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1.  Antioxidant Activity of Essential Oil and Extracts of Valeriana jatamansi Roots 
BioMed Research International  2014;2014:614187.
Valeriana jatamansi is an indigenous medicinal plant used in the treatment of a number of diseases. In the present study, chemical composition of the essential oil was determined by GC-MS. Seven major components were identified in Valeriana jatamansi essential oil, namely, β-vatirenene, β-patchoulene, dehydroaromadendrene, β-gurjunene, patchoulic alcohol, β-guaiene, and α-muurolene. Methanolic, aqueous, and chloroform extracts of Valeriana jatamansi roots were also prepared and analyzed for their polyphenols and flavonoid content. Antioxidant activity of essential oil and different extracts of Valeriana jatamansi roots was determined by DPPH radical scavenging and chelation power assay. A linear correlation has been obtained by comparing the antioxidant activity and polyphenols and flavonoid content of the extracts. Results indicated that antioxidant activity of methanolic extract could be attributed to the presence of rich amount of polyphenols and flavonoid. Essential oil of Valeriana jatamansi roots showed moderate antioxidant activity.
PMCID: PMC3997129  PMID: 24804225
2.  Demonstration of choreic movements in a case of chorea gravidarum 
BMJ Case Reports  2013;2013:bcr2012008234.
PMCID: PMC3618557  PMID: 23417936
3.  Acute respiratory failure following traumatic tooth aspiration 
BMJ Case Reports  2013;2013:bcr2012008393.
Foreign body aspiration can infrequently occur following trauma. Tooth aspiration after trauma is a rare clinical scenario. Here, we report a case in which tooth aspiration after trauma led to a presentation of acute respiratory failure with clinical findings mimicking tension pneumothorax. Successful removal of the aspirated tooth was accomplished by rigid bronchoscopy. Tooth aspiration must be considered in the list of differential diagnosis for any patient having signs or symptoms of respiratory distress following trauma especially maxillofacial trauma.
PMCID: PMC3603903  PMID: 23391960
4.  Genetics of follicular lymphoma transformation 
Cell reports  2014;6(1):130-140.
Follicular lymphoma (FL) is an indolent disease, but 30-40% of cases undergo histologic transformation to an aggressive malignancy, typically represented by diffuse large B cell lymphoma (DLBCL). The pathogenesis of this process remains largely unknown. Using whole-exome sequencing and copy-number analysis, here we show that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through the acquisition of distinct genetic events. Mutations in epigenetic modifiers and anti-apoptotic genes are introduced early in the common precursor, while tFL is specifically associated with alterations deregulating cell-cycle progression and DNA-damage responses (CDKN2A/B, MYC, TP53), as well as with aberrant somatic hypermutation. The genomic profile of tFL shares similarities with that of germinal center B-cell-type de novo DLBCL, but also displays unique combinations of altered genes, with diagnostic and therapeutic implications.
PMCID: PMC4100800  PMID: 24388756
5.  Systemic inflammatory response syndrome and platelet count ≥250×109 are associated with venous thromboembolic disease 
Prior research has demonstrated that platelet count and inflammation are dominant contributors to hypercoagulability. Our objective is to determine whether elevated platelet count and systemic inflammatory response syndrome (SIRS) have an association with the development of venous thromboembolism (VTE) in hospitalized patients with a high clinical index of suspicion for thromboembolic disease.
We performed a retrospective medical record review of 844 medical and surgical patients with suspected VTE hospitalized from July 2012 to May 2013 who underwent screening by venous duplex and computed tomography pulmonary angiogram. For our purposes, thrombocytosis was arbitrarily defined as platelet count ≥250×109/L.
Venous thromboembolic disease was detected in 229 patients (25.9%). Thrombocytosis was present in 389 patients (44%) and SIRS was present in 203 patients (23%) around the time of imaging. Thrombocytosis and SIRS were positively correlated with VTE (P<0.001). There was no correlation between thrombocytosis and SIRS. Multivariate analysis revealed that SIRS (odds ratio 1.91, 95% confidence interval 1.36–2.68, P<0.001) and thrombocytosis (odds ration 1.67, 95% confidence interval 1.23–2.26, P=0.001) were independently associated with VTE.
Patients at high risk for VTE should be routinely assessed for thrombocytosis (≥250×109/L) and SIRS; if either is present, consideration for empiric anticoagulation should be given while diagnostic imaging is undertaken.
PMCID: PMC4298346  PMID: 25609994
SIRS; thrombocytosis; VTE; platelet count
6.  Breast Implant–Associated Anaplastic Large-Cell Lymphoma: Long-Term Follow-Up of 60 Patients 
Journal of Clinical Oncology  2013;32(2):114-120.
