Enhancing respiratory sinus arrhythmia increases cardiac output in rats with left ventricular dysfunction.

KEY POINTS: Respiratory sinus arrhythmia is physiological pacing of the heart that disappears in cardiovascular disease and is associated with poor cardiac prognosis. In heart failure, cardiac pacing has little, if any, variation in rate at rest. We proposed that reinstatement of respiratory sinus arrhythmia would improve cardiac function in rats with heart failure. Heart failure rats were paced daily for 2 weeks with either respiratory sinus arrhythmia or paced monotonically at a matched heart rate; cardiac function was measured using non-invasive echocardiography. Cardiac output and stroke volume were increased in rats paced with respiratory sinus arrhythmia compared to monotonic pacing, via improvement in systolic function that persisted beyond the pacing treatment period. We propose that respiratory sinus arrhythmia pacing reverse-remodels the heart in heart failure and is worth considering as a new form of cardiac pacemaking. ABSTRACT: Natural pacing of the heart results in heart rate variability, an indicator of good health and cardiac function. A contributor to heart rate variability is respiratory sinus arrhythmia or RSA - an intrinsic respiratory modulated pacing of heart rate. The loss of RSA is associated with poor cardiac prognosis and sudden cardiac death. We tested if reinstatement of respiratory-modulated heart rate (RMH) would improve cardiac performance in heart failure. Heart failure was induced in Wistar rats by ligation of the left anterior descending coronary artery. Rats were unpaced, monotonically paced and RMH paced; the latter had the same average heart rate as the monotonically paced animals. Cardiac function was assessed non-invasively using echocardiography before and after 2 weeks of daily pacing at a time when pacing was turned off. RMH increased cardiac output by 20 ± 8% compared to monotonic pacing (-3 ± 5%; P < 0.05). This improvement in cardiac output was associated with an increase in stroke volume compared to monotonic pacing (P = 0.03) and improvement in circumferential strain (P = 0.02). Improvements in ejection fraction (P = 0.08) and surrogate measures of left ventricle compliance did not reach significance. Increases in contractility (P < 0.05) and coronary blood flow (P < 0.05) were seen in vitro during variable pacing to mimic RMH. Thus, in rats with left ventricular dysfunction, chronic RMH pacing improved cardiac function through improvements in systolic function. As these improvements were made with pacing switched off, we propose the novel idea that RMH pacing causes reverse-remodelling.

Neuron-microglia interaction induced bi-directional cytotoxicity associated with calpain activation.

Activated microglia release pro-inflammatory factors and calpain into the extracellular milieu, damaging surrounding neurons. However, mechanistic links to progressive neurodegeneration in disease such as multiple sclerosis (MS) remain obscure. We hypothesize that persistent damaged/dying neurons may also release cytotoxic factors and calpain into the media, which then activate microglia again. Thus, inflammation, neuronal damage, and microglia activation, i.e., bi-directional interaction between neurons and microglia, may be involved in the progressive neurodegeneration. We tested this hypothesis using two in vitro models: (i) the effects of soluble factors from damaged primary cortical neurons upon primary rat neurons and microglia and (ii) soluble factors released from CD3/CD28 activated peripheral blood mononuclear cells of MS patients on primary human neurons and microglia. The first model indicated that neurons due to injury with pro-inflammatory agents (IFN-γ) release soluble neurotoxic factors, including COX-2, reactive oxygen species, and calpain, thus activating microglia, which in turn released neurotoxic factors as well. This repeated microglial activation leads to persistent inflammation and neurodegeneration. The released calpain from neurons and microglia was confirmed by the use of calpain inhibitor calpeptin or SNJ-1945 as well as µ- and m-calpain knock down using the small interfering RNA (siRNA) technology. Our second model using activated peripheral blood mononuclear cells, a source of pro-inflammatory Th1/Th17 cytokines and calpain released from auto-reactive T cells, corroborated similar results in human primary cell cultures and confirmed calpain to be involved in progressive MS. These insights into reciprocal paracrine regulation of cell injury and calpain activation in the progressive phase of MS, Parkinson's disease, and other neurodegenerative diseases suggest potentially beneficial preventive and therapeutic strategies, including calpain inhibition.

