Potent anti-mycobacterial and immunomodulatory activity of some bioactive molecules of Indian ethnomedicinal plants that have the potential to enter in TB management.

Tuberculosis (TB) is one of the deadliest infectious diseases of human civilization. Approximately one-third of global population is latently infected with the TB pathogen Mycobacterium tuberculosis (M.tb). The discovery of anti-TB antibiotics leads to decline in death rate of TB. However, the evolution of antibiotic-resistant M.tb-strain and the resurgence of different immune-compromised diseases re-escalated the death rate of TB. WHO has already cautioned about the chances of pandemic situation in TB endemic countries until the discovery of new anti-tubercular drugs, that is, the need of the hour. Analysing the pathogenesis of TB, it was found that M.tb evades the host by altering the balance of immune response and affects either by killing the cells or by creating inflammation. In the pre-antibiotic era, traditional medicines were only therapeutic measures for different infectious diseases including tuberculosis. The ancient literatures of India or ample Indian traditional knowledge and ethnomedicinal practices are evidence for the treatment of TB using different indigenous plants. However, in the light of modern scientific approach, anti-TB effects of those plants and their bioactive molecules were not established thoroughly. In this review, focus has been given on five bioactive molecules of different traditionally used Indian ethnomedicinal plants for treatment of TB or TB-like symptom. These compounds are also validated with proper identification and their mode of action with modern scientific approaches. The effectiveness of these molecules for sensitive or drug-resistant TB pathogen in clinical or preclinical studies was also evaluated. Thus, our specific aim is to highlight such scientifically validated bioactive compounds having anti-mycobacterial and immunomodulatory activity for future use as medicine or adjunct-therapeutic molecule for TB management.

Effects of water deficit stress on agronomic and physiological responses of rice and greenhouse gas emission from rice soil under elevated atmospheric CO2.

Rice is the foremost staple food in the world, safeguarding the global food and nutritional security. Rise in atmospheric carbon dioxide (CO2) and water deficits are threatening global rice productivity and sustainability. Under real field conditions these climatic factors often interact with each other resulting in impacts that are remarkably different compared to individual factor exposure. Rice soils exposed to drought and elevated CO2 (eCO2) alters the biomass, diversity and activity of soil microorganisms affecting greenhouse gas (GHG) emission dynamics. In this review we have discussed the impacts of eCO2 and water deficit on agronomic, biochemical and physiological responses of rice and GHGs emissions from rice soils. Drought usually results in oxidative stress due to stomatal closure, dry weight reduction, formation of reactive oxygen species, decrease in relative water content and increase in electrolyte leakage at almost all growth and developmental phases of rice. Elevated atmospheric CO2 concentration reduces the negative effects of drought by improving plant water relations, reducing stomatal opening, decreasing transpiration, increasing canopy photosynthesis, shortening crop growth period and increasing the antioxidant metabolite activities in rice. Increased scientific understanding of the effects of drought and eCO2 on rice agronomy, physiology and GHG emission dynamics of rice soil is essential for devising adaptation options. Integration of novel agronomic practices viz., crop establishment methods and alternate cropping systems with improved water and nutrient management are important steps to help rice farmers cope with drought and eCO2. The review summarizes future research needs for ensuring sustained global food security under future warmer, drier and high CO2 conditions.

Microsurgical treatment of distal anterior cerebral artery aneurysms: A 25 year institutional experience.

