplasm. The present case concerns with a 69 year old male, who presented with vague abdominal discomfort and history of malena. Upper alimentary tract endoscopy showed an ulcero-proliferative growth in the antrum. Computed tomography abdomen revealed thickening of the gastric antrum, a subtotal gastrectomy was performed after correction of anemia. Microscopic evaluation revealed a neuroendocrine neoplasm. Immunohistochemically positive for Chromogranin A and Synaptophysin.A diagnosis of Neuroendocrine carcinoma of the stomach was given based on recent WHO classification of Neuroendocrine carcinoma of the stomach and on mitotic index with reference to grading scale.
PMCID: PMC3972542
Stomach; Neuroendocrine carcinoma; Chromogranin A; Synaptophysin; Mitotic figures
11.  Three-dimensional mapping of hippocampal and amygdalar structure in euthymic adults with bipolar disorder not treated with lithium 
Psychiatry research  2012;211(3):195-201.
Structural neuroimaging studies of the amygdala and hippocampus in bipolar disorder have been largely inconsistent. This may be due in part to differences in the proportion of subjects taking lithium or experiencing an acute mood state, as both factors have recently been shown to influence gray matter structure. To avoid these problems, we evaluated euthymic subjects not currently taking lithium. Thirty-two subjects with bipolar type I disorder and 32 healthy subjects were scanned using magnetic resonance imaging. Subcortical regions were manually traced, and converted to three-dimensional meshes to evaluate the main effect of bipolar illness on radial distance. Statistical analyses found no evidence for a main effect of bipolar illness in either region, although exploratory analyses found a significant age by diagnosis interaction in the right amygdala, as well as positive associations between radial distance of the left amygdala and both prior hospitalizations for mania and current medication status. These findings suggest that, when not treated with lithium or in an acute mood state, patients with bipolar disorder exhibit no structural abnormalities of the amygdala or hippocampus. Future studies, nevertheless, that further elucidate the impact of age, course of illness, and medication on amygdala structure in bipolar disorder are warranted.
PMCID: PMC3594485  PMID: 23149020
mood disorder; magnetic resonance imaging; hippocampus; amygdala; lithium; bipolar disorder
12.  ‘Ping pong’ fracture in a term infant 
BMJ Case Reports  2012;2012:bcr0120125631.
PMCID: PMC3316809  PMID: 22605800
13.  Draft Genome Sequence of an Invasive Multidrug-Resistant Strain, Pseudomonas aeruginosa BK1, Isolated from a Keratitis Patient 
Genome Announcements  2014;2(2):e00153-14.
Pseudomonas aeruginosa infections are difficult to treat due to the presence of a multitude of virulence factors and antibiotic resistance. Here, we report the draft genome sequence of P. aeruginosa BK1, an invasive and multidrug-resistant strain, isolated from a bacterial keratitis patient in southern India.
PMCID: PMC3968328  PMID: 24675850
14.  Discriminating Risk and Resilience Endophenotypes From Lifetime Illness Effects in Familial Major Depressive Disorder 
JAMA psychiatry  2014;71(2):136-148.
The neural systems that confer risk or vulnerability for developing familial depression, and those that protect against or confer resilience to becoming ill, can be disentangled from the effects of prior illness by comparing brain imaging measures in previously ill and never ill persons who have either a high or low familial risk for depression.
To distinguish risk and resilience endophenotypes for major depression from the effects of prior lifetime illness.
We used functional magnetic resonance imaging to measure and compare brain function during performance of an attentional, self-regulatory task across a large sample of multigenerational families ascertained specifically to be at either high or low risk for developing major depression. Study procedures were performed in a university setting. A total of 143 community participants were followed up prospectively for more than 20 years in a university setting. The sample was enriched with persons who were at higher or lower familial risk for developing depression based on being biological offspring of either a clinical sample of persons with major depression or a community control sample of persons with no discernible lifetime illness.
Task-related change in blood oxygen level–dependent functional magnetic resonance imaging signal.
A risk endophenotype included greater activation of cortical attention circuits. A resilience endophenotype included greater activation of the dorsal anterior cingulate cortex. The effects of prior lifetime illness were common to both risk groups and included greater deactivation of default-mode circuits.
These findings identify neural systems that increase risk for depression, those that protect from illness, and those that endure following illness onset, and they suggest circuits to target for developing novel preventive and therapeutic interventions.
PMCID: PMC3965257  PMID: 24369340
15.  Frontiers in Pulmonary Hypertension in Infants and Children With Bronchopulmonary Dysplasia 
Pediatric pulmonology  2012;47(11):1042-1053.
