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.

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.

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.

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.

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.

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.

Plasma alpha-tocopherol, retinol, and carotenoids in children with falciparum malaria.

Cross-sectional interactions by malaria status were investigated between plasma alpha-tocopherol, retinol, and several carotenoids (lutein, beta-cryptoxanthin, lycopene, and alpha- and beta-carotene) and indicators of disease severity (blood parasite count, hemoglobin concentration), acute-phase response (plasma albumin and ceruloplasmin concentrations), hepatic involvement (plasma alanine aminotransferase), oxidant status and antioxidant status (plasma thiobarbituric acid-reactive material and ascorbate), nutritional (weight-for-age) and carrier protein [retinol binding protein (RBP)] status, and cholesterol concentration (as a proxy for lipoprotein) in 100 consecutively admitted children with malaria. There were 50 children with severe and 50 with mild malaria and 50 age- and sex-matched control subjects. alpha-Tocopherol, retinol, and all the carotenoid concentrations were lower in the patients than in the control subjects (P < 0.001). The differences were greater in severe than in mild malaria, except for lutein. In severe malaria only, both retinol and alpha-tocopherol correlated with albumin, ceruloplasmin, and RBP concentrations whereas in all three groups retinol correlated with RBP and alpha-tocopherol correlated with cholesterol (all P < 0.01)). Using multivariate analysis on data from all patients combined, cholesterol was the most significant factor explaining the variance in alpha-tocopherol (29%) whereas RBP was responsible for 95% of the variance in retinol. Plasma cholesterol and RBP values in turn (in the absence of alpha-tocopherol and retinol, respectively) were influenced primarily by acute-phase markers (mainly albumin and ceruloplasmin). Alanine aminotransferase (r = -0.17) and thiobarbituric acid-reactive material (r = -0.17) also showed a small contribution to the variance of RBP but 60-70% remained unexplained. In conclusion, low plasma lipid-soluble micronutrient concentrations in malaria are strongly influenced by the reductions in their carrier molecules, which, in turn, are low as a consequence of the acute-phase response.

Increased plasma lipid peroxidation in riboflavin-deficient, malaria-infected children.

Plasma lipid peroxides were measured as malonyldialdehyde (MDA) by the thiobarbituric acid (TBA) method in 75 children suffering from Plasmodium falciparum malaria. Their riboflavin status was assessed by measuring erythrocyte glutathione reductase activation coefficients (EGRACs), and values greater than 1.40 were regarded as indicating biochemical deficiency. Plasma MDA was higher (p less than 0.001) in patients than in control subjects; the concentrations were 3.65 +/- 0.70 and 1.77 +/- 0.45 mumol/L (means +/- SD), respectively. The riboflavin-deficient group had higher plasma MDA values (3.98 +/- 0.70 mumol/L) than did the nondeficient group (3.30 +/- 0.68 mumol/L, p less than 0.001). Plasma MDA concentrations correlated with EGRACs (r = 0.46, p less than 0.01) in the patients. It is proposed that riboflavin deficiency restricts regeneration of reduced glutathione making the parasitized erythrocytes more vulnerable to destructive lipid peroxidation and increasing plasma lipid hydroperoxides.

Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas.

PURPOSE: Evaluation of tolerance, toxicity, and feasibility of combining large fraction (5 Gy) radiotherapy with 2-deoxy-D-glucose (2DG), an inhibitor of glucose transport and glycolysis, which has been shown to differentially inhibit repair of radiation damage in cancer cells. METHODS AND MATERIALS: Twenty patients with supratentorial glioma (Grade 3/4), following surgery were treated with four weekly fractions of oral 2DG (200 mg/kg body weight) followed by whole brain irradiation (5 Gy). Two weeks later, supplement focal radiation to the tumor (14 Gy/7 fractions) was given. Routine clinical evaluation, x-ray computerized tomography (CT), and magnetic resonance (MR) imaging were carried out to study the acute and late radiation effects. RESULTS: All the 20 patients completed the treatment without any interruption. The vital parameters were within normal limits during the treatment. None reported headache during the treatment. Mild to moderate nausea and vomiting were observed during the days of combined therapy (2DG + RT) in 10 patients. No significant deterioration of the neurological status was observed during the treatment period. Seven patients were alive at 63, 43, 36, 28, 27, 19, and 18 months of follow-up. In these patients, the clinical and MR imaging studies did not reveal any late radiation effects. CONCLUSIONS: Feasibility of administering the treatment (2DG + 5 Gy) is demonstrated by the excellent tolerance observed in all 20 patients. Further, the clinical and MR studies also show the absence of any brain parenchymal damage.