Breast implant–associated anaplastic large-cell lymphoma (ALCL) is a recently described clinicopathologic entity that usually presents as an effusion-associated fibrous capsule surrounding an implant. Less frequently, it presents as a mass. The natural history of this disease and long-term outcomes are unknown.
Patients and Methods
We reviewed the literature for all published cases of breast implant–associated ALCL from 1997 to December 2012 and contacted corresponding authors to update clinical follow-up.
The median overall survival (OS) for 60 patients was 12 years (median follow-up, 2 years; range, 0-14 years). Capsulectomy and implant removal was performed on 56 of 60 patients (93%). Therapeutic data were available for 55 patients: 39 patients (78%) received systemic chemotherapy, and of the 16 patients (28%) who did not receive chemotherapy, 12 patients opted for watchful waiting and four patients received radiation therapy alone. Thirty-nine (93%) of 42 patients with disease confined by the fibrous capsule achieved complete remission, compared with complete remission in 13 (72%) of 18 patients with a tumor mass. Patients with a breast mass had worse OS and progression-free survival (PFS; P = .052 and P = .03, respectively). The OS or PFS were similar between patients who received and did not receive chemotherapy (P = .44 and P = .28, respectively).
Most patients with breast implant–associated ALCL who had disease confined within the fibrous capsule achieved complete remission. Proper management for these patients may be limited to capsulectomy and implant removal. Patients who present with a mass have a more aggressive clinical course that may be fatal, justifying cytotoxic chemotherapy in addition to removal of implants.
PMCID: PMC4062709  PMID: 24323027
7.  Prevalence of +405G>C,−1154G>A Vascular Endothelial Growth Factor Polymorphism in Breast Cancer 
Vascular endothelial growth factor (VEGF) plays an important role in the development of Breast Cancer. The aim of this study was to investigate the association of polymorphisms in the VEGF gene on prognosis of Breast Cancer patients. This study comprised 200 patients with histologically confirmed cases of Breast cancer and 200 controls. Genotyping of the VEGF gene polymorphisms at +405G>C,−1154G>A, were performed by PCR-RFLP analysis. Preoperative plasma VEGF levels were determined by ELISA. Amongst both cases and controls, the genotypic distribution of the individual SNPs were all in Hardy–Weinberg equilibrium. Mean VEGF level was significantly elevated in cases compared to controls (t = 8.248; P < 0.001). No significant association was found between +405G>C,−1154G>A VEGF polymorphism and Breast Cancer. Logistic regression analysis revealed that 405GG & 1154GG were associated with higher levels of VEGF.
PMCID: PMC3903925  PMID: 24478545
Breast cancer; VEGF polymorphism; Genotype; Plasma VEGF; ELISA
8.  Astrocytes refine cortical connectivity at dendritic spines 
eLife  null;3:e04047.
During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.
eLife digest
The central nervous system—which is made up of the brain and spinal cord—processes information from all over the body. The information travels through cells called neurons, which connect to each other at junctions called synapses. A single neuron can receive information from many different places because it is covered with protrusions known as dendritic spines that enable it to form synapses with a variety of other neurons.
In recent years, it has become apparent that brain cells other than neurons can influence synapse formation. The most abundant cells in the central nervous system are star-shaped cells known as astrocytes, which secrete molecules that control the timing and extent of synapse formation. Many previous studies on synapses have used a type of neuron found in the eye—called retinal ganglion cells—because these cells can be purified and grown in the laboratory in the absence of astrocytes. Under these conditions, they form very few synapses. However, in the presence of astrocytes the retinal ganglion cells form many more synapses, which is thought to be due to a protein called hevin and several other proteins that are secreted by the astrocytes.
Risher et al. studied a region of the brain called the cerebral cortex in mice that were missing hevin. In the cortex of normal mice, the neurons generally form synapses with other neurons within the cortex, or with neurons from other parts of the brain that send long-distance projections into the cortex. The experiments revealed that fewer of these long-distance synapses formed in the cortex of the mice missing hevin compared to normal mice. When hevin was injected directly into the brains of the mice, more long-distance synapses were formed.
Using a technique called three-dimensional electron microscopy, Risher et al. examined the structure of the synapses. In mice missing hevin, the synapses were much smaller and the dendritic spines were thin and long, indicating that they were not fully grown. The images also show that in normal mice, the dendritic spines often have multiple synapses when the animal is young, but many are lost as the brain matures so that only a single synapse remains in each dendritic spine. However, multiple synapses persist in the dendritic spines of mice lacking hevin, which could lead to competition between short and long distance synapses and may contribute to neurological diseases.
