Immunotherapy for Alzheimer's Disease: Current Scenario and Future Perspectives.

Alzheimer's disease (AD) is a global health concern owing to its complexity, which often poses a great challenge to the development of therapeutic approaches. No single theory has yet accounted for the various risk factors leading to the pathological and clinical manifestations of dementia-type AD. Therefore, treatment options targeting various molecules involved in the pathogenesis of the disease have been unsuccessful. However, the exploration of various immunotherapeutic avenues revitalizes hope after decades of disappointment. The hallmark of a good immunotherapeutic candidate is not only to remove amyloid plaques but also to slow cognitive decline. In line with this, both active and passive immunotherapy have shown success and limitations. Recent approval of aducanumab for the treatment of AD demonstrates how close passive immunotherapy is to being successful. However, several major bottlenecks still need to be resolved. This review outlines recent successes and challenges in the pursuit of an AD vaccine.

Enhanced oral bioavailability and hepatoprotective activity of thymoquinone in the form of phospholipidic nano-constructs.

Background: The poor biopharmaceutical properties of thymoquinone (TQ) obstruct its development as a hepatoprotective agent. To surmount the delivery challenges of TQ, phospholipid nanoconstructs (PNCs) were constructed.Method: PNCs were constructed employing microemulsification technique and systematic optimization by three-factor three level Box-Behnken design.Result: Optimized PNC composition exhibited nano size (<100 nm), spherical morphology, within acceptable range of polydispersity index (0.55), high drug entrapment efficiency (>90%), controlled drug release pattern, and neutral surface charge (zeta potential of -0.65 mV). After oral administration of a single dose of PNC, it showed a relative bioavailability of 386.03% vis-à-vis plain TQ suspension. Further, TQ-loaded PNC demonstrated significant enhanced hepato-protective effect vis-à-vis pure TQ suspension and silymarin, as evidenced by reduction in the ALP, ALT, AST, bilirubin, and albumin level and ratified by histopathological analysis.Conclusion: TQ-loaded PNCs can be efficient nano-platforms for the management of hepatic disorders and promising drug delivery systems to enhance oral bioavailability of this hydrophobic molecule.

The 2018 ISDE achalasia guidelines.

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

Development of groundwater vulnerability zones in a data-scarce eogenetic karst area using Head-Guided Zonation and particle-tracking simulation methods.

Delineation of groundwater vulnerability zones based on a valid groundwater model is crucial towards an accurate design of management strategies. However, limited data often restrain the development of a robust groundwater model. This study presents a methodology to develop groundwater vulnerability zones in a data-scarce area. The Head-Guided Zonation (HGZ) method was applied on the recharge area of Oemau Spring in Rote Island, Indonesia, which is under potential risk of contamination from rapid land use changes. In this method the model domain is divided into zones of piecewise constant into which the values of subsurface properties are assigned in the parameterisation step. Using reverse particle-tracking simulation on the calibrated and validated groundwater model, the simulation results (travel time and pathline trajectory) were combined with the potential groundwater contamination risk from human activities (land use type and current practice) to develop three vulnerability zones. The corresponding preventive management strategies were proposed to protect the spring from contamination and to ensure provision of safe and good quality water from the spring.

Prevalence of parasitic infection in captive wild animals in Bir Moti Bagh mini zoo (Deer Park), Patiala, Punjab.

AIM: The study was conducted to know the prevalence of gastrointestinal parasites of captive wild animals at Bir Moti Bagh Mini Zoo (Deer Park), Patiala, Punjab. MATERIALS AND METHODS: A total of 31 fecal samples from eight species of captive animals including Civet cat (Viverra zibetha), Porcupine (Hystrix indica), Nilgai (Boselaphus tragocamelus), Spotted deer (Axis axis), Black buck (Antelope cervicapra), Sambar deer (Cervus unicolor), Hog deer (Axis porcinus), and Barking deer (Muntiacus muntjak) were screened using classical parasitological techniques including sedimentation and floatation technique. RESULTS: Out of 31 fecal samples examined, 20 were positive for parasitic ova/oocysts of different species indicating an overall prevalence of 68.0%. The six different types of parasites observed in the study included strongyle (67%), Strongyloides spp. (14%), coccidia (38%), Trichuris spp. (19%), ascarid (10%), and Capillaria spp. (10%). Strongyles were the most common parasites observed (67%) followed by coccidia (38%). Mixed helminth and protozoan infection were observed in 48% of animals. No cestode or trematodes were detected during the study. CONCLUSION: The high prevalence of gastrointestinal parasites without overt clinical signs of disease or mortality as observed in this study is suggestive of subclinical infection. The findings will help in formulating the appropriate deworming protocol for parasitic control in these captive animals.

