Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID.

SARS-CoV-2, the etiological agent of COVID-19, is devoid of any metabolic capacity; therefore, it is critical for the viral pathogen to hijack host cellular metabolic machinery for its replication and propagation. This single-stranded RNA virus with a 29.9 kb genome encodes 14 open reading frames (ORFs) and initiates a plethora of virus-host protein-protein interactions in the human body. These extensive viral protein interactions with host-specific cellular targets could trigger severe human metabolic reprogramming/dysregulation (HMRD), a rewiring of sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well as altered or impaired bioenergetics, immune dysfunction, and redox imbalance in the body. In the infectious process, the viral pathogen hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2 and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases, TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL) for fusogenic release of its viral genome. The virus-induced HMRD results in 5 possible infectious outcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acute COVID-19 condition could manifest into 3 clinical phases: (i) hypoxia and hypoxemia (Warburg effect), (ii) hyperferritinemia ('cytokine storm'), and (iii) thrombocytosis (coagulopathy). The mean incubation period for COVID-19 onset was estimated to be 5.1 days, and most cases develop symptoms after 14 days. The mean viral clearance times were 24, 30, and 39 days for acute, severe, and ICU-admitted COVID-19 patients, respectively. However, about 25-70% of virus-free COVID-19 survivors continue to sustain virus-induced HMRD and exhibit a wide range of symptoms that are persistent, exacerbated, or new 'onset' clinical incidents, collectively termed as post-acute sequelae of COVID-19 (PASC) or long COVID. PASC patients experience several debilitating clinical condition(s) with >200 different and overlapping symptoms that may last for weeks to months. Chronic PASC is a cumulative outcome of at least 10 different HMRD-related pathophysiological mechanisms involving both virus-derived virulence factors and a multitude of innate host responses. Based on HMRD and virus-free clinical impairments of different human organs/systems, PASC patients can be categorized into 4 different clusters or sub-phenotypes: sub-phenotype-1 (33.8%) with cardiac and renal manifestations; sub-phenotype-2 (32.8%) with respiratory, sleep and anxiety disorders; sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders; and sub-phenotype-4 (10.1%) with digestive and pulmonary dysfunctions. This narrative review elucidates the effects of viral hijack on host cellular machinery during SARS-CoV-2 infection, ensuing detrimental effect(s) of virus-induced HMRD on human metabolism, consequential symptomatic clinical implications, and damage to multiple organ systems; as well as chronic pathophysiological sequelae in virus-free PASC patients. We have also provided a few evidence-based, human randomized controlled trial (RCT)-tested, precision nutrients to reset HMRD for health recovery of PASC patients.

Fetoscopic laser ablation for twin-to-twin transfusion syndrome in Malaysia: A 15-month retrospective cohort review from an emerging centre in South East Asia.

INTRODUCTION: The authors aim to review the early outcomes of fetostopic laser ablation (FLA) to improve outcomes for twin-to-twin transfusion syndrome (TTTS) in an emerging national centre in Malaysia. MATERIALS AND METHODS: This is a retrospective cohort study of 17 monochorionic diamniotic (MCDA) twin pregnancies with severe TTTS treated by FLA over 15 months in a single centre by a single operator after performing simulations. RESULT: The overall survival rate at day 28 after birth for at least one twin was 76% while the dual-twin survival was 64%. The survival rates at day 28 after birth for at least one twin for stages II, III and IV were 90% vs 40% vs 100% (p=0.054) while dual survival rates were 80% vs 0% vs 100% (p=0.05), respectively. The rate of miscarriage was higher with anterior placentation compared to posterior placentation (33% vs 18%, p=0.660). There was one case of recurrent TTTS and no twin anaemia-polycythaemia sequence post-FLA. The fetal medicine unit in Ipoh is the national centre in Malaysia which covers the whole country, including the western coast of the Borneo Island (Sabah, Sarawak and Labuan) accessible only by air travel. All three cases from Borneo Island had resolved TTTS after FLA and dual neonatal survival at day 28 after birth. CONCLUSION: This data from an emerging new fetoscopic laser centre in Malaysia indicates results consistent with the published international learning curve and within the limits of good clinical governance.