These results indicate that astrocytes are crucial for controlling the formation of synapses in dendritic spines. In humans, defects in hevin have been implicated in autism, schizophrenia and other neurological conditions. Future studies will seek to determine the precise role of astrocytes in these conditions, which may help us to develop new therapies.
PMCID: PMC4286724  PMID: 25517933
synaptogenesis; thalamocortical; dendritic spines; astrocytes; mouse
9.  Proctitis following stereotactic body radiation therapy for prostate cancer 
Proctitis after radiation therapy for prostate cancer remains an ongoing clinical challenge and critical quality of life issue. SBRT could minimize rectal toxicity by reducing the volume of rectum receiving high radiation doses and offers the potential radiobiologic benefits of hypofractionation. This study sought to evaluate the incidence and severity of proctitis following SBRT for prostate cancer.
Between February 2008 and July 2011, 269 men with clinically localized prostate cancer were treated definitively with SBRT monotherapy at Georgetown University Hospital. All patients were treated to 35-36.25Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). Rectal bleeding was recorded and scored using the CTCAE v.4. Telangiectasias were graded using the Vienna Rectoscopy Score (VRS). Proctitis was assessed via the Bowel domain of the Expanded Prostate Index Composite (EPIC)-26 at baseline and at 1, 3, 6, 9, 12, 18 and 24 months post-SBRT.
The median age was 69 years with a median prostate volume of 39 cc. The median follow-up was 3.9 years with a minimum follow-up of two years. The 2-year actuarial incidence of late rectal bleeding ≥ grade 2 was 1.5%. Endoscopy revealed VRS Grade 2 rectal telangiectasias in 11% of patients. All proctitis symptoms increased at one month post-SBRT but returned to near-baseline with longer follow-up. The most bothersome symptoms were bowel urgency and frequency. At one month post-SBRT, 11.2% and 8.5% of patients reported a moderate to big problem with bowel urgency and frequency, respectively. The EPIC bowel summary scores declined transiently at 1 month and experienced a second, more protracted decline between 6 months and 18 months before returning to near-baseline at two years post-SBRT. Prior to treatment, 4.1% of men felt their bowel function was a moderate to big problem which increased to 11.5% one month post-SBRT but returned to near-baseline at two years post-SBRT.
In this single institution cohort, the rate and severity of proctitis observed following SBRT is low. QOL decreased on follow-up; however, our results compare favorably to those reported for patients treated with alternative radiation modalities. Future prospective randomized studies are needed to confirm these observations.
PMCID: PMC4272823  PMID: 25497602
Prostate cancer; SBRT; Rectal endoscopy; Telangiectasias; CyberKnife; Expanded prostate index composite; Bother; Proctitis; Rectal bleeding; Vienna rectoscopy score
10.  MYC Protein Expression in Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System 
PLoS ONE  2014;9(12):e114398.
Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a rare, aggressive subtype of DLBCL, the biology of which is poorly understood. Recent studies have suggested a prognostic role of MYC protein expression in systemic DLBCL, but little is known about the frequency and significance of MYC protein expression in CNS DLBCL. Hence, we investigated MYC protein expression profiles of CNS DLBCL and assessed the relationship between MYC expression and a variety of histopathologic, immunophenotypic, genetic, and clinical features. Fifty-nine CNS DLBCL diagnosed at our institution over the past 13 years were evaluated. The majority of cases (80%) showed centroblastic morphology, and 12 (20%) displayed a perivascular pattern of infiltration. According to the Hans criteria, 41 (69%) cases had a non-germinal center B-cell and 18 (31%) had a germinal center B-cell cell-of-origin (COO) phenotype. Mean MYC protein expression was 50% (median: 50%, range: 10-80%). Forty-three cases (73%) showed MYC overexpression (≥40%), and 35 (60%) showed MYC/BCL2 coexpression. MYC overexpression was seen in the single case harboring MYC translocation and in the cases showing increased copies of MYC (27%); however, no significant difference in mean MYC expression was seen between groups harboring or lacking MYC aberrations. In our series, age was associated with a significantly increased risk of death, and the perivascular pattern of infiltration was associated with a significantly increased risk of disease progression. Neither MYC expression (with or without BCL2 coexpression) nor other variables, including COO subtype were predictive of clinical outcome. Our findings indicate that the proportion of CNS DLBCL overexpressing MYC is higher compared to systemic DLBCL, and MYC overexpression appears to be independent of genetic MYC abnormalities. Thus, MYC expression and other immunophenotypic markers used for prognostication of systemic DLBCL might not apply to CNS DLBCL due to differences in disease biology.
