Proximate and mineral composition of Kadamba (Neolamarckia cadamba) fruit and its use in the development of nutraceutical enriched beverage.

Neolamarckia cadamba, commonly known as Kadamba, is one of the economically important trees, which is being exploited for paper, pulp and wood industries, however uses of its fruits are not reported. In the present investigation the N. cadamba fruits were analysed for their proximate and mineral content at different stages of maturity, and the ripe fruit was used for nectar preparation. Proximate analysis of the ripe edible fruit showed that it is rich in fat (2.4%) and proteins (2.1%), and has calorific value of 103.7 kcal/100 g. The nectar prepared from the ripe fruits showed mean overall acceptability score of more than 6 indicating its suitability for nectar preparation. The shelf life of nectar was found to be 150 days at ambient conditions (28 ± 3 °C). The nectar was rich in minerals and antioxidants, and can be recommended for consumption by various age groups. However, studies are required to ascertain its physiological effect on consumers.

Nicotine exposure, blood pressure, and inflammation in tobacco smokers and chewers in a rural community in Nepal.

Tobacco consumption is high amongst the people of Xxx. This study was carried out in 2011 in a rural community of Xxx, to compare pathological parameters associated with tobacco use in relation to nicotine metabolism between smokers, chewers, and a control group. A total of 216 volunteers provided blood and urine samples for testing nicotine metabolites, C-reactive protein, and cell counts. Data were analyzed using ANOVA, correlation, and t-tests using STATA. Differences in blood pressure amongst the groups indicate a role of smoking in preventing a rise in BP with age, likely attributable to a different mechanism of metabolism of tobacco constituents.

Performance of Tumor Surveillance for Children With Cancer Predisposition.

Importance: Pediatric oncology patients are increasingly recognized as having an underlying cancer predisposition syndrome (CPS). Surveillance is often recommended to detect new tumors at their earliest and most curable stages. Data on the effectiveness and outcomes of surveillance for children with CPS are limited. Objective: To evaluate the performance of surveillance across a wide spectrum of CPSs. Design, Setting, and Participants: This cohort study reviewed surveillance outcomes for children and young adults from birth to age 23 years with a clinical and/or molecular CPS diagnosis from January 1, 2009, through September 31, 2021. Patients were monitored using standard surveillance regimens for their corresponding CPS at a specialty pediatric oncology center. Patients with hereditary retinoblastoma and bone marrow failure syndromes were excluded. Data were analyzed between August 1, 2021, and December 6, 2023. Exposure: Cancer predisposition syndrome. Main Outcomes and Measures: Outcomes of surveillance were reviewed to evaluate the incidence, spectrum, and clinical course of newly detected tumors. Surveillance modalities were classified for accuracy and assessed for common strengths and weaknesses. Results: A total of 274 children and young adults (mean age, 8 years [range, birth to 23 years]; 144 female [52.6%]) with 35 different CPSs were included, with a median follow-up of 3 years (range, 1 month to 12 years). During the study period, 35 asymptomatic tumors were detected in 27 patients through surveillance (9.9% of the cohort), while 5 symptomatic tumors were detected in 5 patients (1.8% of the cohort) outside of surveillance, 2 of whom also had tumors detected through surveillance. Ten of the 35 tumors (28.6%) were identified on first surveillance imaging. Malignant solid and brain tumors identified through surveillance were more often localized (20 of 24 [83.3%]) than similar tumors detected before CPS diagnosis (71 of 125 [56.8%]; P < .001). Of the 24 tumors identified through surveillance and surgically resected, 17 (70.8%) had completely negative margins. When analyzed across all imaging modalities, the sensitivity (96.4%), specificity (99.6%), positive predictive value (94.3%), and negative predictive value (99.6%) of surveillance were high, with few false-positive (6 [0.4%]) or false-negative (5 [0.3%]) findings. Conclusions and Relevance: These findings suggest that standardized surveillance enables early detection of new tumors across a wide spectrum of CPSs, allowing for complete surgical resection and successful treatment in the majority of patients.