Pulmonary hypertension (PH) is an increasingly recognized complication of premature birth and bronchopulmonary dysplasia (BPD), and is associated with increased morbidity and mortality. Extreme phenotypic variability exists among preterm infants of similar gestational ages, making it difficult to predict which infants are at increased risk for developing PH. Intrauterine growth retardation or drug exposures, postnatal therapy with prolonged positive pressure ventilation, cardiovascular shunts, poor postnatal lung and somatic growth, and genetic or epigenetic factors may all contribute to the development of PH in preterm infants with BPD. In addition to the variability of severity of PH, there is also qualitative variability seen in PH, such as the variable responses to vasoactive medications. To reduce the morbidity and mortality associated with PH, a multi-pronged approach is needed. First, improved screening for and increased recognition of PH may allow for earlier treatment and better clinical outcomes. Second, identification of both prenatal and postnatal risk factors for the development of PH may allow targeting of therapy and resources for those at highest risk. Third, understanding the pathophysiology of the preterm pulmonary vascular bed may help improve outcomes through recognizing pathways that are dysregulated in PH, identifying novel biomarkers, and testing novel treatments. Finally, the recognition of conditions and exposures that may exacerbate or lead to recurrent PH is needed to help with developing treatment guidelines and preventative strategies that can be used to reduce the burden of disease.
PMCID: PMC3963167  PMID: 22777709
pulmonary hypertension; bronchopulmonary dysplasia; prematurity; chronic lung disease
16.  Aging, Nutrient Signaling, Hematopoietic Senescence, and Cancer 
Critical reviews in oncogenesis  2013;18(6):559-571.
It is well known that cancer is one of the main causes of mortality in the aged population. Recent studies suggest that oncogenic pathways, such as the insulin-like growth factor-1 (IGF-I), Ras, and Akt/PKB, can contribute to both aging and cancer not only by promoting growth and preventing apoptosis, but also by promoting DNA damage and genomic instability. Epidemiological studies suggest that the chronic, low-grade inflammation that accompanies aging also contributes to tissue damage and tumor progression. Coupled with the accumulation of senescent cells and declining immune function, this leads to the generation and survival of cancer cells, possibly explaining why advanced age is the primary risk factor for cancer.
PMCID: PMC3959897  PMID: 24579735
aging; cancer; inflammation; immunosenescence; hematopoietic stem cells
17.  Progesterone receptor isoform-specific promoter methylation — Association of PRA promoter methylation with worse outcome in breast cancer patients 
ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.
Experimental Design
We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n=500), and in patients who underwent surgery only (n=500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand binding assay, respectively.
Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen treated group.
Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this study shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.
PMCID: PMC3955277  PMID: 21459801
18.  The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: Lessons learned from infantile Pompe disease 
Enzyme replacement therapy with rhGAA (Myozyme®) has lead to improved survival, which is largely attributable to improvements in cardiomyopathy and skeletal muscle function. However, crossreactive immunologic material-negative patients have a poor clinical response to enzyme replacement therapy secondary to high sustained antibody titers. Furthermore, although the majority of crossreactive immunologic material-positive patients tolerize or experience a downtrend in anti-rhGAA antibody titers, antibody response is variable with some crossreactive immunologic material-positive infants also mounting high sustained antibody titers.
We retrospectively analyzed 34 infants with Pompe disease: 11 crossreactive immunologic material-negative patients, nine high-titer crossreactive immunologic material-positive patients, and 14 low-titer crossreactive immunologic material-positive patients. Clinical outcome measures were overall survival, ventilator-free survival, left ventricular mass index, Alberta Infant Motor Scale score, and urine Glc4 levels.
Clinical outcomes in the high-titer crossreactive immunologic material-positive group were poor across all areas evaluated relative to the low-titer crossreactive immunologic material-positive group. For the crossreactive immunologic material-negative and high-titer crossreactive immunologic material-positive groups, no statistically significant differences were observed for any outcome measures, and both patient groups did poorly.
Our data indicate that, irrespective of crossreactive immunologic material status, patients with infantile Pompe disease with high sustained antibody titer have an attenuated therapeutic response to enzyme replacement therapy. With the advent of immunomodulation therapies, identification of patients at risk for developing high sustained antibody titer is critical.
PMCID: PMC3954622  PMID: 21637107
Pompe disease; enzyme replacement therapy (ERT); crossreactive immunologic material (CRIM); CRIM negative (CN); high sustained antibody titers (HSAT); high-titer CRIM-positive (HTCP); low-titer CRIM-positive (LTCP); therapeutic proteins
19.  Heat-Related Mortality in India: Excess All-Cause Mortality Associated with the 2010 Ahmedabad Heat Wave 
PLoS ONE  2014;9(3):e91831.