PMCID: PMC4257680  PMID: 25479599
11.  Impact of Sarcopenia on Outcomes Following Intra-arterial Therapy of Hepatic Malignancies 
Assessment of patient performance status is often subjective. Sarcopenia—measurement of muscle wasting—may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT).
Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IATof hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors.
Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm2/m2) was greater than women (413 mm2/m2). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3-year survival was 39 %. Factors associated with risk of death were tumor size (HR=1.84) and Child's score (HR=2.15) (all P <0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR=1.84; P =0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients.
Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies.
PMCID: PMC3982291  PMID: 24065364
Sarcopenia; Intra-arterial therapy; Frailty; Outcomes; Performance status
12.  Malignant Conversion of Oral Submucous Fibrosis in Surgically Treated Case 
Oral submucous fibrosis (OSMF) is an insidious chronic disease affecting any part of the oral cavity and sometimes the pharynx with epithelial atrophy leading to stiffness of the oral mucosa, causing trismus and inability to eat. However a more serious complication of this disease is the risk of the development of oral carcinoma.
We reported the histopathologically proven case of OSMF with initial interincisal mouth opening 2mm which was treated surgically with nasolabial flap technique but failed to follow up and could not do active mouth opening exercises. Malignant conversion of OSMF was seen in this case. This is required to assess the progress and evaluate any malignant transformation at the earliest. So, the importance of active co-operation and frequent follow up cannot be overemphasized. The purpose of this study is to emphasize the importance of regular follow up and frequent biopsies to facilitate oral examination and to check any malignant conversion after the surgery.
PMCID: PMC4253287  PMID: 25478469
Follow-up; Mouth opening exercise; Malignant transformation; Nasolabial flap; Oral submucous fibrosis
13.  Comparison of the Release Profile and Pharmacokinetics of Intact and Fragmented Dexamethasone Intravitreal Implants in Rabbit Eyes 
Purpose: Dexamethasone intravitreal implant (DEX implant, Ozurdex®; Allergan, Inc.) is used to treat noninfectious posterior uveitis and macular edema associated with retinal vein occlusion and diabetic retinopathy. Two recently published reports of DEX implant fragmentation shortly after injection have raised concerns about the potential for faster implant dissolution and elevated ocular dexamethasone concentrations. This study compared the in vivo release profile and pharmacokinetic behavior of intact and fragmented DEX implants.
Methods: DEX implant was surgically implanted as a single unit or fragmented into 3 pieces in the posterior segment of opposing eyes of 36 New Zealand white rabbits. The release of dexamethasone over time from 1-piece and 3-piece fragmented implants dissolved in solution in vitro was compared with that from the 1-piece and 3-piece fragmented implants placed in the rabbit eyes. In addition, dexamethasone concentrations in the vitreous and aqueous humors of each eye were measured at 3 h and days 1, 7, 14, 21, and 28. High-performance liquid chromatography and liquid chromatography–tandem mass spectrometry were used for assays.
Results: Dexamethasone release from the 1-piece and 3-piece DEX implants in vivo was not different and was consistent with the in vitro release pattern. Moreover, the concentration profile of dexamethasone in the vitreous and aqueous humors was similar for the 1-piece and 3-piece DEX implants at each time point measured.
Conclusions: DEX implant fragmentation neither accelerated its dissolution nor increased the dexamethasone concentration delivered at a given time. Accordingly, DEX implant fragmentation is unlikely to have clinically significant effects in patients.
PMCID: PMC4259187  PMID: 25411827
14.  Relationship between promoter methylation & tissue expression of MGMT gene in ovarian cancer 
Background & objectives:
Epigenetic alterations, in addition to multiple gene abnormalities, are involved in the genesis and progression of human cancers. Aberrant methylation of CpG islands within promoter regions is associated with transcriptional inactivation of various tumour suppressor genes. O6-methyguanine-DNA methyltransferase (MGMT) is a DNA repair gene that removes mutagenic and cytotoxic adducts from the O6-position of guanine induced by alkylating agents. MGMT promoter hypermethylation and reduced expression has been found in some primary human carcinomas. We studied DNA methylation of CpG islands of the MGMT gene and its relation with MGMT protein expression in human epithelial ovarian carcinoma.
A total of 88 epithelial ovarian cancer (EOC) tissue samples, 14 low malignant potential (LMP) tumours and 20 benign ovarian tissue samples were analysed for MGMT promoter methylation by nested methylation-specific polymerase chain reaction (MSP) after bisulphite modification of DNA. A subset of 64 EOC samples, 10 LMP and benign tumours and five normal ovarian tissue samples were analysed for protein expression by immunohistochemistry.