Binding modes of potential anti-prion phytochemicals to PrPC structures in silico.

BACKGROUND: Prion diseases involve the conversion of a normal, cell-surface glycoprotein (PrPC) into a misfolded pathogenic form (PrPSc). One possible strategy to inhibit PrPSc formation is to stabilize the native conformation of PrPC and interfere with the conversion of PrPC to PrPSc. Many compounds have been shown to inhibit the conversion process, however, no promising drugs have been identified to cure prion diseases. OBJECTIVE: This study aims to identify potential anti-prion compounds from plant phytochemicals by integrating traditional ethnobotanical knowledge with modern in silico drug design approaches. MATERIALS AND METHODS: In the current study medicinal phytochemicals were docked with swapped and non-swapped crystal structures of PrPCin silico to identify potential anti-prions to determine their binding modes and interactions. RESULTS: Eleven new phytochemicals were identified based on their binding energies and pharmacokinetic properties. The binding sites and interactions of the known and new anti-prion compounds are similar, and differences in binding modes occur in structures with very subtle differences in side chain conformations. Binding of these compounds poses steric hindrance to neighbouring molecules. Residues shown to be associated with the inhibition of PrPC to PrPSc conversion form interactions with most of the compounds. CONCLUSION: Identified compounds might act as potent inhibitors of PrPC to PrPSc conversion. These might be attractive candidates for the development of novel anti-prion therapy although further tests in vitro cell cultures and in vivo mouse models are needed to confirm these findings.

Roles of the redox-active disulfide and histidine residues forming a catalytic dyad in reactions catalyzed by 2-ketopropyl coenzyme M oxidoreductase/carboxylase.

NADPH:2-ketopropyl-coenzyme M oxidoreductase/carboxylase (2-KPCC), an atypical member of the disulfide oxidoreductase (DSOR) family of enzymes, catalyzes the reductive cleavage and carboxylation of 2-ketopropyl-coenzyme M [2-(2-ketopropylthio)ethanesulfonate; 2-KPC] to form acetoacetate and coenzyme M (CoM) in the bacterial pathway of propylene metabolism. Structural studies of 2-KPCC from Xanthobacter autotrophicus strain Py2 have revealed a distinctive active-site architecture that includes a putative catalytic triad consisting of two histidine residues that are hydrogen bonded to an ordered water molecule proposed to stabilize enolacetone formed from dithiol-mediated 2-KPC thioether bond cleavage. Site-directed mutants of 2-KPCC were constructed to test the tenets of the mechanism proposed from studies of the native enzyme. Mutagenesis of the interchange thiol of 2-KPCC (C82A) abolished all redox-dependent reactions of 2-KPCC (2-KPC carboxylation or protonation). The air-oxidized C82A mutant, as well as wild-type 2-KPCC, exhibited the characteristic charge transfer absorbance seen in site-directed variants of other DSOR enzymes but with a pK(a) value for C87 (8.8) four units higher (i.e., four orders of magnitude less acidic) than that for the flavin thiol of canonical DSOR enzymes. The same higher pK(a) value was observed in native 2-KPCC when the interchange thiol was alkylated by the CoM analog 2-bromoethanesulfonate. Mutagenesis of the flavin thiol (C87A) also resulted in an inactive enzyme for steady-state redox-dependent reactions, but this variant catalyzed a single-turnover reaction producing a 0.8:1 ratio of product to enzyme. Mutagenesis of the histidine proximal to the ordered water (H137A) led to nearly complete loss of redox-dependent 2-KPCC reactions, while mutagenesis of the distal histidine (H84A) reduced these activities by 58 to 76%. A redox-independent reaction of 2-KPCC (acetoacetate decarboxylation) was not decreased for any of the aforementioned site-directed mutants. We interpreted and rationalized these results in terms of a mechanism of catalysis for 2-KPCC employing a unique hydrophobic active-site architecture promoting thioether bond cleavage and enolacetone formation not seen for other DSOR enzymes.