INTRODUCTION: We present a retrospective study of distal anterior cerebral artery (DACA) aneurysms operated at our institute. MATERIAL AND METHODS: From 1988 to 2013, a total of 132 DACA aneurysms were managed surgically. The retrospective data of these patients was collected and analysed. RESULTS: They comprised 6.2% of all 2137 aneurysms operated during the same period. The mean age at presentation was 48.3 years (range: 24-77 years) and the male: female ratio was 1:2. The notable symptom in 114 (86.4%) patients was headache, in 94 (71.2%) was loss of consciousness, in 25 (18.9%) was seizures, and in 17 (12.9%) was limb weakness. There were 99 (75%) patients in World Federation of Neurosurgical Societies (WFNS) grade <3 at admission. On plain computed tomography (CT) scan, intracerebral hemorrhage was seen in 49 (37.1%) and intraventricular hemorrhage in 23 (17.4%) patients. The most common site of aneurysm was the pericallosal (A3 segment) artery noted in 65 (49.2%) patients. Multiple aneurysms were observed in 16 (12.1%) cases. The mean timing of surgery from the first ictus was 17.8 days. The delay was due to a late referral, poor general condition, recurrent bleeding, and worse WFNS grade at presentation. Aneurysms were operated through the following approaches: parasaggital craniotomy in 61 (46.2%), bifrontal craniotomy in 64 (48.5%), and frontotemporal craniotomy in 7 (5.3%). Aneurysms could be successfully clipped in 93.2% of the cases. Postoperative mortality was 8 (6%). The follow-up data was available for 83 (62.9%) patients. The mean duration of follow-up was 15.1 months (1-70 months), with more than 41 (31%) patients having a follow-up of more than 6 months. A favorable outcome (good recovery or moderate disability) was seen in 71 (85.5%) cases. CONCLUSIONS: A meticulous attention to the surgical technique provides gratifying results in DACA aneurysms even in patients who present initially in a compromised clinical status.

Association of p53 codon72 Arg>Pro polymorphism with susceptibility to nasopharyngeal carcinoma: evidence from a case-control study and meta-analysis.

Tumor suppressor p53 is a critical player in the fight against cancer as it controls the cell cycle check point, apoptotic pathways and genomic stability. It is known to be the most frequently mutated gene in a wide variety of human cancers. Single-nucleotide polymorphism of p53 at codon72 leading to substitution of proline (Pro) in place of arginine (Arg) has been identified as a risk factor for development of many cancers, including nasopharyngeal carcinoma (NPC). However, the association of this polymorphism with NPC across the published literature has shown conflicting results. We aimed to conduct a case-control study for a possible relation of p53 codon72 Arg>Pro polymorphism with NPC risk in underdeveloped states of India, combine the result with previously available records from different databases and perform a meta-analysis to draw a more definitive conclusion. A total of 70 NPC patients and 70 healthy controls were enrolled from different hospitals of north-eastern India. The p53 codon72 Arg>Pro polymorphism was typed by polymerase chain reaction, which showed an association with NPC risk. In the meta-analysis consisting of 1842 cases and 2330 controls, it was found that individuals carrying the Pro allele and the ProPro genotype were at a significantly higher risk for NPC as compared with those with the Arg allele and the ArgArg genotype, respectively. Individuals with a ProPro genotype and a combined Pro genotype (ProPro+ArgPro) also showed a significantly higher risk for NPC over a wild homozygote ArgArg genotype. Additionally, the strength of each study was tested by power analysis and genotype distribution by Hardy-Weinberg equilibrium. The outcome of the study indicated that both allele frequency and genotype distribution of p53 codon72 Arg>Pro polymorphism were significantly associated with NPC risk. Stratified analyses based on ethnicity and source of samples supported the above result.

Spinal epidural cavernous hemangioma with myelopathy: a rare lesion.

A case of pure epidural cavernous angioma involving the dorsal region of the spine is presented. The clinical picture was of a slowly progressive compressive myelopathy. Imaging studies only showed a dorsally located epidural mass lesion. Histology confirmed the diagnosis of this rare type of lesion. The patient improved after excision of the lesion.

Renal failure in malaria.

Acute renal failure (ARF) is seen mostly in Plasmodium falciparum infection, but P vivax and P. malariae can occasionally contribute for renal impairment. Malarial ARF is commonly found in non-immune adults and older children with falciparum malaria. Occurance of ARF in severe falciparum malaria is quite common in southeast Asia and Indian subcontinent where intensity of malaria transmission is usually low with occasional microfoci of intense transmission. Since precise mechanism of malarial ARF is not known, several hypotheses including mechanical obstruction by infected erythrocytes, immune mediated glomerular and tubular pathology, fluid loss due to multiple mechanisms and alterations in the renal microcirculation, etc, have been proposed. Increased fluid administration, oxygen toxicity, and yet unidentified factors may contribute to pulmonary edema, acute respiratory distress syndrome (ARDS), multiorgan failure and death. Mainstay of treatment consists of appropriate antimalarial drug therapy, fluid replacement, and renal replacement therapy. Loop diuretics can convert an oliguric renal failure to non-oliguric renal failure without affecting outcome of the disease though the conversion reduces the risk of volume overload. There is little evidence on beneficial effect of vasoactive drugs. Nephrotoxic drugs such as ACE inhibitors, NSAIDs, aminoglycosides, cephalosporins should be avoided. Currently, high quality intensive care, early institution of renal replacement therapy, and avoidance of nephrotoxic drugs are standard practice of the prevention and management of ARF.