Utility of dysphagia grade in predicting endoscopic ultrasound T-stage of non-metastatic esophageal cancer.

Patients with non-metastatic esophageal cancer routinely undergo endoscopic ultrasound (EUS) for loco-regional staging. Neoadjuvant therapy is recommended for ≥T3 tumors while upfront surgery can be considered for ≤T2 lesions. The aim of this study was to determine if the degree of dysphagia can predict the EUS T-stage of esophageal cancer. One hundred eleven consecutive patients with non-metastatic esophageal cancer were retrospectively reviewed from a database. Prior to EUS, patients' dysphagia grade was recorded. Correlation between dysphagia grade and EUS T-stage, especially in reference to predicting ≥T3 stage, was determined. The correlation of dysphagia grade with EUS T-stage (Kendall's tau coefficient) was 0.49 (P < 0.001) for the lower and 0.59 (P = 0.008) for the middle esophagus. The sensitivity and specificity of dysphagia grade ≥2 (can only swallow semi-solids/liquids) for T3 cancer were 56% (95% confidence interval [CI] 43-67%) and 93% (95% CI 79-98%), respectively. The sensitivity, specificity, and positive predictive value of dysphagia grade ≥3 (can only swallow liquids or total dysphagia) for T3 lesions were 36% (95% CI 25-48%), 100% (95% CI 89-100%), and 100% (95% CI 83-100%), respectively. Overall, there was a significant positive correlation between dysphagia grade and the EUS T-stage of esophageal cancer. All patients with dysphagia grade ≥3 had T3 lesions. This may have clinical implications for patients who can only swallow liquids or have complete dysphagia by allowing for prompt initiation of neoadjuvant therapy, especially in countries/centers where EUS service is difficult to access in a timely manner or not available.

Bioautography and its scope in the field of natural product chemistry / 药物分析学报

Medicinal plants, vegetables and fruits are the sources of huge number of bioactive lead/scaffolds with therapeutic and nutraceutical importance. Bioautography is a means of target-directed isolation of active molecules on chromatogram. Organic solvents employed in chromatographic separation process can be completely removed before biological detection because these solvents cause inactivation of enzymes and/or death of living organisms. They offer a rapid and easy identification of bioactive lead/scaffolds in complex matrices of plant extracts. Bioautography is a technique to isolate hit(s)/lead(s) by employing a suitable chromatographic process followed by a biological detection system. This review critically describes the methodologies to identify antimicrobial, antioxidant, enzyme inhibitor lead/scaffolds by employing bioautography. A significant number of examples have been incorporated to authenticate the methodologies.

Clinico-hemato-biochemical profile of dogs with liver cirrhosis.

AIM: The aim of this study was to determine the relevant tools in the diagnosis of liver cirrhosis in dogs. MATERIAL AND METHODS: A total of 140 dogs presented at Veterinary Teaching Hospital, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana, showing clinical signs of hepatic insufficiency were subjected to clinico-hemato biochemical, urological, ultrasonographic (USG), and USG guided fine-needle biopsy examinations by standard methods. On the basis of these results, 6 dogs out of 140 dogs were found to be suffering from liver cirrhosis. Six clinically healthy dogs constituted the control group. RESULTS: The dogs suffering from liver cirrhosis manifested inappetence, halitosis, abdominal distension, weight loss, melena, icterus, anemia, and neutrophilic leukocytosis with the left shift. Levels of hemoglobin, lymphocytes, packed cell volume, mean corpuscular volume, mean corpuscular Hb (MCH), and platelet count were significantly lower in liver cirrhosis group than control group while total leukocyte count, neutrophils, and MCH concentration were significantly higher. Glucose, total protein, albumin, A/G ratio, and fibrinogen were significantly lower, and creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, prothrombin time, and APTT were significantly higher than the control values. Ultrasound revealed diffuse increase in echogenicity with rounded and irregular liver margins. Cytological examination of the ascitic fluid and fine-needle aspiration biopsy of liver was not fruitful in the diagnosis of liver cirrhosis. CONCLUSIONS: Liver cirrhosis causes clinical and hemo-biochemical alterations, which require special consideration when treating diseased animals. USG, diffuse increase in echogenicity of liver, rounding and irregularity of liver margins and microhepatica were the consistent findings. It is suggested that USG along with hemo-biochemical alterations may be used as a diagnostic tool for liver cirrhosis in dogs.