Vascular clogging, mononuclear cell margination, and enhanced vascular permeability in the pathogenesis of human cerebral malaria.

To document histopathologic evidence on the pathogenic mechanism of human cerebral malaria, we used light microscopy to study brain specimens from 23 patients who died of central nervous system involvement with Plasmodium falciparum. Sequestration of parasitized red blood cells (PRBCs) leading to cerebral capillary clogging was seen. In a few specimens, vascular clogging by PRBCs was associated with margination of mononuclear cells. In others, capillaries were virtually empty and lymphocytes and monocytes were seen in apposition (marginated) to the capillary endothelial surface. The endothelial cells appeared plump, hypertrophied, and prominent. The capillary wall appeared thickened by fibrinous material. Massive intercellular brain edema along with extravasated red blood cells, mononuclear cells, and plasmatic fluid was also noticed. In addition to hypoxia induced by PRBC-mediated vascular clogging, marginating mononuclear cells may contribute to the pathogenesis of cerebral malaria. The precise role played by this phenomenon needs further evaluation.

Plasma antioxidants and lipid peroxidation products in falciparum malaria.

To investigate the influence of Plasmodium falciparum malaria on plasma antioxidants and lipid peroxidation, plasma ascorbate, urate, total protein and albumin, ceruloplasmin and malondialdehyde (MDA) were determined in two groups of 42 patients each, one with mild and the other with severe falciparum malaria, and in an equal number of age- and sex-matched control subjects. Plasma MDA was found to be significantly higher in malaria patients, and the increase was proportional to the severity of the disease. Of the antioxidants, ascorbate and albumin decreased with severity of disease while urate and ceruloplasmin increased. Only ascorbate correlated inversely with MDA both in mild (r = -0.341, P < 0.05) and severe malaria (r = 0.545, P < 0.01). While plasma albumin correlated inversely (r = -0.442, P < 0.01), urate and ceruloplasmin correlated directly (r = 0.419, P < 0.01 and r = 0.349, P < 0.05, respectively) only in patients with severe malaria. These antioxidants also correlated well with markers of disease severity, indicating the influence of disease severity in regulating their levels in plasma. The presence of significant quantities of ascorbate and albumin, along with increases in some of the other antioxidants and MDA, indicates ineffectiveness of the antioxidant defense system in controlling plasma lipid peroxide content. Increased amounts of thiobarbituric acid-reactive material could have been the result of spillover from increased tissue peroxidation or the presence of pro-oxidants in malarial plasma.

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.

Increased cerebrospinal fluid protein and lipid peroxidation products in patients with cerebral malaria.

Membrane lipid peroxidation by reactive oxygen species leading to increased capillary permeability is considered an important event in the pathogenesis of severe malaria. A significant decrease in plasma albumin and increases in cerebrospinal fluid (CSF) protein and malondialdehyde (MDA) were observed in 73 patients with cerebral malaria, compared to values in 23 control patients. The greatest effect was noticed in the most severely ill patients. The ratio of CSF protein to plasma albumin was increased in the patients compared to the controls, and in fatal cases of cerebral malaria compared to non-fatal cases. Brain necropsies showed oedema, fibrin deposits and mononuclear cell infiltration. It is proposed that cerebral oedema due to enhanced permeability of vascular endothelium induced by increased lipid peroxidation plays a crucial role in the causation of cerebral malaria.