Endocytosis of human immunodeficiency virus 1 (HIV-1) in astrocytes: a fiery path to its destination.

Despite successful suppression of peripheral HIV-1 infection by combination antiretroviral therapy, immune activation by residual virus in the brain leads to HIV-associated neurocognitive disorders (HAND). In the brain, several types of cells, including microglia, perivascular macrophage, and astrocytes have been reported to be infected by HIV-1. Astrocytes, the most abundant cells in the brain, maintain homeostasis. The general consensus on HIV-1 infection in astrocytes is that it produces unproductive viral infection. HIV-1 enters astrocytes by pH-dependent endocytosis, leading to degradation of the virus in endosomes, but barely succeeds in infection. Here, we have discussed endocytosis-mediated HIV-1 entry and viral programming in astrocytes.

Desulfurization of thianthrene by a Gordonia sp. IITR100.

Thianthrene (TA) was desulfurized by an isolated strain, Gordonia sp. IITR100. The reaction is accompanied with the formation of TA-sulfoxide, TA-sulfone and 2-phenylsulfanylphenol. The formed 2-phenylsulfanylphenol undergoes further oxidation to o-hydroxyphenyl phenylsulfone that accumulates as an end product. Metabolism of TA to TA-sulfone can also occur by E. coli-DszC i.e. E. coli cells that were harboring the gene coding for the enzyme dibenzothiophene desulfurase C. When presented to E. coli-DszC in a binary combination with dibenzothiophene, TA metabolism was completely inhibited. Metabolism of TA-TA-sulfone by E. coli-DszC, as well as the nature of metabolites formed by IITR100, suggests that the desulfurization pathway for TA is similar to that of the thiophenic compounds. This is first report on the desulfurization of thianthrene, and has implications on biodesulfurization when multiple sulfur compounds are present together.

Male breast cancer: a 30 year retrospective analysis from a tertiary cancer care centre.

Background: Male breast cancer (MBC) is one of the rare malignancies that account for less than 1% of all malignancies in males. However, the clinicopathological characteristics of MBC are not entirely similar to female breast cancer; but still, it is treated in line with the female breast cancer protocols. Aims: To retrospectively analyse trends in MBC as to its distribution, presentation, treatment, and outcome. Material and method: A total of 106 patients with MBC from 1991 to 2020 were analysed retrospectively. Frequency distribution analysis of the demographic and clinicopathological data and treatment variables was done. Results: Median age of presentation was 57 years; ranging from 30 to 86 years. Either of the sides was almost equally affected with an R: L ratio of 1.2:1. The average duration of complaint was 26.2 months (range 1-240 months). History of gynaecomastia was noted in 18 patients, significant benign prostate hypertrophy in 13, and hypertension needing medical treatment in 14 patients. The majority of the patients were smokers (72/106) and alcoholics (43/106). Five patients reported positive family history. 21 patients had metastatic disease at presentation and received palliative treatment. Stage II was seen in 36.8%, stage III in 43.4%, and stage IV in 19.8% of patients. Node positives were 63.2%. Pathology was invariably (90.5%) infiltrative ductal carcinoma. Radiation was administered in 85.8% of the patients, chemotherapy in 72.6% of patients, and hormonal treatment was given in 47.2% of patients. The median overall survival (OS) was 78 months. OS at 5 and 10 years was 78% and 58% respectively. Conclusion: Despite the possibility of MBC being apparent at an early stage, patients present with locally advanced disease. Radical surgery with adjuvant/neoadjuvant chemotherapy and adjuvant radiotherapy remains the gold standard. Cancer education campaigns must be run to catch the early disease and to radically treat the disease.

