Stereoselective Synthesis of ß-d-Manno-heptopyranoside via Cs2CO3-Mediated Anomeric O-Alkylation: Synthesis of a Tetrasaccharide Repeat Unit of Bacillus thermoaerophilus Surface-Layer Glycoprotein.

Stereoselective synthesis of d-glycero- and l-glycero-ß-d-mannoheptosides has been achieved by cesium carbonate-mediated ß-selective anomeric O-alkylation of the corresponding d-mannoheptoses. In addition, this method has been utilized in the total synthesis of a tetrasaccharide repeat unit of Bacillus thermoaerophilus surface-layer glycoprotein.

Cationic gold(I)-catalyzed glycosylation with glycosyl N-1,1-dimethylpropargyl carbamate donors.

A mild and efficient cationic gold(I)-catalyzed O-glycosylation methodology involving the use of bench-stable glycosyl N-1,1-dimethylpropargyl carbamate donors has been developed. In the presence of 1-2 mol% [tris(2,4-di-tert-butylphenyl)phosphite]gold(I) chloride and 5 mol% silver triflate, both "armed" and "disarmed" glycosyl N-1,1-dimethylpropargyl carbamate donors react with various sugar acceptors at room temperature to afford the corresponding glycosides in good to excellent yields. These glycosyl N-1,1-dimethylpropargyl carbamates are found to be orthogonal to regular phenyl thioglycoside donors. The utilization of this method has been demonstrated in the synthesis of a trisaccharide.

Formulation Optimization and in Vitro Characterization of Orally Disintegrating Films Using a Factorial Design and Mathematical Modeling for Drug Release.

Even though experimental designs are becoming popular especially for conventional dosage forms, limited studies have been performed to optimize formulations of orally disintegrating films (ODFs). This study aimed to evaluate sildenafil citrate-loaded ODFs for a controlled release with hydroxypropyl methylcellulose as a film-forming polymer. A factorial design was utilized for optimization with three control factors: ethanol ratio, plasticizer ratio, and the type of plasticizer. Tensile strength, disintegration time, water contact angle, and thickness were chosen as responses. For optimization, water contact angle, disintegration time, and thickness were minimized, while the tensile strength was maximized. Based on the conditions, optimal formulations were achieved for each type of plasticizer. Evaluation of desirability indicated that the response values were close to the target. When these optimal formulations were validated, the optimal solutions and target values were similar with small biases. The formulations were characterized using scanning electron microscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy, surface pH, in vitro dissolution, and drug release simulation with a mathematical modeling. After the drug was homogenously dispersed throughout the film, the crystalline form of the drug provided strong hydrogen bonds between the drug and the film components. Moreover, it showed a controlled drug release profiles that were well matched with simulated results. This study suggests that the optimized films may present a better alternative to conventional tablets for the treatment of male erectile dysfunction.

Synthesis of 2-Amino-2-deoxy-ß-d-mannosides via Stereoselective Anomeric O-Alkylation of 2N,3O-Oxazolidinone-Protected d-Mannosamine: Synthesis of the Trisaccharide Repeating Unit of Streptococcus pneumoniae 19F Polysaccharide.

Cesium carbonate-mediated stereoselective anomeric O-alkylation of a 2N,3O-oxazolidinone-protected d-mannosamine with sugar-derived primary or secondary alkyl triflates afforded the corresponding 2-amino-2-deoxy-ß-d-mannosides in moderate to good yields and excellent stereoselectivity. The oxazolidinone ring can be opened with aqueous alkali hydroxide to liberate the amine functionality. This method has been successfully applied to the synthesis of the trisaccharide repeating unit of Streptococcus pneumoniae 19F polysaccharide.

Intranasal but not intravenous delivery of the adjuvant α-galactosylceramide permits repeated stimulation of natural killer T cells in the lung.