The methylation frequencies of the MGMT gene promoter were found to be 29.5, 28.6 and 20 per cent for EOC samples, LMP tumours and benign cases, respectively. Positive protein expression was observed in 93.8 per cent of EOC and 100 per cent in LMP, benign tumours and normal ovarian tissue samples. Promoter hypermethylation with loss of protein expression was seen only in one case of EOC.
Interpretation & conclusions:
Our results suggest that MGMT promoter hypermethylation does not always reflect gene expression.
PMCID: PMC4311314  PMID: 25579142
epithelial ovarian tumour; MGMT; ovarian cancer; promoter methylation; protein expression
15.  Cytotoxic potential of Anisochilus carnosus (L.f.) wall and estimation of luteolin content by HPLC 
Anisochilus carnosus (L.f.) wall (Lamiaceae), an annual herb which grows at high altitude is used extensively in folk medicine for the treatment of ailments such as gastric ulcer and skin diseases. The aim of our study was to evaluate the anticancer activity of different extracts of the leaves of A.carnosus. An attempt was also made to estimate the luteolin content in different extracts of Anisochilus carnosus by HPLC (High Performance Liquid Chromatography).
In the current study, we explored the cytotoxic potential of petroleum ether, ethanolic and aqueous extracts of A.carnosus against breast adenocarcinoma cell line (BT-549), by in vitro MTT and SRB assay. We also detected the luteolin content in different extracts (ethanolic and aqueous) of A.carnosus by using HPLC as a tool of analysis.
The results demonstrate that petroleum ether and ethanolic extract of A.carnosus showed potent cytotoxic effect against BT-549 with an IC50 of 22.5 μg/ml (petroleum ether extract) and 87.24 μg/ml (ethanolic extract), by SRB assay, and 18.35 μg/ml (petroleum ether extract) and 58.64 μg/ml (ethanolic extract), by MTT assay. The aqueous extracts showed less cytotoxic effect with an IC50 of 211.26 μg/ml (by SRB assay) and 238.91 μg/ml (by MTT assay). HPLC results of luteolin content in various extracts using luteolin as the marker compound indicated the ethanol extract to contain the highest concentration of luteolin (0.372% w/w). The aqueous extract contained lower concentration of luteolin (0.282% w/w).
Our findings demonstrate that petroleum ether and ethanolic extract of A.carnosus shows promising anticancer activity and has the potential to be developed into a therapeutic option for the treatment of cancer.
PMCID: PMC4226858  PMID: 25348394
A.carnosus; Anticancer activity; BT-549; Luteolin; High performance liquid chromatography
16.  A Knowledge, Attitudes and Practices Survey regarding Sex, Contraception and Sexually Transmitted Diseases among Commerce College Students in Mumbai 
Introduction: One in four Indians is a juvenile. Sexual crimes, pre marital sex, sexually transmitted diseases and unwanted pregnancies are on the rise. It has been shown that lack of sexuality education can significantly contribute to the above.
Aim: We conducted this study to determine the knowledge and awareness of college students regarding sex and related matters and the factors affecting the prevalent outlook and practices of youth towards the same.
Methodology: A prospective cross-sectional survey was conducted amongst 500 students of the K.P.B. Hinduja College of Commerce from December 2012 to March 2013 as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
Main Outcome Measures: 1. Sex knowledge scores of males and females regarding contraception, sexually transmitted diseases and HIV/AIDS.
2. Percentage response of males and females to questions depicting attitudes and perceptions regarding premarital sex and promiscuity, sexual fantasy and masturbation, unwanted pregnancies and contraception.
3. Responses depicting participant’s premarital and high risk sexual activities.
Results: The mean age was 18.6 ±1.6 years, 46% of participants were female. The total sex related knowledge scores of males and females were 8.2±1.2 and 6.2±2.4 (p<0.0001), respectively. 84% males and 72% females disagree that virginity should be preserved till marriage. Premarital sex was reported by 48% males and 18% females. Out of those who had premarital sex, 68% males and none of the females had more than one sex partner and 21% males and 12% females had used a contraceptive during their sexual encounter. 87% males and 82% females disagree that sex education in secondary schools will cause a rise in premarital intercourse. 40% males and 13% females are of the view that birth control is primarily a female’s responsibility. 14% of males and 21% of females (p = 0.2) reported being forced to have sex.
Conclusion: Participants, especially females, lacked basic information about sexuality and related concepts. Male participants had a very casual attitude towards having sex with multiple partners. Premarital sex is more common than once believed. In the light of our finds and the current scenario, sexuality education is indispensable in order to guide the youth to develop and adopt healthy and appropriate sexual practices.