Pretreament neutrophil-lymphocyte ratio (NLR): A felicitous prognostic marker in carcinoma lung.

BACKGROUND: Mechanics of inflammation and oncogenesis are intertwined with each other. Thus, the role of inflammatory markers like neutrophil-lymphocyte ratio (NLR) as a foreteller of lung carcinoma is retrospectively appraised in this study. MATERIAL AND METHODS: Retrospective assessment of hospital records of carcinoma lung patients was done between January 2018 and January 2020 and pretreatment NLR was calculated. Median NLR was taken as cut off and thereafter correlation was studied between pretreatment NLR and overall survival, using Kaplan-Meier survival analysis. Cox regression analysis was applied to identify factors affecting survival. RESULTS: Study population included 135 eligible patients with median age of 60 years and male to female ratio of 8.6:1. 47.41% patients were of stage III and 52.59% patients belonged to stage IV. The duration of follow-up ranged between 0.5 and 22 months. Median NLR was 3.1 (range, 0.90-11.25) and median overall survival in patients with NLR <3.1 and ≥3.1 was 6 months versus 3 months, respectively (P-value = 0.001). NLR value in nonsmall cell and small cell lung cancer was analyzed separately and showed significant variation in median survival in nonsmall cell lung cancer patients only (P-value = 0.001). CONCLUSIONS: Study results summarized that pretreatment NLR can be taken as a cheap and easily available predictor of prognosis in carcinoma lung cases and more so in nonsmall cell lung carcinoma cases. Large prospective trials are warranted to further potentiate this fact.

Bryostatin-1, a naturally occurring antineoplastic agent, acts as a Toll-like receptor 4 (TLR-4) ligand and induces unique cytokines and chemokines in dendritic cells.

Bryostatin-1 (Bryo-1), a natural macrocyclic lactone, is clinically used as an anti-cancer agent. In this study, we demonstrate for the first time that Bryo-1 acts as a Toll-like receptor 4 (TLR4) ligand. Interestingly, activation of bone marrow-derived dendritic cells (in vitro with Bryo-1) led to a TLR4-dependent biphasic activation of nuclear factor-κB (NF-κB) and the unique induction of cytokines (IL-5, IL-6, and IL-10) and chemokines, including RANTES (regulated on activation normal T cell expressed and secreted) and macrophage inflammatory protein 1α (MIP1-α). In addition, EMSA demonstrated that Bryo-1-mediated induction of RANTES was regulated by NF-κB and the interferon regulatory factors (IRF)-1, IRF-3, and IRF-7 to the RANTES independently of myeloid differentiation primary response gene-88 (MyD88). Bryo-1 was able to induce the transcriptional activation of IRF-3 through the TLR4/MD2-dependent pathway. In vivo administration of Bryo-1 triggered a TLR-4-dependent T helper cell 2 (Th2) cytokine response and expanded a subset of myeloid dendritic cells that expressed a CD11c(high)CD8α(-) CD11b(+)CD4(+) phenotype. This study demonstrates that Bryo-1 can act as a TLR4 ligand and activate innate immunity. Moreover, the ability of Bryo-1 to trigger RANTES and MIP1-α suggests that Bryo-1 could potentially be used to prevent HIV-1 infection. Finally, induction of a Th2 response by Bryo-1 may help treat inflammatory diseases mediated by Th1 cells. Together, our studies have a major impact on the clinical use of Bryo-1 as an anti-cancer and immunopotentiating agent.

Programming of neurotoxic cofactor CXCL-10 in HIV-1-associated dementia: abrogation of CXCL-10-induced neuro-glial toxicity in vitro by PKC activator.