Heartbeat sound classification using a hybrid adaptive neuro-fuzzy inferences system (ANFIS) and artificial bee colony.

Cardiovascular disease is one of the main causes of death worldwide which can be easily diagnosed by listening to the murmur sound of heartbeat sounds using a stethoscope. The murmur sound happens at the Lub-Dub, which indicates there are abnormalities in the heart. However, using the stethoscope for listening to the heartbeat sound requires a long time of training then only the physician can detect the murmuring sound. The existing studies show that young physicians face difficulties in this heart sound detection. Use of computerized methods and data analytics for detection and classification of heartbeat sounds will improve the overall quality of sound detection. Many studies have been worked on classifying the heartbeat sound; however, they lack the method with high accuracy. Therefore, this research aims to classify the heartbeat sound using a novel optimized Adaptive Neuro-Fuzzy Inferences System (ANFIS) by artificial bee colony (ABC). The data is cleaned, pre-processed, and MFCC is extracted from the heartbeat sounds. Then the proposed ABC-ANFIS is used to run the pre-processed heartbeat sound, and accuracy is calculated for the model. The results indicate that the proposed ABC-ANFIS model achieved 93% accuracy for the murmur class. The proposed ABC-ANFIS has higher accuracy in compared to ANFIS, PSO ANFIS, SVM, KSTM, KNN, and other existing studies. Thus, this study can assist physicians to classify heartbeat sounds for detecting cardiovascular disease in the early stages.

Phytonutrient Inhibitors of SARS-CoV-2/NSP5-Encoded Main Protease (Mpro) Autocleavage Enzyme Critical for COVID-19 Pathogenesis.

The genomic reshuffling, mutagenicity, and high transmission rate of the SARS-CoV-2 pathogen highlights an urgent need for effective antiviral interventions for COVID-19 control. Targeting the highly conserved viral genes and/or gene-encoded viral proteins such as main proteinase (Mpro), RNA-dependent RNA polymerase (RdRp) and helicases are plausible antiviral approaches to prevent replication and propagation of the SARS-CoV-2 infection. Coronaviruses (CoVs) are prone to extensive mutagenesis; however, any genetic alteration to its highly conserved Mpro enzyme is often detrimental to the viral pathogen. Therefore, inhibitors that target the Mpro enzyme could reduce the risk of mutation-mediated drug resistance and provide effective antiviral protection. Several existing antiviral drugs and dietary bioactives are currently repurposed to treat COVID-19. Dietary bioactives from three ayurvedic medicinal herbs, 18 ß-glycyrrhetinic acid (ΔG = 8.86 kcal/mol), Solanocapsine (ΔG = 8.59 kcal/mol), and Vasicoline (ΔG = 7.34 kcal/mol), showed high-affinity binding to Mpro enzyme than the native N3 inhibitor (ΔG = 5.41 kcal/mol). Flavonoids strongly inhibited SARS-CoV-2 Mpro with comparable or higher potency than the antiviral drug, remdesivir. Several tannin hydrolysates avidly bound to the receptor-binding domain and catalytic dyad (His41 and Cys145) of SARS-CoV-2 Mpro through H-bonding forces. Quercetin binding to Mpro altered the thermostability of the viral protein through redox-based mechanism and inhibited the viral enzymatic activity. Interaction of quercetin-derivatives with the Mpro seem to be influenced by the 7-OH group and the acetoxylation of sugar moiety on the ligand molecule. Based on pharmacokinetic and ADMET profiles, several phytonutrients could serve as a promising redox nutraceutical for COVID-19 management.

Plant-Derived Natural Non-Nucleoside Analog Inhibitors (NNAIs) against RNA-Dependent RNA Polymerase Complex (nsp7/nsp8/nsp12) of SARS-CoV-2.