Selection criteria and pre-clinical academic performance in a private medical college in Nepal: a case study.

BACKGROUND: All medical schools in Nepal use academic merit as the criterion for selecting students. Medical educationists in Nepal seek to make the selection process more transparent and fair to applicants from different socio-economic backgrounds, while striving to raise the educational standards. AIM: To evaluate the efficacy of selection methods in relation to academic success. METHOD: Formative and Summative scores of three groups that had used different selection criteria were obtained and subjected to statistical analysis. RESULTS: The group selected through an interview (INT) showed significantly better performance on the formative exam in Year 1. Scores of the first come first served group (FCF) on Summative exam in Year 1 were significantly lower than those of INT or the group selected from the entrance exam merit list (KUM), with also the lowest pass rate. No significant differences were present amongst the formative or summative scores of the groups in Year 2, albeit INT which showed the highest pass rate. CONCLUSION: The academic performance of students at the end of two years of basic sciences does not appear to correlate with pre-admission academic merit. The usefulness of an interview is reflected in a higher pass rate. It might be worthwhile to include an interview in the selection process with a concomitant change in the methods of student assessment.

Temperature-dependent near-surface interstitial segregation in niobium.

Niobium's superconducting properties are affected by the presence and precipitation of impurities in the near-surface region. A systematic wide-temperature range x-ray diffraction study is presented addressing the effect of low temperatures (108 K-130 K) and annealing treatments (523 K in nitrogen atmosphere, 400 K in UHV) on the near-surface region of a hydrogen-loaded Nb(100) single-crystal. Under these conditions, the response of the natural surface oxides (Nb2O5, NbO2, and NbO) and the changes in the subsurface concentration of interstitial species in Nb are explored, thereby including the cryogenic temperature regime relevant for device operation. The formation and suppression of niobium hydrides in such conditions are also investigated. These treatments are shown to result in: (i) an increase in the concentration of interstitial species (oxygen and nitrogen) occupying the octahedral sites of the Nb bcc lattice at room temperature, both in the near-surface region and in the bulk. (ii) A decrease in the concentration of interstitials within the first 10 nm from the surface at 130 K. (iii) Hydride formation suppression at temperatures as low as 130 K. These results show that mild annealing in nitrogen atmosphere can suppress the formation of superconducting-detrimental niobium hydrides, while subsurface interstitial atoms tend to segregate towards the surface at 130 K, therefore altering the local concentration of impurities within the RF penetration depth of Nb. These processes are discussed in the context of the improvement of niobium superconducting radio-frequency cavities for next-generation particle accelerators.

Metabolic disease in Nepal: a perspective.

Inborn errors of metabolism or metabolic diseases, are a group of genetically determined metabolic disorders that result in mental retardation or early death. The prevalence of IEM in various countries shows a prevalence varying between 1 in 800 to 1 in 5000. As the technology for detecting metabolites has become more advanced, studies utilizing more modern methods report a higher prevalence. There have been reports of a few Inborn errors of metabolisms in Nepal, but studies to gauge the prevalence of these disorders in the Nepalese population are lacking. With conflicting statistical numbers from different sources regarding mental retardation cases in Nepalese population and a substantial rate of consanguinity and inter caste marriages, it would be prudent to initiate some pilot studies to estimate the prevalence of a group of disorders that can be diagnosed through simple laboratory tests, to be followed by a screening programme depending upon the results. The presented review discusses the need for and the possibilities of screening for these errors for early intervention in Nepal.

Neurootological differentiations in endogenous tinnitus.