BACKGROUND: More than 50% of patients undergoing lifelong suppressive antiviral treatment for HIV-1 infection develop minor HIV-1-associated neurocognitive disorders. Neurological complications during HIV-1 infection are the result of direct neuronal damage by proinflammatory products released from HIV-1-infected or -uninfected activated lymphocytes, monocytes, macrophages, microglia and astrocytes. The specific pro-inflammatory products and their roles in neurotoxicity are far from clear. We investigated proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) of HIV-demented (HIV-D) and HIV-nondemented (HIV-ND) patients and studied their affect on neuroglial toxicity. METHODS AND RESULTS: Bioplex array showed elevated levels of signatory chemokines or cytokines (IL-6, IFN-γ, CXCL10, MCP-1 and PDGF) in the CSF of HIV-D patients (n = 7) but not in that of HIV-ND patients (n = 7). Among the signatory cytokines and chemokines, CXCL10 was distinctly upregulated in-vitro in HIV-1 (NLENG1)-activated human fetal astrocytes, HIV-1 (Ba-L)-infected macrophages, and HIV-1 (NLENG1)-infected lymphocytes. Virus-infected macrophages also had increased levels of TNF-α. Consistently, human fetal astrocytes treated with HIV-1 and TNF-α induced the signatory molecules. CXCL10 in combination with HIV-1 synergistically enhanced neuronal toxicity and showed chemotactic activity (~ 40 fold) for activated peripheral blood mononuclear cells (PBMC), suggesting the intersection of signaling events imparted by HIV-1 and CXCL10 after binding to their respective surface receptors, CXCR4 and CXCR3, on neurons. Blocking CXCR3 and its downstream MAP kinase (MAPK) signaling pathway suppressed combined CXCL10 and HIV-1-induced neurotoxicity. Bryostatin, a PKC modulator and suppressor of CXCR4, conferred neuroprotection against combined insult with HIV-1 and CXCL10. Bryostatin also suppressed HIV-1 and CXCL10-induced PBMC chemotaxis. Although, therapeutic targeting of chemokines in brain may have adverse consequences on the host, current findings and earlier evidence suggest that CXCL10 could strongly impede neuroinflammation. CONCLUSION: We have demonstrated induction of CXCL10 and other chemokines/cytokines during HIV-1 infection in the brain, as well as synergism of CXCL10 with HIV-1 in neuronal toxicity, which was dampened by bryostatin.

Endogenous hormones in postmenopausal females with breast cancer--before and after treatment.

BACKGROUND: Breast cancer is usually present for many years (as long as 5-10 years) before it can be clinically diagnosed (theory of the 'dormant malignant cell'). This implies that breast cancer cells, during their subclinical period, are likely to have been exposed for a considerable time to endogenous sex hormones and endogenous hormonal milieu predicts the chances of breast cancer in females. So, we planned this study to evaluate the role of endogenous hormones in postmenopausal females excluding the patients on hormone replacement therapy as the relationship between breast cancer and hormone replacement therapy is well known. METHODS: Hormone therapy is known to affect these hormone levels but whether treatment of breast cancer per se also decreases the hormone levels is not known. We planned the present study to determine hormone levels in patients before and after 4 months of treatment (chemotherapy/surgery and radiotherapy). Circulating hormone levels were measured using a chemiluminescence method. Their results were compared with a group of 25 age matched healthy controls. RESULTS: We found that serum prolactin, testosterone and estrogen levels were very significantly higher in patients before treatment (Group I) as compared to controls (Group III). Serum prolactin and serum estrogen levels were significantly higher and serum testosterone was very significantly higher in patients before treatment (Group I) when compared after 4 months of treatment (Group II). Only serum estrogen levels were significantly high in patients after treatment (Group II) as compared to controls (Group III). Serum progesterone levels showed no significant difference to any of the groups. CONCLUSIONS: We concluded that postmenopausal females with breast cancer have abnormalities in hormone levels. These abnormalities may be considered in the pathogenesis of the disease and should be taken into account in the treatment of patients of breast cancer. It might also be helpful to delay the onset of cancer by normalizing the levels of these hormones and in deciding the treatment modality for the patients once breast cancer has been diagnosed but further studies are required to prove the benefit of measuring serum hormone levels as a screening test.