The emergence of fast-spreading SARS-CoV-2 mutants has sparked a new phase of COVID-19 pandemic. There is a dire necessity for antivirals targeting highly conserved genomic domains on SARS-CoV-2 that are less prone to mutation. The nsp12, also known as the RNA-dependent RNA-polymerase (RdRp), the core component of 'SARS-CoV-2 replication-transcription complex', is a potential well-conserved druggable antiviral target. Several FDA-approved RdRp 'nucleotide analog inhibitors (NAIs)' such as remdesivir, have been repurposed to treat COVID-19 infections. The NAIs target RdRp protein translation and competitively block the nucleotide insertion into the RNA chain, resulting in the inhibition of viral replication. However, the replication proofreading function of nsp14-ExoN could provide resistance to SARS-CoV-2 against many NAIs. Conversely, the 'non-nucleoside analog inhibitors (NNAIs)' bind to allosteric sites on viral polymerase surface, change the redox state; thereby, exert antiviral activity by altering interactions between the enzyme substrate and active core catalytic site of the RdRp. NNAIs neither require metabolic activation (unlike NAIs) nor compete with intracellular pool of nucleotide triphosphates (NTPs) for anti-RdRp activity. The NNAIs from phytonutrient origin are potential antiviral candidates compared to their synthetic counterparts. Several in-silico studies reported the antiviral spectrum of natural phytonutrient-NNAIs such as Suramin, Silibinin (flavonolignan), Theaflavin (tea polyphenol), Baicalein (5,6,7-trihydroxyflavone), Corilagin (gallotannin), Hesperidin (citrus bioflavonoid), Lycorine (pyrrolidine alkaloid), with superior redox characteristics (free binding energy, hydrogen-bonds, etc.) than antiviral drugs (i.e. remdesivir, favipiravir). These phytonutrient-NNAIs also exert anti-inflammatory, antioxidant, immunomodulatory and cardioprotective functions, with multifunctional therapeutic benefits in the clinical management of COVID-19.

Lactoferrin for Mental Health: Neuro-Redox Regulation and Neuroprotective Effects across the Blood-Brain Barrier with Special Reference to Neuro-COVID-19.

Overall mental health depends in part on the blood-brain barrier, which regulates nutrient transfer in-and-out of the brain and its central nervous system. Lactoferrin, an innate metal-transport protein, synthesized in the substantia nigra, particularly in dopaminergic neurons and activated microglia is vital for brain physiology. Lactoferrin rapidly crosses the blood-brain barrier via receptor-mediated transcytosis and accumulates in the brain capillary endothelial cells. Lactoferrin receptors are additionally present on glioma cells, brain micro-vessels, and neurons. As a regulator of neuro-redox, microglial lactoferrin is critical for protection/repair of neurons and healthy brain function. Iron imbalance and oxidative stress are common among patients with neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, dementia, depression, and multiple sclerosis. As an endogenous iron-chelator, lactoferrin prevents iron accumulation and dopamine depletion in Parkinson's disease patients. Oral lactoferrin supplementation could modulate the p-Akt/PTEN pathway, reduce Aß deposition, and ameliorate cognitive decline in Alzheimer's disease. Novel lactoferrin-based nano-therapeutics have emerged as effective drug-delivery systems for clinical management of neurodegenerative disorders. Recent emergence of the Coronavirus disease-2019 (COVID-19) pandemic, initially considered a respiratory illness, demonstrated a broader virulence spectrum with the ability to cross the blood-brain barrier and inflict a plethora of neuropathological manifestations in the brain - the Neuro-COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are widely reported in Parkinson's disease, Alzheimer's disease, dementia, and multiple sclerosis patients with aggravated clinical outcomes. Lactoferrin, credited with several neuroprotective benefits in the brain could serve as a potential adjuvant in the clinical management of Neuro-COVID-19.

SARS-CoV-2 Infection Dysregulates Host Iron (Fe)-Redox Homeostasis (Fe-R-H): Role of Fe-Redox Regulators, Ferroptosis Inhibitors, Anticoagulants, and Iron-Chelators in COVID-19 Control.