PMCID: PMC4190736  PMID: 25302214
Epidemiology; HIV/AIDS; Sexuality education; Sex offences; Safe sex
17.  Concurrent Malaria and Dengue Fever: A Need for Rapid Diagnostic Methods 
Malaria and dengue fever are endemic in the South-East Asian region including India. Both the illnesses share similar symptomatology, but differ in certain respects such as different- causative organisms and mosquito vector with diverse habitat. Hence, concurrent malaria and dengue fever in the same patient is said to be unusual. There have been cases of concurrent malaria and dengue, but they are scarce from highly endemic region like ours. Here, we describe three unusual cases of Plasmodium vivax and dengue co-infection diagnosed by use of rapid diagnostic tests. Early diagnosis and timely intervention is crucial in managing such patients.
PMCID: PMC4311362  PMID: 25657963
Co-infection; dengue; malaria
18.  A Potential Oncogenic Activity of Platelet-Derived Growth Factor D in Prostate Cancer Progression 
Cancer research  2004;64(5):1722-1729.
The platelet-derived growth factor (PDGF) proteins are potent stimulators of cell proliferation/transformation and play a major role in cell-cell communication. For over two decades, PDGFs were thought to exist as three dimeric polypeptides (the homodimers AA and BB and the heterodimer AB). Recently, however, the PDGF C and D chains were discovered in a BLAST search of the expressed sequence tag databases. The PDGF CC and DD dimers have a unique two-domain structure with an NH2-terminal CUB (compliment subcomponents C1r/C1s, Uegf, and Bmp1) domain and a COOH-terminal PDGF/vascular endothelial growth factor domain. Whereas secreted PDGF AA, BB, and AB readily activate their cell surface receptors, it was suggested that extracellular proteolytic removal of the CUB domain is required for the PDGF/vascular endothelial growth factor domain of PDGF CC and DD to activate PDGF receptors. In the present study, we examined the processing of latent PDGF D into its active form and the effects of PDGF D expression on prostate cancer progression. We show that LNCaP cells auto-activate latent PDGF DD into the active PDGF domain, which can induce phosphorylation of the β-PDGF receptor and stimulates LNCaP cell proliferation in an autocrine manner. Additionally, LNCaP-PDGF D-conditioned medium induces migration of the prostate fibroblast cell line 1532-FTX, indicating LNCaP-processed PDGF DD is active in a paracrine manner as well. In a severe combined immunodeficient mouse model, PDGF DD expression accelerates early onset of prostate tumor growth and drastically enhances prostate carcinoma cell interaction with surrounding stromal cells. These demonstrate a potential oncogenic activity of PDGF DD in the development and/or progression of prostate cancer.
PMCID: PMC4171134  PMID: 14996732
19.  Efficacy and Safety of Nadifloxacin for Bacterial Skin Infections: Results from Clinical and Post-Marketing Studies 
Dermatology and Therapy  2014;4(2):233-248.
Skin and soft tissue infections involve microbial invasion of the skin and underlying soft tissues and are estimated to affect 7–10% of hospitalized patients worldwide. Nadifloxacin, a topical fluoroquinolone, has been shown to be effective against aerobic Gram-negative, Gram-positive (including MRSA and coagulase-negative staphylococci), and anaerobic bacteria. However, there is paucity of data comparing efficacy and safety of 1% nadifloxacin with other anti-bacterials for skin infections in Indian patients.
This article presents the results of one post-marketing surveillance (PMS) and three randomized, open, non-blinded, multi-centric clinical studies that compared nadifloxacin with mupirocin and framycetin, and nadifloxacin with fusidic acid. Patients in India, aged from 1 to 65 years old, suffering from mild to moderate bacterial skin infections including impetigo, secondarily infected wounds, folliculitis, infected atopic dermatitis, and furunculosis were randomly allocated to three treatment groups within the studies. Efficacy was assessed by the evaluation of symptoms of erythema, exudation, swelling, pruritus, crusting, pain and tenderness in all the studies.
A total of 272 subjects were enrolled in the study and subjects were randomly assigned to one of the three treatment groups; 92 in the nadifloxacin group, 90 in the mupirocin group, and 90 in the framycetin group. A significant reduction in the mean scores for bacterial infection symptoms in the nadifloxacin groups was observed when compared to mupirocin, framycetin and fusidic acid groups. Both physician and patients rated nadifloxacin as excellent (complete remission of symptoms) on a 4-point scale in the studies. No adverse events (AEs) were reported in the clinical studies. In the PMS, only two patients (of 329, 0.6%) reported AEs including burning and itching, one in each patient that had resolved at the time of reporting.