Nanoparticles in the treatment and diagnosis of neurological disorders: untamed dragon with fire power to heal.

The incidence of neurological diseases of unknown etiology is increasing, including well-studied diseases such as Alzhiemer's, Parkinson's, and multiple sclerosis. The blood-brain barrier provides protection for the brain but also hinders the treatment and diagnosis of these neurological diseases, because the drugs must cross the blood-brain barrier to reach the lesions. Thus, attention has turned to developing novel and effective delivery systems that are capable of carrying drug and that provide good bioavailability in the brain. Nanoneurotechnology, particularly application of nanoparticles in drug delivery, has provided promising answers to some of these issues in recent years. Here we review the recent advances in the understanding of several common forms of neurological diseases and particularly the applications of nanoparticles to treat and diagnose them. In addition, we discuss the integration of bioinformatics and modern genomic approaches in the development of nanoparticles. FROM THE CLINICAL EDITOR: In this review paper, applications of nanotechnology-based diagnostic methods and therapeutic modalities are discussed addressing a variety of neurological disorders, with special attention to blood-brain barrier delivery methods. These novel nanomedicine approaches are expected to revolutionize several aspects of clinical neurology.

Noise-activated barrier crossing in multiattractor dissipative neural networks.

Noise-activated transitions between coexisting attractors are investigated in a chaotic spiking network. At low noise level, attractor hopping consists of discrete bifurcation events that conserve the memory of initial conditions. When the escape probability becomes comparable to the intrabasin hopping probability, the lifetime of attractors is given by a detailed balance where the less coherent attractors act as a sink for the more coherent ones. In this regime, the escape probability follows an activation law allowing us to assign pseudoactivation energies to limit cycle attractors. These pseudoenergies introduce a useful metric for evaluating the resilience of biological rhythms to perturbations.

Point-Prevalence Survey for the Hospital-Acquired Infections in Intensive Care Units of Trauma Center in a Tertiary Care Hospital of Northern India.

Background The burden of hospital-acquired infections (HAIs) is all assumption based, and the true burden remains unknown in most countries, particularly in the developing countries where healthcare facilities are suboptimal and knowledge is limited. Methodology This cross-sectional study was conducted at the trauma center of a tertiary care institute from August to September 2019, to assess the burden of HAI and antibiotic resistance pattern of HAI. The total sample size in our study was 105. Our objective was to estimate the point prevalence of HAI and study the associated factors in a tertiary care hospital. Result In this study, the point prevalence of HAI was five to six times higher when compared with that of developed countries. Gram-negative organisms were the predominant bacteria; with Acinetobacter baumannii the most common among them. Conclusion Point-prevalence survey is an important objective of the antimicrobial stewardship program; it will be helpful in controlling antimicrobial resistance and this tool plays a significant role in hospital settings. Our study is quite pertinent to assess the point prevalence of HAI. It will help in knowing the current prevalence and pattern of the HAI. Therefore, as healthcare administrators, we can further decrease the HAI for better patient outcomes in the future.

CBF-1 Promotes the Establishment and Maintenance of HIV Latency by Recruiting Polycomb Repressive Complexes, PRC1 and PRC2, at HIV LTR.

The C-promoter binding factor-1 (CBF-1) is a potent and specific inhibitor of the human immunodeficiency virus (HIV)-1 LTR promoter. Here, we demonstrate that the knockdown of endogenous CBF-1 in latently infected primary CD4+ T cells, using specific small hairpin RNAs (shRNA), resulted in the reactivation of latent HIV proviruses. Chromatin immunoprecipitation (ChIP) assays using latently infected primary T cells and Jurkat T-cell lines demonstrated that CBF-1 induces the establishment and maintenance of HIV latency by recruiting polycomb group (PcG/PRC) corepressor complexes or polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Knockdown of CBF-1 resulted in the dissociation of PRCs corepressor complexes enhancing the recruitment of RNA polymerase II (RNAP II) at HIV LTR. Knockdown of certain components of PRC1 and PRC2 also led to the reactivation of latent proviruses. Similarly, the treatment of latently infected primary CD4+ T cells with the PRC2/EZH2 inhibitor, 3-deazaneplanocin A (DZNep), led to their reactivation.