Severe imbalance in iron metabolism among SARS-CoV-2 infected patients is prominent in every symptomatic (mild, moderate to severe) clinical phase of COVID-19. Phase-I - Hypoxia correlates with reduced O2 transport by erythrocytes, overexpression of HIF-1α, altered mitochondrial bioenergetics with host metabolic reprogramming (HMR). Phase-II - Hyperferritinemia results from an increased iron overload, which triggers a fulminant proinflammatory response - the acute cytokine release syndrome (CRS). Elevated cytokine levels (i.e. IL6, TNFα and CRP) strongly correlates with altered ferritin/TF ratios in COVID-19 patients. Phase-III - Thromboembolism is consequential to erythrocyte dysfunction with heme release, increased prothrombin time and elevated D-dimers, cumulatively linked to severe coagulopathies with life-threatening outcomes such as ARDS, and multi-organ failure. Taken together, Fe-R-H dysregulation is implicated in every symptomatic phase of COVID-19. Fe-R-H regulators such as lactoferrin (LF), hemoxygenase-1 (HO-1), erythropoietin (EPO) and hepcidin modulators are innate bio-replenishments that sequester iron, neutralize iron-mediated free radicals, reduce oxidative stress, and improve host defense by optimizing iron metabolism. Due to its pivotal role in 'cytokine storm', ferroptosis is a potential intervention target. Ferroptosis inhibitors such as ferrostatin-1, liproxstatin-1, quercetin, and melatonin could prevent mitochondrial lipid peroxidation, up-regulate antioxidant/GSH levels and abrogate iron overload-induced apoptosis through activation of Nrf2 and HO-1 signaling pathways. Iron chelators such as heparin, deferoxamine, caffeic acid, curcumin, α-lipoic acid, and phytic acid could protect against ferroptosis and restore mitochondrial function, iron-redox potential, and rebalance Fe-R-H status. Therefore, Fe-R-H restoration is a host biomarker-driven potential combat strategy for an effective clinical and post-recovery management of COVID-19.

COVID-19 during Pregnancy and Postpartum.

Coronavirus Disease 2019 (COVID-19) triggered by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection has been declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Oxidative stress and its related metabolic syndromes are potential risk factors in the susceptibility to, and severity of COVID-19. In concert with the earliest reports of COVID-19, obstetricians started to diagnose and treat SARS-CoV-2 infections during pregnancy ("COVID-19-Pregnancy"). High metabolic demand to sustain normal fetal development increases the burden of oxidative stress in pregnancy. Intracellular redox changes intertwined with acute phase responses at the maternal-fetal interface could amplify during pregnancy. Interestingly, mother-to-fetus transmission of SARS-CoV-2 has not been detected in most of the COVID-19-Pregnancy cases. This relative absence of vertical transmission may be related to the presence of lactoferrin in the placenta, amniotic fluid, and lacteal secretions. However, the cytokine-storm induced during COVID-19-Pregnancy may cause severe inflammatory damage to the fetus, and if uncontrolled, may later result in autism spectrum-like disorders and brain development abnormalities in neonates. Considering this serious health threat to child growth and development, the prevention of COVID-19 during pregnancy should be considered a high priority. This review summarizes the intricate virulence factors of COVID-19 and elucidate its pathobiological spectrum during pregnancy and postpartum periods with a focus on the putative and complex roles of endogenous and exogenous lactoferrin in conferring immunological advantage to the host.

COVID-19 during Pregnancy and Postpartum.

As the COVID-19 pandemic intensified the global health crisis, the containment of SARS-CoV-2 infection in pregnancies, and the inherent risk of vertical transmission of virus from mother-to-fetus (or neonate) poses a major concern. Most COVID-19-Pregnancy patients showed mild to moderate COVID-19 pneumonia with no pregnancy loss and no congenital transmission of the virus; however, an increase in hypoxia-induced preterm deliveries was apparent. Also, the breastmilk of several mothers with COVID-19 tested negative for the virus. Taken together, the natural barrier function during pregnancy and postpartum seems to deter the SARS-CoV-2 transmission from mother-to-child. This clinical observation warrants to explore the maternal-fetal interface and identify the innate defense factors for prevention and control of COVID-19-Pregnancy. Lactoferrin (LF) is a potent antiviral iron-binding protein present in the maternal-fetal interface. In concert with immune co-factors, maternal-LF modulates chemokine release and lymphocyte migration and amplify host defense during pregnancy. LF levels during pregnancy may resolve hypertension via down-regulation of ACE2; consequently, may limit the membrane receptor access to SARS-CoV-2 for cellular entry. Furthermore, an LF-derived peptide (LRPVAA) has been shown to block ACE receptor activity in vitro. LF may also reduce viral docking and entry into host cells and limit the early phase of COVID-19 infection. An in-depth understanding of LF and other soluble mammalian milk-derived innate antiviral factors may provide insights to reduce co-morbidities and vertical transmission of SARS-CoV-2 infection and may lead to the development of effective nutraceutical supplements.