Vertigo and tinnitus are very frequent complaints. Often, we find multisensory syndromes combined with tinnitus, hearing impairment, vertigo, and nausea. From more than 10,000 cases, we evaluated 757 randomly selected neurootological patients suffering from endogenous tinnitus. First, we classified the 10,000 patients into those suffering from the basic tetrad of tinnitus forms: bruits, endogenous (maskable) tinnitus, exogenous (nonmaskable) tinnitus, and other syndromes such as the slow brainstem syndrome. Then, of all the endogenous tinnitus patients, we randomly selected our study sample (n = 757), and those patients underwent a complex neurosensory investigation, including neurootological history; classic audiometry; acoustic brainstem-evoked potentials; acoustic cortically evoked potentials; visually evoked potentials; electronystagmography of spontaneous, caloric, rotatory, and optokinetic nystagmus; and craniocorpography with several vestibulospinal tests. For this study, we primarily examined the historical findings. The statistical results demonstrate that tinnitus is interconnected to a multifactorial disease background with a broad spectrum of individual complaints. Finally, the topodiagnostics of the functional neurootometric analysis shows that this type of endogenous tinnitus constitutes decidedly more central than peripheral statoacoustic pathology.

Case reports of metabolic disorders from Nepal.

BACKGROUND: The prevalence of metabolic disease in Nepal is largely unknown. Some consideration has been given by the nepalese government for high prevalence of congenital disorders in some populations, but disorders due to enzymatic deficiencies have not been considered as a class of diseases where timely diagnosis and intervention might be possible. No case for these disorders has been made so far, however, findings of many rare metabolic diseases have been reported in literature by the nepalese medical fraternity. METHODS: A search for case reports on metabolic disorders listed according to International Classification of Diseases -11 was performed using the google search engine. RESULTS: A total of 443 cases have been discovered presented in the literature. This does not include disorders that might be due to lifestyle and behaviour. Most of the reported cases have been identified based on clinical acumen, radiological and histopathological findings. CONCLUSIONS: Glucose 6 phosphate dehydrogenase deficiency, Wilson's disease and lysosomal disorders should be considered for early diagnosis through newborn screening along with the acknowledged disorders hypothyroidism and hemoglobinopathies in Nepal. Early intervention in these disorders can significantly reduce morbidity and mortality in infancy.

Newborn Screening for Selected Disorders in Nepal: A Pilot Study.

The prevalence of metabolic disorders in Nepal is yet unknown, although many case reports occur in literature. Heel-prick blood samples from newborns were collected on Dried Blood Spot (DBS) collection cards and tested through Tandem Mass Spectroscopy and fluorescence assays for disorders included in the Swiss neonatal screening program; two cases of hypothyroidism and one case of cystic fibrosis were identified. Thyroid stimulating hormone (TSH), immuoreactive trypsinogen (IRT), hydroxyprogesterone (OHP), tyrosine (Tyr), and octanoylcarnitine (C8) showed significant differences with gestation age. Most of the parameters were positively correlated with each other except galactose, galactose 1 phosphate uridyl transferase (GALT), and biotinidase. First and ninety-ninth percentiles in the Nepalese newborns were found to be different when compared with the Swiss newborns. Congenital hypothyroidism and cystic fibrosis are candidates to be considered for a newborn screening program in Nepal. Differences between the Nepalese and Swiss newborns in parametric values that change with gestation age can be attributed to a higher survival rate of pre-term babies in Switzerland. Others could be explained in part by early and exclusive breastfeeding in Nepalese newborns.

Dithiomethylether as a ligand in the hydrogenase h-cluster.

An X-ray crystallographic refinement of the H-cluster of [FeFe]-hydrogenase from Clostridium pasteurianum has been carried out to close-to atomic resolution and is the highest resolution [FeFe]-hydrogenase presented to date. The 1.39 A, anisotropically refined [FeFe]-hydrogenase structure provides a basis for examining the outstanding issue of the composition of the unique nonprotein dithiolate ligand of the H-cluster. In addition to influencing the electronic structure of the H-cluster, the composition of the ligand has mechanistic implications due to the potential of the bridge-head gamma-group participating in proton transfer during catalysis. In this work, sequential density functional theory optimizations of the dithiolate ligand embedded in a 3.5-3.9 A protein environment provide an unbiased approach to examining the most likely composition of the ligand. Structural, conformational, and energetic considerations indicate a preference for dithiomethylether as an H-cluster ligand and strongly disfavor the dithiomethylammonium as a catalytic base for hydrogen production.