In the recent past, spells of extreme heat associated with appreciable mortality have been documented in developed countries, including North America and Europe. However, far fewer research reports are available from developing countries or specific cities in South Asia. In May 2010, Ahmedabad, India, faced a heat wave where the temperatures reached a high of 46.8°C with an apparent increase in mortality. The purpose of this study is to characterize the heat wave impact and assess the associated excess mortality.
We conducted an analysis of all-cause mortality associated with a May 2010 heat wave in Ahmedabad, Gujarat, India, to determine whether extreme heat leads to excess mortality. Counts of all-cause deaths from May 1–31, 2010 were compared with the mean of counts from temporally matched periods in May 2009 and 2011 to calculate excess mortality. Other analyses included a 7-day moving average, mortality rate ratio analysis, and relationship between daily maximum temperature and daily all-cause death counts over the entire year of 2010, using month-wise correlations.
The May 2010 heat wave was associated with significant excess all-cause mortality. 4,462 all-cause deaths occurred, comprising an excess of 1,344 all-cause deaths, an estimated 43.1% increase when compared to the reference period (3,118 deaths). In monthly pair-wise comparisons for 2010, we found high correlations between mortality and daily maximum temperature during the locally hottest “summer” months of April (r = 0.69, p<0.001), May (r = 0.77, p<0.001), and June (r = 0.39, p<0.05). During a period of more intense heat (May 19–25, 2010), mortality rate ratios were 1.76 [95% CI 1.67–1.83, p<0.001] and 2.12 [95% CI 2.03–2.21] applying reference periods (May 12–18, 2010) from various years.
The May 2010 heat wave in Ahmedabad, Gujarat, India had a substantial effect on all-cause excess mortality, even in this city where hot temperatures prevail through much of April-June.
PMCID: PMC3954798  PMID: 24633076
20.  Rates of Complications and Mortality in Older Diabetes Patients: The Diabetes and Aging Study 
JAMA internal medicine  2014;174(2):251-258.
In the coming decades, the population of older adults with diabetes is expected to grow substantially. Understanding the clinical course of diabetes in this population is critical for establishing evidence-based clinical practice recommendations, research priorities, allocating resources, and setting health policies.
Contrast rates of diabetes complications and mortality across age and diabetes duration categories.
Design, Setting, Participants
This cohort study (2004–2010) included 72,310 older (≥60 years of age) patients with type 2 diabetes enrolled in a large, integrated healthcare delivery system. Incidence densities (events per 1000 person-years (pys)) were calculated for each age category (60s, 70s, 80+ years) and duration of diabetes (shorter: 0–9 years vs. longer: 10+ years).
Main Outcome Measures
Incident acute hyperglycemic events, acute hypoglycemic events (hypoglycemia), microvascular complications [end-stage renal disease (ESRD), peripheral vascular disease, lower extremity amputation, advanced eye disease], cardiovascular complications [coronary artery disease (CAD), cerebrovascular disease (CVD), congestive heart failure (CHF)], and all-cause mortality.
Among older adults with diabetes of short duration, cardiovascular complications followed by hypoglycemia were the most common non-fatal complications. For example, among 70–79 year olds with short duration of diabetes, CAD and hypoglycemia rates were higher (11.5 and 5.0/1000 pys respectively), compared to ESRD (2.6/1000), amputation (1.3/1000), and acute hyperglycemic events (0.8/1000). We observed a similar pattern among subjects in the same age group with long diabetes duration where CAD and hypoglycemia had some of the highest incidence rates (19.0 and 15.9 /1000 pys respectively), compared to ESRD (7.6/1000), amputation (4.3/1000), and acute hyperglycemic events (1.8/1000). For a given age group, rates of each outcome, particularly hypoglycemia and microvascular complications, increased dramatically with longer duration. However, for a given duration of diabetes, rates of hypoglycemia, cardiovascular complications, and mortality increased steeply with advancing age, while rates of microvascular complications remained stable or declined.
Duration of diabetes and advancing age independently predict diabetes morbidity and mortality rates. As long-term survivorship with diabetes increases and as the population ages, more research and public health efforts to reduce hypoglycemia will be needed, to complement ongoing efforts to reduce cardiovascular and microvascular complications.
PMCID: PMC3950338  PMID: 24322595
21.  Transport properties of pancreatic cancer describe gemcitabine delivery and response 
The Journal of Clinical Investigation  2014;124(4):1525-1536.
Background. The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.
Methods. We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.
Results. Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.
Conclusion. Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.
Trial registration. NCT01276613.
Funding. Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).
PMCID: PMC3973100  PMID: 24614108
22.  The emerging phenotype of long-term survivors with infantile Pompe disease 
Enzyme replacement therapy with alglucosidase alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors.