Efficient induction of antigen-specific immunity is achieved by delivering multiple doses of vaccine formulated with appropriate adjuvants that can harness the benefits of innate immune mediators. The synthetic glycolipid α-galactosylceramide (α-GalCer) is a potent activator of NKT cells, a major innate immune mediator cell type effective in inducing maturation of DCs for efficient presentation of co-administered antigens. However, systemic administration of α-GalCer results in NKT cell anergy in which the cells are unresponsive to subsequent doses of α-GalCer. We show here that α-GalCer delivered as an adjuvant by the intranasal route, as opposed to the intravenous route, enables repeated activation of NKT cells and DCs, resulting in efficient induction of cellular immune responses to co-administered antigens. We show evidence that after intranasal delivery,α-GalCer is selectively presented by DCs for the activation of NKT cells, not B cells. Furthermore, higher levels of PD-1 expression, a potential marker for functional exhaustion of the NKT cells when α-GalCer is delivered by the intravenous route, are not observed after intranasal delivery. These results support a mucosal route of delivery for the utility of α-GalCer as an adjuvant for vaccines, which often requires repeated dosing to achieve durable protective immunity.

Climate change induced declines in fuel moisture may turn currently fire-free Pyrenean mountain forests into fire-prone ecosystems.

Fuel moisture limits the availability of fuel to wildfires in many forest areas worldwide, but the effects of climate change on moisture constraints remain largely unknown. Here we addressed how climate affects fuel moisture in pine stands from Catalonia, NE Spain, and the potential effects of increasing climate aridity on burned area in the Pyrenees, a mesic mountainous area where fire is currently rare. We first quantified variation in fuel moisture in six sites distributed across an altitudinal gradient where the long-term mean annual temperature and precipitation vary by 6-15 °C and 395-933 mm, respectively. We observed significant spatial variation in live (78-162%) and dead (10-15%) fuel moisture across sites. The pattern of variation was negatively linked (r = |0.6|-|0.9|) to increases in vapor pressure deficit (VPD) and in the Aridity Index. Using seasonal fire records over 2006-2020, we observed that summer burned area in the Mediterranean forests of Northeast Spain and Southern France was strongly dependent on VPD (r = 0.93), the major driver (and predictor) of dead fuel moisture content (DFMC) at our sites. Based on the difference between VPD thresholds associated with large wildfire seasons in the Mediterranean (3.6 kPa) and the maximum VPD observed in surrounding Pyrenean mountains (3.1 kPa), we quantified the "safety margin" for Pyrenean forests (difference between actual VPD and that associated with large wildfires) at 0.5 kPa. The effects of live fuel moisture content (LFMC) on burned area were not significant under current conditions, a situation that may change with projected increases in climate aridity. Overall, our results indicate that DFMC in currently fire-free areas in Europe, like the Pyrenees, with vast amounts of fuel in many forest stands, may reach critical dryness thresholds beyond the safety margin and experience large wildfires after only mild increases in VPD, although LFMC can modulate the response.

Cross-sectional study of Facebook addiction in a sample of Nepalese population.

Background: Facebook addiction is said to occur when an individual spends an excessive amount of time on Facebook, disrupting one's daily activities and social life. The present study aimed to find out the level of Facebook addiction in the Nepalese context and briefly discuss the issues associated with its unintended use. Methods: A descriptive cross-sectional study was conducted in the Department of Forensic Medicine of Lumbini Medical College. The study instrument was the Bergen Facebook Addiction Scale typed into a Google Form and sent randomly to Facebook contacts of the authors. The responses were downloaded in a Microsoft Excel spreadsheet and analyzed using Statistical Package for Social Sciences version 16. Results: The study consisted of 103 Nepalese participants, of which 54 (52.42%) were males and 49 females (47.58%). There were 11 participants (10.68%) who had more than one Facebook account. When different approaches were applied it was observed that 8.73% (n=9) to 39.80% (n=41) were addicted to Facebook. Conclusion: When used properly Facebook has its own advantages. Excessive use is linked with health hazards including addiction and dependency. Students who engage more on Facebook may have less time studying, leading to poor academic performance. People need to be made aware of the issues associated with the misuse of Facebook.

Foreign body esophagus: Six years of silence.