Comparative Investigation on in vitro release of extemporaneously prepared norfloxacin semisolid formulations with marketed silver sulfadiazine 1% cream, USP using model independent approach

ObjectiveIn an attempt for better treatment of bacterial infections, various semisolid formulations containing 5%w/w of norfloxacin were prepared and evaluated for in vitro drug release and in vitro skin permeabilityusing dialysis membrane and rat abdominal skin respectively. The in vitro diffusion and permeationprofile of the prepared formulation was compared with marketed silver sulfadiazine cream 1%, USPusing model independent approach.MethodsVarious semisolid formulations were prepared with different dermatological bases usingstandard procedures. In vitro diffusion and permeation studies were carried out using Keshary-Chein(KC) type diffusion cell using dialysis membrane and rat abdominal skin respectively.ResultsThe f1 lower than 15 and f2 higher than 50 indicated similarities in the in vitro diffusion andpermeation profiles of the extemporaneously prepared selected semisolid formulations and marketedsilver sulfadiazine 1% cream, USP.ConclusionAmongst all the semisolid formulations prepared, carbopol gel base was found to be most suitabledermatological base for norfloxacin, the results obtained for in vitro diffusion, and in vitro skinpermeation studies are comparable with that of marketed silver sulphadiazine 1% cream, USP(AU)

Antimicrobial evaluation of mangiferin analogues.

The naturally occurring xanthone glycoside mangiferin has been isolated by column chromatography from the ethanol extract of stem bark of Mangifera indica. Mangiferin was further converted to 5-(N-phenylaminomethyleno)mangiferin, 5-(N-p-chlorophenylaminomethyleno) mangiferin, 5-(N-2-methylphenylaminomethyleno) mangiferin, 5-(N-p-methoxyphenylaminomethyleno) mangiferin, 5-(N, N-diphenylaminomethyleno) mangiferin, 5-(N--napthylaminomethyleno) mangiferin and 5-(N-4-methylphenylaminomethyleno) mangiferin. Mangiferin and its analogues were characterized by melting point and R(f) value determination and through spectral technique like UV, IR, and NMR spectral analysis. The synthesized compounds were screened for antimicrobial activity.

A novel use of esophageal tracheal airway: the control of torrential oral bleeding.

Combitube has been included in the American Society of Anesthesiologists (ASA) difficult airway algorithm for the emergency management of patients who can be neither intubated nor ventilated. The main advantages of the Combitube are minimal training required for its use and blind insertion with 90% success rate upon first attempt. The authors report a case of torrential oral bleeding in which the airway was secure and isolated by Combitube. The pharyngeal cuff of the Combitube was overinflated so as to create a tamponade effect to control otherwise uncontrollable and inaccessible oral bleeding.

Effect of biotin supplementation on hoof health and ceramide composition in dairy cattle.

The effect of biotin supplementation on various foot lesions and hoof ceramide composition of toe (wall) and sole portions of hooves was studied in crossbred dairy cattle. Biotin supplementation was done for five months in 14 cattle at a farm and the other 14 animals kept as control. A significant decline was observed in heel erosions and sole avulsions along with total disappearance of white line fissures and double soles in the biotin supplemented cattle resulting in decrease in the overall disease score. Thin layer chromatographs of the hoof lipids revealed 11 types of ceramides in sole lipids and 6 types of ceramides in toe (wall) lipids. The ceramides were typed and identified according to their Rf values. A qualitative increase in the density of thin layer chromatographs of sole lipids was observed in biotin supplemented cattle whereas a non-significant difference in density of thin layer chromatographs of toe lipids was observed after supplementation of biotin.

Efficacy of Lagenidium giganteum metabolites on mosquito larvae with reference to nontarget organisms.