Phytochemical composition, in vitro antioxidant activity and antibacterial mechanisms of Neolamarckia cadamba fruits extracts.

Aqueous extracts of Neolamarckia cadamba fruits prepared at different maturity stages were used for the analysis of various phytochemicals, and their antioxidant and antibacterial activities were determined. Ripe fruit extract had highest phenolics (3.14 mM GAE/ g fruit extract) with caffeic acid, tannic acid, syringic acid and quercetin as major phenolic compounds. The ripe fruit extract showed lowest IC50 values in DPPH radical scavenging assay (231.33 µg fruit extract/ mL), and highest ABTS radical scavenging activity (111.18 µM TEAC/g). Immature fruit extract showed lowest minimum inhibitory concentration against tested bacteria, and the antibacterial activity was probably due to membrane permeation, as was evident by leakage of genetic material and reduction in propidium iodide uptake by bacterium; and by inhibition of sugar and amino acid uptake. The appreciable amount of phenolic compounds and biological activities in the aqueous extracts of N. cadamba fruits suggests it's potential application as natural preservative.

A novel frameshift mutation in the MLH1 gene in a patient with Lynch syndrome.

A novel mutation in the MLH1 gene likely to be pathogenic for Lynch syndrome was discovered in a proband with a family history of colon cancer. Immunohistochemistry showed negative expression of PMS2 and MLH1 in the resected tumor sample. The mutation lies at the highly conserved C-terminus of the MLH1 protein, the region through which it dimerizes with PMS2 to carry out its mismatch repair function.

Traditional uses, phytochemistry and pharmacological properties of Neolamarckia cadamba: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: There are more than 3000 officially documented plants in the Indian subcontinent that hold great medicinal potential. One such under-explored plant is an evergreen tropical tree Neolamarckia cadamba (Roxb.) Bosser (Rubiaceae). It is widely distributed in tropical and subtropical regions of the world and has therapeutic potential against many diseases such as diabetes, anaemia, stomatitis, leprosy, cancer and infectious diseases. Neolamarckia cadamba has historical existence in India and it is mentioned in mythical stories. There are several reports on medicinal values of root, bark and leaves of N. cadamba; but the literature on its fruits is scanty. Therefore, the present review aims to provide updated comprehensive information on the phytochemistry and pharmacological properties of different parts of N. cadamba tree with special reference to its fruit, in order to open new perspectives for future food and pharmacological research. MATERIALS AND METHODS: A literature search was performed on N. cadamba using ethnobotanical textbooks, published articles in peer-reviewed journals, unpublished materials, government survey reports and scientific databases such as Pubmed, Scopus, Web of Science, Science Direct, Google Scholar and other web search engines (Google, Yahoo). The Plant List, International Plant Name Index and Kew Botanical Garden Plant name databases were used to validate the scientific names. RESULTS AND DISCUSSION: Neolamarckia cadamba is one of the economically important trees, which is being exploited for paper, pulp and wood industry. In folk medicine, various parts of N. cadamba are used in the treatment of various ailments such as fever, uterine complaints, blood diseases, skin diseases, tumour, anaemia, eye inflammation and diarrhoea. Other reported uses of N. cadamba include antihepatotoxic, antimalarial, analgesic, anti-inflammatory, antipyretic, diuretic and laxative. Various phytochemicals such as cadambine and its derivatives (dihydrocadambine and isodihydrocadambine) and indole alkaloids (Neolamarckines) were isolated from the leaves; whereas the presence of quinovic acid derivatives have been reported in the bark of N. cadamba. CONCLUSION: The present review compiles information on an ethnopharmacologically useful plant N. cadamba. Bioactive compounds responsible for its various medicinal properties and their effects at the molecular level need to be investigated in more detail. Furthermore, the detailed study of toxicity and pharmacological properties of extracts as well as molecules in N. cadamba is required to confirm the ethnomedicinal claims of N. cadamba for food and pharmaceutical applications.