Foreign body esophagus remains one of the common medical emergencies which may lead to significant morbidity and mortality. Sharp objects, batteries, and elderly with foreign body esophagus should be treated with emergent removal owing to the complications that might ensue. Endoscopic removal is the preferred choice of treatment but for large foreign body, sharp foreign body, and so on, rigid esophagoscopic removal might be more preferable. Foreign body esophagus though an obvious situation might at times be missed. It is important to make an early definitive diagnosis. We report a unique case of missed foreign body (denture) esophagus despite the obvious signs and symptoms. Definitive diagnosis was made only after 6 years due to the lack of definitive diagnostic procedures and expertise. The foreign body was impacted in the mucosal wall of the esophagus requiring Gastric resection and anastomosis (with McKeown procedure). With this we have tried to highlight the pitfalls in the diagnosis and management of foreign body esophagus. We report a case of a 55-year-old female who presented to the Emergency Room with history of progressive dysphagia and odynophagia for 6 years which was aggravated for the past 6 months. A radiological diagnosis was made. It was followed by a failed attempt of endoscopic removal which warranted the surgical removal of the foreign body.

Current State and Future Perspectives on Gastroretentive Drug Delivery Systems.

In recent years, many attempts have been made to enhance the drug bioavailability and therapeutic effectiveness of oral dosage forms. In this context, various gastroretentive drug delivery systems (GRDDS) have been used to improve the therapeutic efficacy of drugs that have a narrow absorption window, are unstable at alkaline pH, are soluble in acidic conditions, and are active locally in the stomach. In this review, we discuss the physiological state of the stomach and various factors that affect GRDDS. Recently applied gastrointestinal technologies such as expandable, superporous hydrogel; bio/mucoadhesive, magnetic, ion-exchange resin; and low- and high-density-systems have also been examined along with their merits and demerits. The significance of in vitro and in vivo evaluation parameters of various GRDDS is summarized along with their applications. Moreover, future perspectives on this technology are discussed to minimize the gastric emptying rate in both the fasted and fed states. Overall, this review may inform and guide formulation scientists in designing the GRDDS.

Buccal oncocytoma: Report of a case and literature review.

INTRODUCTION: More common in major salivary glands, oncocytomas are very rare tumors. They commonly occur in the parotid gland and are painless slow growing predominantly benign tumors. The term "oncocytoma" was introduced by Jaffe to designate those tumors of the salivary glands that consist predominantly of oncocytic cells lining the salivary ducts (1) Similalry, Meza- Chavez had proposed the name "oxyphilic granular cell adenoma. (2) Oncocytomas are extremely rare, benign and slow growing in nature. Here we present a rare case of buccal oncocytoma which is to our knowledge the 19th case of intraoral minor salivary gland tumor and the 7th reported case of buccal oncocytoma. CASE PRESENTATION: Here we present an exceedingly rare case of buccal oncocytoma in a 14 years boy who presented to the department of ENT with right buccal swelling for 6 months. He was posed the diagnosis of buccal cyst after cytological examination supported by CT scan. He then underwent an excisional biopsy where the final diagnosis was made as Buccal Oncocytoma. CONCLUSIONS: Though very rare in the picture, conditions like salivary gland oncocytomas still are reported on and off in the literature. The treatment of which is complete surgical excision.

Vestibular Schwanomma: An Experience in a Developing World.