Post-surgical unilateral left pulmonary edema after mitral valve replacement - A diagnostic challenge.

Unilateral left pulmonary edema due to inadvertent surgical occlusion of left superior and inferior pulmonary veins is not only an exceedingly rare complication of mitral valve surgeries but also a diagnostic challenge in the postoperative recovery unit. Described here is a case of a 38-year-old male who developed progressively worsening unilateral left pulmonary edema after mitral valve replacement on postoperative day-1. The diagnosis was mostly by the exclusion of multiple possible differentials and was confirmed during reexploration surgery.

A repeating fast radio burst source localized to a nearby spiral galaxy.

Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes1,2. Their physical origin remains unknown, but dozens of possible models have been postulated3. Some FRB sources exhibit repeat bursts4-7. Although over a hundred FRB sources have been discovered8, only four have been localized and associated with a host galaxy9-12, and just one of these four is known to emit repeating FRBs9. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source6, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure6 further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.

Efficacy and Safety of Combination of NSAIDs and Muscle Relaxants in the Management of Acute Low Back Pain.

INTRODUCTION: Low back pain is a common problem worldwide causing deterioration of health and quality of life. Low back pain is often associated with muscle spasm. We investigated the combined effect of muscle relaxants and pain killers for low back pain. METHODS: In this open-label, prospective, multicenter study, patients with acute low back pain received a single tablet of either the fixed dose combination of chlorzoxazone 500 mg and ibuprofen 400 mg (manufacturer: Dr. Reddy's Laboratories, India) (C + I group) or ibuprofen 400 mg (I group) thrice daily for up to 7 days. Primary outcomes were improvement in pain by Visual Analogue Scale (VAS) and Summed Pain Intensity Difference (SPID) at 3 and 7 days post-treatment. RESULTS: A total of 406 patients were included in this study. When compared to baseline, the absolute mean change in VAS scores on Day 7 was 62.39 ± 18.78 and 57.34 ± 16.29 in the C + I and I groups, respectively (P = 0.0001). In the C + I and I groups, the mean SPID at Days 3 and 7 were 51.27 ± 24.44 and 47.80 ± 22.91, and 300.82 ± 92.40 and 277.16 ± 81.83, respectively. No deaths or serious adverse events were reported. Common adverse events included gastritis, stomach pain, fever, cold, and headache. At the end of the study, excellent to good response was reported in 94.08% and 77.33% of patients in the C + I and I groups, respectively. Excellent to good tolerability was observed in 96.05% and 89.65% patients in the two groups, respectively. CONCLUSION: Fixed dose combination of chlorzoxazone and ibuprofen demonstrated superior efficacy than ibuprofen monotherapy in acute low back pain. Both drugs were well-tolerated and should be considered as judicious therapeutic options in patients with acute low back pain. TRIAL REGISTRATION: This trial is registered with Clinical Trial Registry of India-CTRI/2016/10/007348. FUNDING: Dr. Reddy's Laboratories Ltd.

The modern implementation of patient blood management (PBM) in Malaysia: the use of intravenous iron in severe anaemia with iron deficiency - A Case Report.

Anaemia is a common condition in Malaysia, and is mostly due to iron deficiency. In many cases, allogeneic blood transfusion (ABT) is administered unnecessarily to treat anaemia. Patient blood management (PBM) is a concept whereby a patient becomes his or her "own blood bank", instead of receiving ABT. The concept encompasses three pillars namely optimising erythropoiesis, minimising blood loss and harnessing human physiological reserve. We present a safe and fruitful outcome of managing severe anaemia without utilising any ABT, made possible with the PBM approach including administration of intravenous iron.

Anthrax Toxin Receptor 1 Is Essential for Arteriogenesis in a Mouse Model of Hindlimb Ischemia.