Inclusion criteria included ventilator-free status and age ≤6 months at treatment initiation, and survival to age ≥5 years. Clinical outcome measures included invasive ventilator-free survival and parameters for cardiac, pulmonary, musculoskeletal, gross motor and ambulatory status; growth; speech, hearing, and swallowing; and gastrointestinal and nutritional status.
Eleven of 17 patients met study criteria. All were cross-reactive immunologic material-positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range: 5.4 to 12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux disease, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and four required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-alglucosidase alfa antibody titers.
Long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings.
PMCID: PMC3947503  PMID: 22538254
acid maltase deficiency; enzyme replacement therapy; glycogen storage disease type II; neuromuscular diseases; Pompe disease
23.  Improvement of Sleep Disturbance and Insomnia Following Parathyroidectomy for Primary Hyperparathyroidism 
World journal of surgery  2014;38(3):542-548.
Our aim was to investigate the incidence of sleep disturbance and insomnia in patients with primary hyperparathyroidism (PHPT), and to evaluate the effect of parathyroidectomy.
A questionnaire was prospectively administered to adult patients with PHPT who underwent curative parathyroidectomy over an 11-month period. The questionnaire, administered pre- and 6-months post-operatively, included the Insomnia Severity Index (ISI) and eight additional questions regarding sleep pattern. Total ISI scores range from 0 to 28, with >7 signifying sleep difficulties and scores >14 indicating clinical insomnia.
Of 197 eligible patients undergoing parathyroidectomy for PHPT, 115 (58.3%) completed the pre- and post-operative questionnaires. The mean age was 60.0±1.2 years and 80.0% were female. Pre-operatively, 72 patients (62.6%) had sleep difficulties, and 29 patients (25.2%) met criteria for clinical insomnia. Clinicopathologic variables were not predictive of clinical insomnia. There was a significant reduction in mean ISI score after parathyroidectomy (10.3±0.6 vs 6.2±0.5, p<0.0001). Post-operatively, 79 patients (68.7%) had an improved ISI score. Of the 29 patients with pre-operative clinical insomnia, 21 (72.4%) had resolution after parathyroidectomy. Pre-operative insomnia patients had an increase in total hours slept after parathyroidectomy (5.4±0.3 vs 6.1±0.3 hours, p=0.02), whereas both insomnia and non-insomnia patients had a decrease in the number of awakenings (3.7±0.4 vs 1.9±0.2 times, p=0.0001).
Sleep disturbances and insomnia are common in patients with PHPT, and the majority of patients will improve after curative parathyroidectomy.
PMCID: PMC3945278  PMID: 24142330
24.  LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection 
PLoS Genetics  2014;10(3):e1004196.
Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10−2). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10−11–10−9) and African (p = 10−5–10−3) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement.
Author Summary
Leukocyte immunoglobulin-like receptors B1 and B2 (LILRB1 and LILRB2) bind HLA class I allotypes with variable affinities. Here, we show that the binding strength of LILRB2 to HLA class I positively associates with level of viremia in a large cohort of untreated HIV-1-infected patients. This effect appears to be driven by HLA-B polymorphism and demonstrates independence from class I allelic effects on viral load. Our in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of dendritic cells (DCs). Thus, we propose an impact of LILRB2 on HIV-1 immune control through altered regulation of DCs by LILRB2-HLA engagement.
PMCID: PMC3945438  PMID: 24603468
25.  Centralspindlin and α-catenin regulate Rho signalling at the epithelial zonula adherens 
Nature cell biology  2012;14(8):818-828.
The biological impact of Rho depends critically on the precise subcellular localization of its active, GTP-loaded form. The spatio-temporal balance between molecules that promote nucleotide exchange or GTP hydrolysis can potentially determine the sites of Rho signalling. But how these activities may be coordinated is poorly understood. We now report a molecular pathway that achieves exactly this coordination at the epithelial zonula adherens. We identify an extramitotic activity of the centralspindlin complex, better understood as a cytokinetic regulator, which localises to the zonula adherens during interphase by interacting with the cadherin-associated protein, α-catenin. Centralspindlin recruits the Rho GEF, Ect2, to the zonula adherens to activate Rho and support junctional integrity through myosin IIA. Centralspindlin also inhibits the junctional localisation of p190RhoGAP B, which can inactivate Rho. Thus, a conserved molecular ensemble that governs Rho activation during cytokinesis is utilized in interphase cells to control the Rho GTPase cycle at the zonula adherens.
PMCID: PMC3939354  PMID: 22750944
E-cadherin; junctions; Rho; centralspindlin; Ect2; α-catenin

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