BACKGROUND: Tumors related to the acoustic nerves represent 90% of cerebellopontine angle diseases and have been in the picture for at least 200 years. Famous as acoustic neuromas and vestibular neuromas, these are usually benign, slow-growing tumors of Schwann cells of the myelin sheath. Surgery is the treatment of choice though some authors have suggested "wait and watch" policy. The aims of our study were to study the clinical presentation and management of the tumors, and to evaluate the perioperative outcomes of the surgery. METHODS: A retrospective review of the datasheet of 33 patients diagnosed with vestibular schwanomma who had undergone surgery from January 2014 to January 2017 was performed in National Academy of Medical Sciences, Bir Hospital, Kathmandu, Nepal. Analysis of the demographic data and perioperative outcomes was performed. RESULTS: Hearing loss was the main presenting symptom in 72% cases followed by tinnitus, dizziness, facial numbness and sudden sensorineural hearing loss. Mean tumur size was 39.7 ± 3 mm. The mean age of the patients was 46 ± 3 years with a female preponderance (1.2:1). In particular, the retrosigmoid route was preferred in all the cases since it was the most employed approach at our center and 63% of the tumors presented to us were grade 5. The surgical techniques allowed safe preservation of the facial function which was 93%. The hearing loss did not improve after the surgery in 94% while it worsened in 6% of cases. We did not find any significant relation between outcome and size, age, gender or laterality of the tumor (P > 0.05). There was no perioperative mortality. CONCLUSIONS: The benign and slow-growing nature of vestibular schwanomma usually poses problems for the early diagnosis and treatment especially in a poor resource setting like ours. Likewise, there are very few studies so far done in the country regarding the incidence and management of the disease. Thus, this study might be helpful in providing insight into the occurrence of the disease in the present scenario and the need for much more studies in the future.

Effects of granulation process variables on the physical properties of dosage forms by combination of experimental design and principal component analysis.

The current study was to understand how process variables of high shear wet granulations affect physical properties of granules and tablets. The knowledge gained was intended to be used for Quality-by-Design based process design and optimization. The variables were selected based on the risk assessment as impeller speed, liquid addition rate, and wet massing time. Formulation compositions were kept constant to minimize their influence on granules properties. Multiple linear regression models were built providing understanding of the impact of each variable on granule hardness, Carr's index, tablet tensile strength, surface mean diameter of granules, and compression behavior. The experimental results showed that the impact of impeller speed was more dominant compared to wet massing time and water addition rate. The results also revealed that quality of granules and tablets could be optimized by adjusting specific process variables (impeller speed 1193 rpm, water spray rate 3.7 ml/min, and wet massing time 2.84 min). Overall desirability was 0.84 suggesting that the response values were closer to the target one. The SEM image of granules showed that spherical and smooth granules produced at higher impeller speed, whereas rough and irregular shape granules at lower speed. Moreover, multivariate data analysis demonstrated that impeller speed and massing time had strong correlation with the granule and tablet properties. In overall, the combined experimental design and principal component analysis approach allowed to better understand the correlation between process variables and granules and tablet attributes.

Development of sorafenib loaded nanoparticles to improve oral bioavailability using a quality by design approach.

Sorafenib, a potent anticancer drug, has low absorption in the gastrointestinal tract due to its poor aqueous solubility. The main purpose of this investigation was to design sorafenib nanoparticle using a newly developed technique, nanoparticulation using fat and supercritical fluid (NUFS™) to improve the absorption of sorafenib. The quality by design (QbD) tool was adopted to define the optimal formulation variables: hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone K30 (PVP), and poloxamer. The studied response variables were particle size of nanoparticle, dissolution (5, 60, and 180 min), drug concentration time profile of nanoparticle formulations, and maximum drug concentration. The result of particle size revealed that an increase in concentration of poloxamer and HPMC decreased the particle size of nanoparticles (p < 0.05). Likewise, the concentration of drug release at different time point (5, 60, and 180 min) showed HPMC and poloxamer had positive effects on drug dissolution while PVP had negative effects on it. The design space was built in accordance with the particle size of nanoparticle (target < 500 nm) and dissolution of sorafenib (target > 7 µm/mL), following failure probability analysis using Monte Carlo simulations. In vivo pharmacokinetics studies in beagle dogs demonstrated that optimized formulation of sorafenib (F3 and F4 tablets) exhibited higher blood drug profiles indicating better absorption compared to the reference tablet (Nexavar®). In conclusion, this study showed the importance of systematic formulation design for understanding the effect of formulation variables on the characteristics of nanoparticles of the poorly soluble drug.

Sensitive detection of isoglobo and globo series tetraglycosylceramides in human thymus by ion trap mass spectrometry.