A comparison of phosphonothioic acids with phosphonic acids as phosphatase inhibitors.

Phosphorothioates, analogues of phosphate esters in which a sulfur replaces an oxygen atom in the phosphoryl group, are competent surrogate substrates for a number of phosphatases. In some cases the thio analogues show similar binding (as estimated by K(m)) while other phosphatases show quite different K(m) values for phosphate compared to phosphorothioate esters. On this basis it was hypothesized that there might be different inhibitory tendencies by the nonhydrolyzable analogues, phosphonothioic acids compared with phosphonic acids. A series of phosphonothioic acids and corresponding phosphonic acids were synthesized and their inhibitory properties were compared toward human placental and E. coli alkaline phosphatases, the protein-tyrosine phosphatase from Yersinia, and the serine/threonine protein phosphatases PP2C and lambda. Sulfur substitution for oxygen gives the phosphonothioic acids pK(a) values that are close to those of phosphate esters, in contrast to the higher pK(a) values typical of phosphonic acids. Despite different steric requirements and differences in charge distribution in the anions of phosphonothioic acids compared with phosphonic acids, it was found that, with some exceptions, differences in inhibitory properties were modest.

Structural basis for carbon dioxide binding by 2-ketopropyl coenzyme M oxidoreductase/carboxylase.

The structure of 2-ketopropyl coenzyme M oxidoreductase/carboxylase (2-KPCC) has been determined in a state in which CO(2) is observed providing insights into the mechanism of carboxylation. In the substrate encapsulated state of the enzyme, CO(2) is bound at the base of a narrow hydrophobic substrate access channel. The base of the channel is demarcated by a transition from a hydrophobic to hydrophilic environment where CO(2) is located in position for attack on the carbanion of the ketopropyl group of the substrate to ultimately produce acetoacetate. This binding mode effectively discriminates against H(2)O and prevents protonation of the ketopropyl leaving group.

Mechanistic implications of the structure of the mixed-disulfide intermediate of the disulfide oxidoreductase, 2-ketopropyl-coenzyme M oxidoreductase/carboxylase.

The structure of the mixed, enzyme-cofactor disulfide intermediate of ketopropyl-coenzyme M oxidoreductase/carboxylase has been determined by X-ray diffraction methods. Ketopropyl-coenzyme M oxidoreductase/carboxylase belongs to a family of pyridine nucleotide-containing flavin-dependent disulfide oxidoreductases, which couple the transfer of hydride derived from the NADPH to the reduction of protein cysteine disulfide. Ketopropyl-coenzyme M oxidoreductase/carboxylase, a unique member of this enzyme class, catalyzes thioether bond cleavage of the substrate, 2-ketopropyl-coenzyme M, and carboxylation of what is thought to be an enzyme-stabilized enolacetone intermediate. The mixed disulfide of 2-ketopropyl-coenzyme M oxidoreductase/carboxylase was captured through crystallization of the enzyme with the physiological products of the reaction, acetoacetate, coenzyme M, and NADP, and reduction of the crystals with dithiothreitol just prior to data collection. Density in the active-site environment consistent with acetone, the product of reductive decarboxylation of acetoacetate, was revealed in this structure in addition to a well-defined hydrophobic pocket or channel that could be involved in the access for carbon dioxide. The analysis of this structure and that of a coenzyme-M-bound form provides insights into the stabilization of intermediates, substrate carboxylation, and product release.