Nadifloxacin, a fluoroquinolone, is a new alternative topical agent in the treatment of bacterial skin infection with minimal AEs.
Electronic supplementary material
The online version of this article (doi:10.1007/s13555-014-0062-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4257952  PMID: 25212256
Bacterial skin infections; Dermatology; Fluoroquinolone; Nadifloxacin; SSTIs; Topical antibiotic
20.  Adipose tissue-derived stem cells display a proangiogenic phenotype on 3D scaffolds 
Ischemic heart disease is the leading cause of death worldwide. Recent studies suggest that adipose tissue-derived stem cells (ASCs) can be used as a potential source for cardiovascular tissue engineering due to their ability to differentiate along the cardiovascular lineage and to adopt a proangiogenic phenotype. To understand better ASCs’ biology, we used a novel 3D culture device. ASCs’ and b.END-3 endothelial cell proliferation, migration, and vessel morphogenesis were significantly enhanced compared to 2D culturing techniques. ASCs were isolated from inguinal fat pads of 6-week-old GFP+/BLI+ mice. Early passage ASCs cells (P3-P4), PKH26-labeled murine b.END-3 cells or a co-culture of ASCs and b.END-3 cells were seeded at a density of 1 × 105 on three different surface configurations: (a) a 2D surface of tissue culture plastic, (b) Matrigel, and (c) a highly porous 3D scaffold fabricated from inert polystyrene. VEGF expression, cell proliferation, and tubulization, were assessed using optical microscopy, fluorescence microscopy, 3D confocal microscopy, and SEM imaging (n = 6). Increased VEGF levels were seen in conditioned media harvested from co-cultures of ASCs and b.END-3 on either Matrigel or a 3D matrix. Fluorescence, confocal, SEM, bioluminescence revealed improved cell, proliferation, and tubule formation for cells seeded on the 3D polystyrene matrix. Collectively, these data demonstrate that co-culturing ASCs with endothelial cells in a 3D matrix environment enable us to generate prevascularized tissue-engineered constructs. This can potentially help us to surpass the tissue thickness limitations faced by the tissue engineering community today.
PMCID: PMC4161132  PMID: 21630430
adipose derived stem cells; neovascularization; tissue engineering; scaffolds
21.  Screening Adverse Drug-Induced Arrhythmia Events Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Low-Impedance Microelectrode Arrays 
Circulation  2013;128(11 0 1):10.1161/CIRCULATIONAHA.112.000570.
Drug-induced arrhythmia is the most common cause of drug development failure and withdrawal from market. This study tested whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with a low-impedance microelectrode array (MEA) system could improve upon industry-standard, preclinical cardiotoxicity screening methods, identify the effects of well-characterized drugs, and elucidate underlying risk factors for drug-induced arrhythmia. Human iPSC-CMs may be advantageous over immortalized cell lines because they possess similar functional characteristics as primary human cardiomyocytes and can be generated in unlimited quantities.
Methods and Results
Pharmacological responses of beating embryoid bodies (EBs) exposed to a comprehensive panel of drugs at 65 to 95 days post-induction were determined. Responses of hiPSC-CMs to drugs were qualitatively and quantitatively consistent with the reported drug effects in literature. Torsadogenic hERG blockers such as sotalol and quinidine produced statistically and physiologically significant effects, consistent with patch-clamp studies on human embryonic stem cell-derived cardiomyocytes (hESC-CMs). False negative and false positive hERG blockers were identified accurately. Consistent with published studies using animal models, early afterdepolarizations (EADs) and ectopic beats were observed in 33% and 40% of embryoid bodies treated with sotalol and quinidine, respectively, compared to negligible EADs and ectopic beats in untreated controls.
We found that drug-induced arrhythmias can be recapitulated in hiPSC-CMs and documented with MEA. Our data indicate that the MEA/hiPSC-CM assay is a sensitive, robust, and efficient platform for testing drug effectiveness and for arrhythmia screening. We believe that this system holds great potential for reducing drug development costs and may provide significant advantages over current industry standard assays that use immortalized cell lines or animal models.
PMCID: PMC3855862  PMID: 24030418
stem cell; cardiomyocyte; pharmacology; arrhythmia; genomics; pharmacogenomics
22.  Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts 
Nature  2014;506(7487):240-244.