Glycosphingolipids serve as ligands for receptors involved in signal transduction and immune recognition, as exemplified by isoglobotrihexosylceramide, an antigenic ligand for T cell receptors. Mechanistic studies on the regulation of isoglobotrihexosylceramide require biochemical measurement of its lysosomal precursor, isoglobotetraglycosylceramide. It remains a challenge to distinguish between complex tetraglycosylceramide glycosphingolipid isomers with the same sugar components but diverse internal linkages. Here we established a simple and sensitive method to separate globo- and isoglobotetraglycosylceramide by MS5 ion trap mass spectrometry, and report the identification of isoglobotetraglycosylceramide in a CHO cell line transfected by iGb3 synthase, as well as in human thymus.

Effects of Formulation and Process Variables on Gastroretentive Floating Tablets with A High-Dose Soluble Drug and Experimental Design Approach.

To develop sustained release gastro-retentive effervescent floating tablets (EFT), a quality-based experimental design approach was utilized during the composing of a hydrophilic matrix loaded with a high amount of a highly water-soluble model drug, metformin HCl. Effects of the amount of polyethylene oxide WSR 303 (PEO), sodium bicarbonate, and tablet compression force were used as independent variables. Various times required to release the drug, tablet tensile strength, floating lag time, tablet ejection force, and tablet porosity, were selected as the responses. Polymer screening showed that PEO had the highest gel strength among the various tested polymers. Sodium bicarbonate had the most significant effect on the release rate and floating lag time by retarding the rate from the hydrophilic matrices, whilst tablet compression force and PEO exerted the greatest influence on tablet properties (p < 0.0001). The design space was built in accordance with the drug release profiles, tensile strength, and floating lag time, following failure probability analysis using Monte Carlo simulations. The kinetic modeling revealed that the release mechanism was best described by the Korsmeyer-Peppas model. Overall, the current study provided a perspective on the systematic approach of gastro-retentive EFT, loaded with highly water-soluble drugs by applying quality by design concepts.

Early formulation development of CKD-519, a new CETP inhibitor, for phase 1 clinical study based on in vitro and in vivo evaluation.

CKD-519, a potent cholesteryl ester transfer protein (CETP) inhibitor, is a clinical candidate being developed for the treatment of dyslipidemia. It is considered a Biopharmaceutical Classification System II compound with low solubility and high permeability. The objective of this study was to develop early formulations focusing on the dissolution rate of the compound to achieve dose-dependent exposure. High performance formulation strategies including solid dispersion (SD) and a self-microemulsifying drug delivery system (SMEDDS) were investigated and their in vivo and in vitro correlations were also evaluated in monkeys along with dose optimization in human volunteers. The SD granules were prepared in a fluid bed granulator using microcrystalline cellulose and mannitol as carriers. Poloxamer 407 and Eudragit E PO were each found to be a suitable solubilizing agent and polymer for the improvement of the CKD-519 dissolution rate. Pharmacokinetic studies in monkeys showed that the SD tablets exhibited better absorption than the SMEDDS in a dose-dependent manner from 1.5 mg to 100 mg. The mannitol-based SD tablet formulations were bioequivalent. However, pharmacokinetics studies in humans showed that the dose was saturable above 100 mg of CKD-519. This study was performed to determine how to develop early formulations for clinical studies and to identify rational formulation development strategies for CKD-519 to establish the pharmaceutical proof-of-concept in humans.

Anxiety, Depression and Post-Traumatic Stress Disorder after Earthquake.

BACKGROUND: Prevalence of anxiety, depression and post traumatic stress disorder is high after earthquake. The aim of the study is to study the prevalence and comorbidity of commonly occurring psychological symptoms in people exposed to Nepal mega earthquake in 2015 after a year of the event. METHODS: A community based, cross sectional, descriptive study was carried out in Bhumlichaur area of Gorkha district, Nepal after around 14 months of the first major earthquake. We used self-reporting questionnaire 20, Post-traumatic stress disorder 8 and hospital anxiety and depression scale to screen for presence of symptoms of anxiety and depression or post-traumatic stress disorder in this population. The risk of having these disorders according to different socio-demographic variable was assessed by calculating odds ratio. All calculations were done using predictive and analytical software (PASW) version 16.0. RESULTS: A total of 198 participants were included in the final data analysis. The mean age of study participants was 35.13 years (SD=18.04). Borderline anxiety symptoms were found in 104 (52.5%) while significant anxiety symptoms were found in 40 (20%) of respondents. Borderline depressive symptoms were seen in 40 (20%) while significant depressive symptoms were seen in 16 (8%) of subjects. Around 27% (n= 53) of respondents were classified as having post-traumatic stress disorder. CONCLUSIONS: The prevalence of anxiety and depressive symptoms and post-traumatic stress disorder seems to be high even after one year in people exposed to earthquake.