Hypoglycaemia in severe falciparum malaria.

The incidence of hypoglycaemia and the role of quinine in its causation was assessed in 46 patients with severe Plasmodium falciparum malaria. Plasma glucose and immunoreactive insulin were estimated before, during and after quinine therapy. In 5 patients the plasma glucose was in the hypoglycaemic range, the lowest value being 0.67 mmol/litre (12 mg/dl) in a pregnant patient. Most of the remaining patients showed a significant fall in plasma glucose (P less than 0.05), but not to the hypoglycaemic range, and an increase in plasma insulin after quinine (P less than 0.01). A good correlation was found between these changes (r = 0.79, P less than 0.01). Patients with severe P. falciparum malaria, particularly those on quinine therapy, should be watched carefully for developing hypoglycaemia.

Effectiveness of alpha,beta-arteether in acute falciparum malaria.

With the emergence of widespread chloroquine resistance and a world-wide scarcity of quinine, a search for newer antimalarial drugs has become imperative. Different derivatives of qinghaosu have been successfully tried. alpha,beta-Arteether, an ethyl derivative of qinghaosu, was administered to 51 patients with Plasmodium falciparum malaria, in a dose of 150 mg intramuscularly once a day on 3 consecutive days. Complete parasite clearance from the peripheral blood was observed in 80% of the patients at 48 h and in 98% at 72 h. The median parasite clearance time was 2 d (range 1-4 d). 65% of the patients became afebrile within 48 h and 81% by 72 h. The mean fever clearance time was 52.04 h (standard deviation 27.09). No side effect was seen. Patients were followed-up for 4 weeks; 7 were readmitted with P. falciparum infection but it could not be ascertained definitely whether these cases were reinfections or recrudescences. alpha-beta Arteether was a safe, effective and convenient drug for treating P. falciparum malaria. This is the first clinical study with arteether in falciparum malaria.

Paraganglioma of the orbit with extension to the middle cranial fossa: case report.

Intraorbital paragangliomas are rare. A case of intraorbital paraganglioma with extension to the middle cranial fossa is reported. Progressive throbbing, hemicranial headaches, unilateral proptosis, and visual failure are the presenting symptoms. The computed tomographic and operative findings suggested a meningioma. Surgical removal of the tumor resulted in total relief of symptoms and recovery of vision. The pathogenesis and pathological findings are discussed.

Calvarial tuberculosis: a report of two cases.

Two cases of calvarial tuberculosis associated with neurological involvement are presented. The radiological features and therapeutic management are discussed and the literature is reviewed.

Spinal intramedullary cysticercosis.

OBJECTIVE: Spinal intramedullary cysticercosis is an uncommon manifestation of neurocysticercosis. We review our experience with eight cases of intramedullary cysticercosis. METHODS: Eight patients who were surgically treated for spinal intramedullary cysticercosis between 1982 and 1991 were retrospectively reviewed, and the final outcomes were assessed. RESULTS: In six patients, the cysticercosis involved the thoracic cord, whereas in the other two, the cysticercosis was cervical in location. Only one patient had multiple soft tissue calcifications, as revealed by plain radiography. Myelography indicated an intramedullary lesion in each of seven patients; two of the seven patients had partial myelographic block, suggesting the segmental nature of the lesion. Cerebrospinal fluid studies were noncontributory. One patient had three cysts, whereas the other seven had one cyst each. Four patients had adjacent soft purulent materials, which were revealed by histopathological examination to be granulation tissue. The neurological statuses of seven patients improved after surgery. Six patients were followed up for a mean of 30.6 months (3 mo-5 yr). Three could resume their previous occupations, two others could manage their daily activities, and one required only minimal assistance for daily activities. CONCLUSION: The outcome of intramedullary cysticercosis is not as dismal as reported earlier, and patients with paraplegia also have favorable outcomes. A preoperative diagnosis of cysticercosis can be suspected in an endemic area in the presence of multiple soft tissue calcifications and segmental lesions revealed by myelography or magnetic resonance imaging studies.