Cells of the osteoblast lineage affect homing, 1, 2 number of long term repopulating hematopoietic stem cells (HSCs) 3, 4, HSC mobilization and lineage determination and B lymphopoiesis 5-8. More recently osteoblasts were implicated in pre-leukemic conditions in mice 9, 10. Yet, it has not been shown that a single genetic event taking place in osteoblasts can induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin in osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML) with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSC progenitors induces the malignant changes. Demonstrating the pathogenetic role of the Notch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% of patients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to AML.
PMCID: PMC4116754  PMID: 24429522
23.  Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas 
Nature genetics  2014;46(2):166-170.
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non Hodgkin lymphomas1,2. Here we combined whole exome sequencing of 12 tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing to identify new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA p.Gly17Val (NM_001664) mutation present in 22/35 (67%) of angioimmunoblastic T-cell lymphomas (AITL) and in 8/44 (18%) not otherwise specified PTCL (PTCL NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated Guanine Exchange Factor (GEF) proteins. In addition, we describe new and recurrent, albeit less frequent, genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.
PMCID: PMC3963408  PMID: 24413734
24.  Endoscopic Trans-Nasal Trans-Sphenoidal (TNTS) Approach For Pituitary Adenomas: Our Experience 
Advances in optics, miniaturization, and endoscopic instrumentation have revolutionized surgery in the past decade. Current progress in the field of endoscopy promises to further this evolution: endoscopic telescopes and instruments have improved upon the optical and technical limitations of the microscope, and require an even less invasive approach to the sella. Pituitary surgery is traditionally within the realm of the neurosurgeon. However, since the reintroduction of the transseptal transsphenoidal approach and endoscopic transnasal transsphenoidal approach to the sella turcica for resection of pituitary adenoma, otolaryngologists have been active partners in the surgical management of these patients. Otolaryngologists have lent their expertise in nasal and sinus surgery, assisting the neurosurgeon with the operation. The otolaryngologist has the advantage of familiarity with the techniques and instruments used to gain exposure of the sella turcica by transnasal approach. Hence, the otolaryngologist provides the exposure, and the neurosurgeon resects the tumour. Such collaboration has resulted in decreased rates of complication and morbidity. We hereby discuss our experience of treating 54 cases of pituitary tumour by endoscopic transnasal approach at our hospital.
PMCID: PMC3738807  PMID: 24427667
Pituitary surgery transsphenoidal; Pituitary adenoma; Transphenoid surgery; Endoscopic hypophysectomy
25.  Obstructive voiding symptoms following stereotactic body radiation therapy for prostate cancer 
Obstructive voiding symptoms (OVS) are common following prostate cancer treatment with radiation therapy. The risk of urinary retention (UR) following hypofractionated radiotherapy has yet to be fully elucidated. This study sought to evaluate OVS and UR requiring catheterization following SBRT for prostate cancer.
Patients treated with SBRT for localized prostate cancer from February 2008 to July 2011 at Georgetown University were included in this study. Treatment was delivered using the CyberKnife® with doses of 35 Gy-36.25 Gy in 5 fractions. UR was prospectively scored using the CTCAE v.3. Patient-reported OVS were assessed using the IPSS-obstructive subdomain at baseline and at 1, 3, 6, 9, 12, 18 and 24 months. Associated bother was evaluated via the EPIC-26.
269 patients at a median age of 69 years received SBRT with a median follow-up of 3 years. The mean prostate volume was 39 cc. Prior to treatment, 50.6% of patients reported moderate to severe lower urinary track symptoms per the IPSS and 6.7% felt that weak urine stream and/or incomplete emptying were a moderate to big problem. The 2-year actuarial incidence rates of acute and late UR ≥ grade 2 were 39.5% and 41.4%. Alpha-antagonist utilization rose at one month (58%) and 18 months (48%) post-treatment. However, Grade 3 UR was low with only 4 men (1.5%) requiring catheterization and/or TURP. A mean baseline IPSS-obstructive score of 3.6 significantly increased to 5.0 at 1 month (p < 0.0001); however, it returned to baseline in 92.6% within a median time of 3 months. Late increases in OVS were common, but transient. Only 7.1% of patients felt that weak urine stream and/or incomplete emptying was a moderate to big problem at two years post-SBRT (p = 0.6854).
SBRT treatment caused an acute increase in OVS which peaked within the first month post-treatment, though acute UR requiring catheterization was rare. OVS returned to baseline in > 90% of patients within a median time of three months. Transient Late increases in OVS were common. However, less than 10% of patients felt that OVS were a moderate to big problem at two years post-SBRT.
PMCID: PMC4118163  PMID: 25056726
Prostate cancer; SBRT; CyberKnife; IPSS; Retention; Catheterization; TURP

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