A Case of Probable Amisulpride Induced Mania after Eight Months of Therapy.

Development of manic symptoms during treatment with atypical antipsychotics can be a troublesome side effect that has been described with most atypical antipsychotics. However, reports of amisulpride induced mania have been rare. Here, we report the case of an 18-year-old male patient diagnosed with schizophrenia, who developed manic symptoms while on treatment with amisulpride. While previous reports have described occurrence of mania within days to three months of treatment with amisulpride, we report a case where manic symptoms occurred after around eight months of therapy. We have also attempted to describe the possible risk factors based on the available case studies.

Synthetic Poly(L-Glutamic Acid)-conjugated CpG Exhibits Antitumor Efficacy With Increased Retention in Tumor and Draining Lymph Nodes After Intratumoral Injection in a Mouse Model of Melanoma.

There is an urgent need for new clinically applicable drug-delivery methods to enhance accumulation of immune-activating drugs in tumors. We synthesized a poly(L-glutamic acid)-CpG ODN2216 conjugate (PG-CpG) and injected it intratumorally into C57BL/6 mice bearing subcutaneous B16-ovalbumin melanoma. PG-CpG elicited the same potent antitumoral activity as CpG with respect to reducing tumor growth and triggering antigen-specific CD8 T-cell responses in this well-established solid tumor model. Moreover, PG-CpG was retained significantly longer in both tumor and draining lymph nodes than was free CpG after intratumoral injection. Specifically, 48 hours after injection, 26.5%±16.9% of the injected PG-CpG dose versus 4.72%±2.61% of free CpG remained at the tumor, and 1.53%±1.22% of the injected PG-CpG versus 0.37%±0.33% of free CpG was retained in the draining inguinal lymph nodes. These findings indicate that PG is an effective synthetic polymeric carrier for delivery of immunostimulatory agents to tumors and lymph nodes.

Psychiatric morbidity in elderly patients attending OPD of tertiary care centre in western region of Nepal.

CONTEXT: Aging of population is currently a global phenomenon. At least one in 5 people over the age of 65 years will suffer from a mental disorder by 2030. Study of psychiatric morbidities in this age group is essential to prepare for upcoming challenges. AIMS: To find out the prevalence of different psychiatric morbidities in elderly population and to find out if there are any age and gender specific differences. SETTINGS AND DESIGN: Retrospective review; Psychiatric outpatient department of Manipal Teaching Hospital, Pokhara, Nepal. MATERIALS AND METHODS: Data for patients ≥ 65 years of age attending the psychiatric outpatient department of Manipal Teaching Hospital, Pokhara, Nepal, from 1(st) January 2012 to 15(th) January 2013 were collected retrospectively in a predesigned proforma. STATISTICAL ANALYSIS USED: Risk of having different psychiatric disorders was estimated using odds ratio. RESULTS: The mean age of 120 patients included in this study was 69.67 (SD = 5.94) years. Depressive disorder (26.7%) was the most common diagnosis. There was no statistically significant difference in psychiatric disorders in >75 years compared with ≤75 years except for dementia [odd ratio (OR) (≤75 years/>75 years)=0.055, 95% confidence interval (CI)=0.016; 0.194]. Alcohol dependence syndrome [OR (male/female)=7.826, 95% CI = 1.699;36.705] and dementia [OR (male/female)=3.394, 95% CI = 1.015;11.350] was more common in males. CONCLUSIONS: Depressive disorder was the most common psychiatric morbidity among the elderly patients. The odds suffering from dementia increased with increasing age. The odds of having alcohol related problems and dementia were more in males compared with females.