Anthrax toxin receptor 1/tumor endothelial marker 8 (Antxr1 or TEM8) is up-regulated in tumor vasculature and serves as a receptor for anthrax toxin, but its physiologic function is unclear. The objective of this study was to evaluate the role of Antxr1 in arteriogenesis. The role of Antxr1 in arteriogenesis was tested by measuring gene expression and immunohistochemistry in a mouse model of hindlimb ischemia using wild-type and ANTXR1(-/-) mice. Additional tests were performed by measuring gene expression in in vitro models of fluid shear stress and hypoxia, as well as in human muscle tissues obtained from patients having peripheral artery disease. We observed that Antxr1 expression transiently increased in ischemic tissues following femoral artery ligation and that its expression was necessary for arteriogenesis. In the absence of Antxr1, the mean arterial lumen area in ischemic tissues decreased. Antxr1 mRNA and protein expression was positively regulated by fluid shear stress, but not by hypoxia. Furthermore, Antxr1 expression was elevated in human peripheral artery disease requiring lower extremity bypass surgery. These findings demonstrate an essential physiologic role for Antxr1 in arteriogenesis and peripheral artery disease, with important implications for managing ischemia and other arteriogenesis-dependent vascular diseases.

The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials.

BACKGROUND: Tumors may exploit the coagulation system to enhance the survival and dissemination of cancer cells. Some studies have suggested that heparin and low molecular weight heparin (LMWH) have antitumor effects. We reported a previous meta-analysis that suggested a modest improvement in overall survival with the use of LMWH in patients with cancer. Herein, we present the results of an updated systematic review and meta-analysis. OBJECTIVE: To evaluate the effect of LMWH as compared with placebo or no anticoagulant on the overall survival in patients with solid cancers. METHODS: We conducted a systematic review and meta-analysis of randomized trials evaluating the use of LMWH vs. placebo or no anticoagulant in cancer patients without venous thrombosis. A meta-analysis was conducted with a random-effects model, and data were analyzed by the use of odds ratios (ORs) and relative risks (RRs) calculated for 1-year overall mortality. RESULTS: We identified 724 potentially relevant studies, nine of which met our inclusion criteria, and reported data on 1-year overall mortality. Studies were heterogeneous regarding types of cancer and interventions, and included 5987 patients, 98.4% of whom had advanced-stage disease (III and IV). There was no discernible effect on mortality with the use of LMWH (pooled OR 0.87, 95% CI 0.70-1.08; RR 0.94, 95% CI 0.86-1.04). CONCLUSIONS: In contrast to the previous study, these results did not show a survival benefit in cancer patients receiving LMWH. The effect of LMWH on overall survival in patients with limited-stage disease still is unknown.

Historical changes in trace metals and hydrocarbons in nearshore sediments, Alaskan Beaufort Sea, prior and subsequent to petroleum-related industrial development: part II. Hydrocarbons.

Composition and concentration of hydrocarbons (normal and isoprenoid alkanes, triterpenoids, steranes, and PAHs) in nearshore surface sediments from Elson Lagoon (EL), Colville Delta-Prudhoe Bay (CDPB) and Beaufort Lagoon (BL), Alaskan Beaufort Sea, were assessed for spatio-temporal variability. Principal component analysis of the molecules/biomarkers concentrations delineated CDPB and BL samples into two groups, and cluster analysis identified three station groups in CDPB. Overall there was no geographic distribution pattern in the groups. The diversities between groups and individual samples are attributed to differences in n-alkanes and PAHs contents, which are influenced predominantly by sediment granulometry and sitespecific fluvial input. The predominant hydrocarbon source is biogenic, mainly terrigenous, with hardly any contribution from natural oil seeps, oil drill effluents and/or refined crude. The terrigenous source is corroborated by δ(13)C, δ(15)N, and OC/N of sediment organic matter. Time interval (1976-1977, 1984 and 1997) changes in hydrocarbon compositions and concentrations in CDPB are not significant.

Pre-clinical toxicity & immunobiological evaluation of DNA rabies vaccine & combination rabies vaccine in rhesus monkeys (Macaca mulatta).