Isolated breast metastasis from granulosa cell tumor of the ovary.

Granulosa cell tumors of the ovary are rare neoplasms arising from sex-cord stromal cells. These tumors usually present with stage I disease as they are frequently associated with hormonal effects. Only a small percentage of such tumors metastasize and the common sites of metastasis are lung, liver, and brain. Granulosa cell tumor of ovary metastasizing to breast has never been reported in literature. We present such a case of ovarian granulosa cell tumor with metastasis to the breast, which was the presenting symptom. The patient was treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy which was followed by chemotherapy. The patient is relapse free 2 years after completion of treatment.

Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV-1 Tat transgenic mice.

HIV encephalitis (HIVE) is accompanied by brain inflammation, leukocyte infiltration, and glial activation, and HIV patients who abuse opiates are more likely to develop HIVE. To better understand how opiates could alter HIV-related brain inflammation, the expression of astrocyte (GFAP immunoreactivity) and macrophage/microglial (F4/80 or Mac1 immunoreactivity) markers in the striatum, and the percentage of 3-nitrotyrosine (3-NT) positive macrophages/microglia, was determined following a 2-day exposure to morphine (5 mg/kg/day via time-release, subcutaneous implant) and doxycycline in GFAP-driven, doxycycline-inducible HIV-1 Tat transgenic mice. Data show that both morphine and Tat induction via doxycycline increased astrocyte activation, with significant additive increases achieved with combined morphine and doxycycline exposure. By contrast, combined Tat induction and morphine exposure, but neither manipulation alone, significantly increased the proportion of macrophages/microglia present in the striatum of transgenic mice, although morphine exposure was necessary to elevate 3-NT co-detection in Mac1-positive macrophages/microglia. Finally, Tat induction increased the percentage of neurons expressing active caspase-3, and this was even more significantly elevated by co-administration of morphine. In spite of elevations in caspase-3, neuronal TUNEL reactivity was unchanged in all groups, even after 10 days of Tat induction. Importantly, co-administration of naltrexone completely antagonized the effects of morphine. These findings indicate that morphine rapidly and significantly increases the activation of astrocytes and macrophages/microglia in the brains of inducible Tat transgenic mice, supporting the theory that early inflammatory changes in glia could underlie the development of HIVE in opiate-abusing AIDS patients.

Molecular programming of endothelin-1 in HIV-infected brain: role of Tat in up-regulation of ET-1 and its inhibition by statins.

Human Immune Deficiency Virus-1 (HIV-1) infection can induce severe and debilitating neurological problems, including behavioral abnormalities, motor dysfunction, and dementia. HIV can persistently infect astrocytes, during which viral accessory proteins are produced that are unaffected by current antiretroviral therapy. The effect of these proteins on astrocyte function remains unknown. Astrocytes are the predominant cells within the brain; thus, disruption of astrocyte function could influence the neuropathogenesis of HIV infection. To explore further these effects, we constitutively expressed HIV-Tat protein in astrocytes. Since the nuclear presence of Tat protein leads to alteration of host gene expression, we further analyzed the effects of Tat on host gene transcripts. Endothelin-1 (ET-1) was a significantly elevated transcript as verified by reverse transcription-polymerase chain reaction (RT-PCR), and it was subsequently released extracellularly in Tat-expressing and HIV-infected astrocytes. ET-1 expression was also prominent in reactive astrocytes and neurons in brain tissues from basal ganglia and frontal lobes of HIV encephalitic patients. HIV-Tat regulated ET-1 at the transcriptional level through NF-kappaB (NF-kappaB)-responsive sites in the ET-1 promoter. Intriguingly, simvastatin (10 microM) down-regulated HIV-Tat-induced ET-1 and also inhibited activation of NF-kappaB in astrocytes. Our findings suggest that ET-1 may be critical in mediating the neuropathogenesis of HIV dementia and that statins may have therapeutic potential in these patients.