Management of severe and complicated malaria.

Severe malaria is invariably caused by Plasmodium falciparum. In India, both adults and children are affected by severe malaria. However, children are more prone for developing anemia and convulsions as manifestations of severe malaria, while acute renal failure and jaundice are more common among adults. Pregnant women are vulnerable to hypoglycemia, anemia and pulmonary complications. The case-fatality rate due to severe malaria is 10-15% in spite of therapy but it increases in the presence of renal failure or respiratory distress (pulmonary edema or ARDS). Of late, multi-organ failure and high mortality figures are being reported increasingly from different parts of India. Early diagnosis and prompt treatment will reduce the mortality due to malaria. Cerebral malaria should always be suspected in a patient with altered sensorium in a malaria-endemic area. However, other causes of unconsciousness such as encephalitis, meningitis or hepatic coma should also be excluded. Parenteral quinine is the mainstay of therapy. A recent multi-centric study has demonstrated the efficacy of intravenous artesunate in reducing the mortality by 30%. The usefulness of adjunct therapy is still controversial.

Sorption and degradation of steroid hormones in soils during transport: column studies and model evaluation.

Natural and synthetic analogues of steroid hormones and their metabolites have emerged as contaminants of concern. Characterizing sorption and degradation processes is essential to assess the environmental distribution, persistence, and ecological significance of steroid hormones in terrestrial and aquatic systems. We examined the fate and transport of testosterone and 17beta-estradiol by conducting a series of fast-flow-velocity transport experiments under pulse-type and flow-interruption boundary conditions in columns packed with a surface soil, freshwater sediment, and two sands. Flow-interruption experiments provided independent estimates of degradation coefficients for the parent hormones and their metabolites, while pulse-input type experiments were used to identify transport mechanisms for hormones by employing forward modeling approaches. Estimated degradation rate coefficients (k) for the hormones from flow-interruption experiments ranged from 0.003 to 0.015 h(-1) for testosterone and from 0.0003 to 0.075 h(-1) for estradiol, similar to those observed in batch studies. Degradation rate coefficients for the two primary metabolites were 1-2 orders of magnitude larger than those for the parent chemicals. Estimated k values decreased with column life as a result of nutrient depletion. Large sorption by soils of the parent and metabolites (log Koc approximately 2.77-3.69) did not appear to hinder degradation; k values were an order of magnitude smaller than the estimated sorption mass-transfer constants. Differences in hormone breakthrough curves from a single-pulse displacement and those predicted using independently estimated parameters suggest that modeling hormone degradation as a simple first-order kinetic process may be sufficient, but not accurate.

Influence of renal impairment on plasma concentrations of conjugated bilirubin in cases of Plasmodium falciparum malaria.

In a study of the influence of malaria-associated renal impairment on plasma concentrations of bilirubin, 111 Indian cases of Plasmodium falciparum malaria who had >34.2 microM total bilirubin/litre plasma were investigated. As the aim was to exclude those cases who had concomitant hepatic or (non-malarial) renal dysfunction, 19 cases who had serum concentrations of alanine aminotransferase (ALT) or alkaline phosphatase (AP) that were at least double the normal mean values were withdrawn. Of the remaining 92 patients, 47 showed evidence of renal impairment, the other 45 having plasma concentrations of creatinine that were <177 microM/litre. Plasma concentrations of the liver enzymes ALT and AP were similar for those with and without renal impairment. The plasma concentration of conjugated bilirubin (P<0.02), that of total bilirubin (P<0.05) and the ratio between the two (P<0.01) were, however, all significantly higher in the 47 patients with renal impairment than in the 45 with apparently normal renal function. The plasma concentration of creatinine was found to be not only positively correlated with the plasma concentrations of total (r=0.34; P<0.01) and conjugated (r=0.41; P<0.001) bilirubin but also negatively correlated with the urinary excretion rate for conjugated bilirubin (r=-0.34; P<0.001). The malaria-associated mortality was significantly higher among the patients with renal impairment than among those with apparently normal renal function, with 12 and three deaths, respectively (P<0.001). With increasing renal impairment there therefore appears to be a fall in the renal excretion of conjugated bilirubin. This leads to a disproportionate rise in the plasma concentration of conjugated bilirubin and this, since bilirubin can be toxic to renal tissue, may further worsen the renal impairment.