BACKGROUND & OBJECTIVES: Pre-clinical toxicology evaluation of biotechnology products is a challenge to the toxicologist. The present investigation is an attempt to evaluate the safety profile of the first indigenously developed recombinant DNA anti-rabies vaccine [DRV (100 µg)] and combination rabies vaccine [CRV (100 µg DRV and 1.25 IU of cell culture-derived inactivated rabies virus vaccine)], which are intended for clinical use by intramuscular route in Rhesus monkeys. METHODS: As per the regulatory requirements, the study was designed for acute (single dose - 14 days), sub-chronic (repeat dose - 28 days) and chronic (intended clinical dose - 120 days) toxicity tests using three dose levels, viz. therapeutic, average (2x therapeutic dose) and highest dose (10 x therapeutic dose) exposure in monkeys. The selection of the model i.e. monkey was based on affinity and rapid higher antibody response during the efficacy studies. An attempt was made to evaluate all parameters which included physical, physiological, clinical, haematological and histopathological profiles of all target organs, as well as Tiers I, II, III immunotoxicity parameters. RESULTS: In acute toxicity there was no mortality in spite of exposing the monkeys to 10XDRV. In sub chronic and chronic toxicity studies there were no abnormalities in physical, physiological, neurological, clinical parameters, after administration of test compound in intended and 10 times of clinical dosage schedule of DRV and CRV under the experimental conditions. Clinical chemistry, haematology, organ weights and histopathology studies were essentially unremarkable except the presence of residual DNA in femtogram level at site of injection in animal which received 10X DRV in chronic toxicity study. No Observational Adverse Effects Level (NOAEL) of DRV is 1000 ug/dose (10 times of therapeutic dose) if administered on 0, 4, 7, 14, 28 th day. INTERPRETATION & CONCLUSIONS: The information generated by this study not only draws attention to the need for national and international regulatory agencies in formulating guidelines for pre-clinical safety evaluation of biotech products but also facilitates the development of biopharmaceuticals as safe potential therapeutic agents.

Trend in decline in leprosy disabilities of a LEPRA project in Malkangiri district, Odisha, India.

This a retrospective analysis of the changes in 646 disabilities occurred amongst 3979 cases registered during 19 years from 1992 to 2010 in Malkangiri district. This amounted to 16.2% of cases with disability segregated to 310 (48%) Grade 1 and 336 (52%) Grade 2. In this project, managed by LEPRA India, POD care was in practice from the year 1992 and records were updated regularly. An analysis of the annual records showed that the next year-end balance increased up to the year 2001 followed by gradual decline. Within this period the total cases with disabilities declined by about 369 (57%) due to death by aging 204 (55%), migration from the area 77 (21%) and reversing to normal 88 (24%) in cases. Deletion due to recovery to normal especially with sensory impairment is fairly good with or without steroid. Disability percentage in new cases declined steadily especially Grade 2 from 30% to 1%, initial high rate attributed mostly to backlog cases. In later years the rate is erratic high amongst low number of new cases. Absolute number indicates the situation better. Such study helps to roughly extrapolate the existing disability load in a particular area and assists in planning for care and prevention.

Historical changes in trace metals and hydrocarbons in nearshore sediments, Alaskan Beaufort Sea, prior and subsequent to petroleum-related industrial development: Part I. Trace metals.

Concentrations of Fe, As, Ba, Cd, Cu, Cr, Pb, Mn, Ni, Sn, V and Zn in mud (<63µm size), and total and methyl Hg in gross sediment are reported for Arctic Alaska nearshore. Multivariate-PCA analysis discriminated seven station clusters defined by differences in metal concentrations, attributed to regional variations in granulometry and, as in Elson Lagoon, to focused atmospheric fluxes of contaminants from Eurasia. In Colville Delta-Prudhoe Bay, V increase was noted in 1985 and 1997 compared to 1977, and Ba increase from 1985 to 1997. Presumably the source of increased V is the local gas flaring plant, and the elevated Ba is due to barite accumulation from oil drilling effluents. In Prudhoe Bay, concentration spikes of metals in ∼1988 presumably reflect enhanced metals deposition following maximum oil drilling in 1980s. In summary, the Alaskan Arctic nearshore has remained generally free of metal contamination despite petroleum-related activities in past 40 years.