Dual Mechanism for the Emergence of Synchronization in Inhibitory Neural Networks.

During cognitive tasks cortical microcircuits synchronize to bind stimuli into unified perception. The emergence of coherent rhythmic activity is thought to be inhibition-driven and stimulation-dependent. However, the exact mechanisms of synchronization remain unknown. Recent optogenetic experiments have identified two neuron sub-types as the likely inhibitory vectors of synchronization. Here, we show that local networks mimicking the soma-targeting properties observed in fast-spiking interneurons and the dendrite-projecting properties observed in somatostatin interneurons synchronize through different mechanisms which may provide adaptive advantages by combining flexibility and robustness. We probed the synchronization phase diagrams of small all-to-all inhibitory networks in-silico as a function of inhibition delay, neurotransmitter kinetics, timings and intensity of stimulation. Inhibition delay is found to induce coherent oscillations over a broader range of experimental conditions than high-frequency entrainment. Inhibition delay boosts network capacity (ln2)-N-fold by stabilizing locally coherent oscillations. This work may inform novel therapeutic strategies for moderating pathological cortical oscillations.

Major Risk Factors in Head and Neck Cancer: A Retrospective Analysis of 12-Year Experiences.

BACKGROUND: Head and neck cancer (HNC) is the seventh most common type of cancer in the world and constitute 5% of the entire cancers worldwide. The global burden of HNC accounts for 650,000 new cases and 350,000 deaths worldwide every year and a major proportion of regional malignancies in India. More than 70% of squamous cell carcinoma of the head and neck are estimated to be avoidable by lifestyle changes, particularly by effective reduction of exposure to well-known risk factors such as tobacco smoking and alcohol drinking. METHODS: A retrospective analysis of 12 years (2001 - 2012) of HNC patients attending RCC, PGIMS Rohtak was done. Total numbers of cancer patients seen were 26,295 and out of these 9,950 patients were of HNCs, which were retrospectively analyzed for their associated risk factors in different HNC subtypes. Most of the patients, i.e. 92.3%, were presented as locally advanced HNC (stages III and IV). RESULTS: It has been observed that smoking and alcohol are the strongest independent risk factors responsible for increased risk of HNC and are further having synergetic correlations. CONCLUSION: The present study confirms the principal role of alcohol consumption and smoking in HNC carcinogenesis, as well as the differential associations with HNC subtypes, and a significant, positive, multiplicative interaction with different risk factors.

The taming of the cell penetrating domain of the HIV Tat: myths and realities.

Protein transduction with cell penetrating peptides over the past several years has been shown to be an effective way of delivering proteins in vitro and now several reports have also shown valuable in vivo applications in correcting disease states. An impressive bioinspired phenomenon of crossing biological barriers came from HIV transactivator Tat protein. Specifically, the protein transduction domain of HIV Tat has been shown to be a potent pleiotropic peptide in protein delivery. Various approaches such as molecular modeling, arginine guanidinium head group structural strategy, multimerization of PTD sequence and phage display system have been applied for taming of the PTD. This has resulted in identification of PTD variants which are efficient in cell membrane penetration and cytoplasmic delivery. In spite of these state of the art technologies, the dilemma of low protein transduction efficiency and target specific delivery of PTD fusion proteins remains unsolved. Moreover, some misconceptions about PTD of Tat in the literature require considerations. We have assembled critical information on secretory, plasma membrane penetration and transcellular properties of Tat and PTD using molecular analysis and available experimental evidences.