Thoracic cord compression due to ossified hypertrophied ligamentum flavum.

Ossified ligamentum flavum is increasingly appreciated as an important cause of thoracic myeloradiculopathy. Fifteen patients with age ranging from 30-61 years were studied. Fourteen presented with spastic paraparesis, and radiculopathy was the only complaint in one patient. Routine skiagrams and myelograms showed non-specific changes. Baseline CT and CT myelogram, however, documented the ossification of ligamentum flavum comprehensively. MRI was done in three patients. Multiple levels of the disease were seen in two cases. Four patients had ossified posterior longitudinal ligament. Thickened ligamentum flavum should be considered as an important cause of thoracic cord compression.

Low incidence of the severe complications of malaria and absence of malaria-specific mortality, in Tensa, Sundergarh district, Orissa state, India, an area hyper-endemic for malaria.

The incidence of severe malaria and malaria-specific mortality were investigated in a hospital, for miners and their families, at Tensa in the Sundergarh district of Orissa state in India. Tensa lies in area where malaria (predominantly caused by Plasmodium falciparum) is hyper-endemic. The hospital records for 1995--1999 showed that, although annual admissions for malaria increased over the study period, there were very few admissions for severe, complicated malaria and no reports of malaria-specific deaths. Most of the patients who had been admitted with cerebral malaria either came from areas around but not within the town of Tensa or were recent arrivals in the town. It appears that the outcome of malaria is influenced not only by the intensity of local transmission (which affects the immunological status of the human hosts) but also by social factors such as the education and health-seeking behaviour of the local population and the health-care facilities available. The low incidence of severe malaria observed in Tensa was probably the result of patients presenting early in the course of their illness and taking antimalarial treatment, iron supplementation and supportive therapy at the appropriate times.

Multicentric clinical trials for safety and efficacy evaluation of alpha;beta arteether in complicated P. falciparum malaria.

OBJECTIVE: To evaluate efficacy of alpha;beta arteether in patients of P. falciparum malaria presenting with complications was undertaken in a multicentric clinical trial. METHOD: Each patient who consented to undergo clinical trial with parenteral Arteether was treated with a fixed dose schedule of Arteether given intramuscularly in a dose of 150 mg once a day on three consecutive days. Every patient was followed upto 28 days with clinical, haematological and parasitological monitoring every day upto one week and thereafter at 14, 21 and 28 days. The response was assessed in terms of fever clearance time, parasite clearance time, cure rate and parasite reappearance rate. RESULTS: A total of 211 patients of P. falciparum malaria were included in the study from four centres (Bhilai, Guwahati, Jamshedpur and Rourkela). Results of this study showed that fever clearance time ranged between 24-168 hours, parasite clearance time ranged between 24-120 hours and overall mortality ranged between 4-8.5%. Out of 211, only 14 patients expired during the study, of these, 10 patients expired within first two days i.e. before completing the three day schedule of arteether therapy. Tolerability to arteether injection was good in all these patients and no untoward effects were experienced or reported during the study. Overall cure rate observed in these studies was 93%. CONCLUSION: This study shows a rapid parasite and fever clearance in patients of complicated P. falciparum malaria.

Innate immunity, gut integrity, and vitamin A in Gambian and Indian infants.

Gut integrity, which can be measured by the urinary lactulose:mannitol excretion test, deteriorates with the introduction of weaning foods. In The Gambia, gut integrity measured monthly over 15 months in 119 infants (aged 2-15 months) was least impaired from April to June. This coincides with the time of year of maximum vitamin A (VA) intake-the mango season. Subsequently, two VA intervention studies were done in infants in India. Eighty infants attending a community health center received 16,700 IU weekly or placebo. In another study, 94 hospitalized infants were given 200, 000 IU VA or placebo: 31 received VA on admission, while the rest (32 VA, 31 placebo) received treatment on discharge. All VA-treated groups had more rapid improvement in gut integrity than the placebo groups, but no group had gut integrity normalized by Western standards. The data suggest that VA status may influence gut integrity.