Lagenidium giganteum is a water mold and an effective mosquito control agent with limited use due to poor survival and contamination during storage. Invert extracellular metabolites of L. giganteum is easy to produce, long shelf life, and a potential candidate in tropical climates. This fungus was grown in PYG broth in the laboratory at 25 +/- 2 degrees C, and relative humidity was maintained at 75 +/- 5% for 15 +/- 2 days. Filtration process of metabolites was done using Whatman filter paper, column chromatograph, and range syringe filters techniques. Then 5-ml fractions were collected and used to assay larvicidal efficacies. Larvicidal efficacies were performed against Culex quinquefasciatus, Anopheles stephensi, and Aedes aegypti at five different concentrations, viz. 1.68, 1.99, 2.17, 2.30, and 2.40 ppm. And also, filtrates were assessed against four species of nontarget organisms named Daphnia pulex, Cyclopes, Lymnea auriculeta, and tadpoles of Rana tigrina with different concentrations. The mortality values were subjected by the Probit analysis. The complete mortalities that resulted from applying filtrates dosage on all instars of mosquitoes persisted for a period of 24, 48, and 72 h, respectively. The efficacies in killing instar of three important vectors and safer for nontarget organisms with good biological stability of extracellular metabolites make this a promising alternative to mycelium and conidial-based larvicides. It could be regarded as fungal-based natural larvicide for the use of vector control.

Postoperative management of noniatrogenic traumatic bile duct injuries: role of endoscopic retrograde cholangiopancreaticography.

BACKGROUND: Endoscopic therapy for iatrogenic bile duct injuries is well established. Abdominal trauma-related biliary injuries, however, are complex in nature. The role of endoscopic therapy for these patients needs further evaluation. METHODS: A retrospective study investigated nine patients who had surgery for abdominal trauma (4 gunshot, 4 crush, and 1 stab injury), presented postoperatively with noniatrogenic biliary injuries, and underwent endoscopic retrograde cholangiopancreaticography (ERCP). RESULTS: The ERCP was successful for all the patients. Eight patients had significant bile leak at intra- or extra-hepatic sites, and one patient was discovered to have complete cutoff of the common hepatic duct. All bile leaks were treated successfully using biliary sphincterotomy with or without transpapillary stenting. No complications of ERCP were observed. CONCLUSIONS: In this case series, ERCP was found to be useful as a diagnostic and therapeutic method for managing noniatrogenic traumatic biliary injuries in patients who had undergone previous surgery for abdominal trauma. The ERCP results were similar to those for iatrogenic bile duct injuries.

Laboratory efficacy of metabolites of Lagenidium giganteum (Couch) on Anopheles stephensi (Liston) after filterations by Column Chromatography.

This study was conducted in laboratory to evaluate the efficacy of filtered extracellular metabolites of Lagenidium giganteum against all the four instars of An. stephensi larvae. Fungal colonies have been cultured in PYG broth and after 15 days of culturing the fungus, metabolites have been filtered twice by whatman filter paper. These metabolites were again filtered by column chromatography and by rang syringe filters. Filtered metabolites were then used against all instars of An. stephensi larvae. The bioassays were conducted at five significantly different concentrations (1.68, 1.99, 2.17, 2.30, 2.40 ppm). The results suggest significant mortality on first three instar larvae and very low on fourth instar larvae.

Feasibility and safety of endoscopic evaluation of gastric emptying.

BACKGROUND AND STUDY AIMS: Scintigraphy is the currently accepted method for evaluation of gastric emptying. Although quantitative, this method is complicated, time-consuming, and costly. If a simple endoscopic technique was available for those instances when quantification of an emptying abnormality is not needed, the same clinical information could be obtained in less time and with resource savings. Our aims in this study were therefore to assess the technical feasibility, tolerability, and safety of unsedated transnasal esophagogastroscopy (T-EG) as a technique for qualitative assessment of gastric emptying. METHODS: The study was done in two phases. In the first phase, 18 volunteers (ten men, eight women) underwent T-EG at 4 hours, 5 hours, or 6 hours after ingestion of a standard meal used for scintigraphic evaluation of gastric emptying without radiolabeling. In the second phase, ten volunteers underwent T-EG after scintigraphic imaging had demonstrated complete gastric emptying. RESULTS: Subjects in both phases tolerated the procedure well and completed the study. In the first phase, 13 of 15 volunteers exhibited complete gastric emptying at 6 hours (87%), while two (13%) revealed some particulate matter in the stomach at that time. In the second phase, one of the ten volunteers exhibited a small amount of solid food residue in the stomach despite documentation of scintigraphic complete emptying. CONCLUSIONS: Evaluation of gastric emptying by unsedated T-EG is both feasible and safe. In healthy, asymptomatic individuals, complete gastric emptying of solid food may take as long as 6 hours.