Facial nerve neurinoma presenting as middle cranial fossa and cerebellopontine angle mass: a case report.

Facial nerve neurinomas are rare. The tumours arising from the geniculate ganglion may grow anteriorly and superiorly and present as a mass in the middle cranial fossa. Only a few cases of facial nerve neurinomas presenting as middle cranial fossa mass have so far been reported. These tumours present with either long standing or intermittent facial palsy along with cerebellopontine angle syndrome.

Presence of pro-oxidants in plasma of patients suffering from falciparum malaria.

Haemolysis is the major cause of anaemia in acute Plasmodium falciparum malaria, destroying both parasitized and non-parasitized erythrocytes. Oxidative stress on erythrocytes is considered an important mechanism of haemolysis. Since non-parasitized erythrocytes are also destroyed, the extracellular environment of the erythrocyte may be a contributor to the oxidative stress. To examine the influence of extracellular factors on oxidative stress and haemolysis, baseline values of erythrocyte thio-barbituric acid-reactive substance (ETBAR) and haemolytic indices such as plasma haemoglobin and lactate dehydrogenase (LDH) were estimated in 19 children in Orissa (India) with acute P. falciparum malaria (haemoglobin level < or = 70 g/L). The indices were measured after incubating cross-matched isogroup adult control erythrocytes with patient's plasma, and patient's erythrocytes with adult control plasma both in presence of and in absence of t-butyl hydroperoxide (t-BHP). The procedure was repeated in the blood of 19 age- and sex-matched non-malarial children. Baseline plasma LDH, haemoglobin and ETBAR concentrations were significantly greater in malaria patients than non-malarial children (P < 0.001 for all). Post-incubation values of ETBAR and plasma haemoglobin were significantly higher (P < 0.05) when adult control erythrocytes were incubated with patient plasma, and plasma haemoglobin was significantly higher (P < 0.05) in incubates of patient erythrocytes with adult control plasma, than their respective pre-incubation values when incubated in absence of t-BHP. These differences were not noticed in the incubates of non-malarial children with healthy adult control samples. When incubated in presence of t-BHP all the post-incubation values in the patients were significantly higher than their respective pre-incubation values and post-incubation values without t-BHP (P < 0.001). In non-malarial control samples, only ETBAR concentration was higher than their respective pre-incubation and post-incubation values without t-BHP (P < 0.01). All the values for post-incubation samples with t-BHP were significantly higher in patients than controls (P < 0.001). In post-incubation samples of control erythrocytes and patient plasma in presence of t-BHP, ETBAR correlated inversely with pre-incubation haptoglobin values (P < 0.001). Thus, plasma of acute malaria patients appears to contain pro-oxidants, which may contribute to extracellular oxidative stress on both parasitized and non-parasitized erythrocytes.

Evidence for erythrocyte lipid peroxidation in acute falciparum malaria.

To assess the extent of oxidative stress in erythrocytes of patients with acute Plasmodium falciparum malaria, erythrocyte thiobarbituric acid-reactive substance (ETBAR), and intracellular, membrane and extracellular antioxidants were estimated in 102 cases of P. falciparum malaria and 50 control subjects. The mean concentration of ETBAR was significantly higher (P < 0.001) and many of the antioxidants were significantly lower in patients than controls. Among the erythrocyte antioxidants, catalase, reduced glutathione (GSH) and tocopherol were significantly lower in the patients (P < 0.05, 0.001, 0.001, respectively). Erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were not reduced to a statistically significant level. Similarly, the plasma antioxidants ascorbate and albumin were significantly lower (P < 0.001) but not urate. ETBAR correlated inversely with erythrocyte GSH and tocopherol (P < 0.001), and plasma ascorbate and albumin (P < 0.001) but not with the erythrocyte enzymic antioxidants. However, on multiple regression analysis only tocopherol correlated strongly with ETBAR, followed by GSH and plasma ascorbate. ETBAR also correlated well with haemolytic indices such as haemoglobin, plasma unconjugated bilirubin and haptoglobin concentrations (P < 0.001, for all). On follow-up after 2 weeks, ETBAR and different antioxidants reached near control levels. These observations indicate an enhanced oxidative stress on erythrocytes in acute falciparum malaria that may contribute substantially to haemolysis and anaemia.