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.

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.

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.

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.

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.

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.

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.

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.

Antireflux stents in tumors of the cardia.

Self-expanding metal esophageal stents (SMES) are highly effective in relieving dysphagia in patients with esophageal carcinoma. As the incidence of cancer at the lower esophagus/cardia continues to increase, SMES also are being deployed across the gastroesophageal junction (GEJ). However, use of SMES in this location makes the stomach and the esophagus, in effect, a common cavity, which predisposes patients to gastroesophageal reflux (GER) and aspiration. Reflux may result from an increase in intra-abdominal pressure or it may occur passively when the patient is recumbent. Acid-suppression medications do not protect against regurgitation and aspiration. We developed a modified antireflux SMES and evaluated its efficacy in vitro, in dogs, and in 11 patients with distal esophageal/GEJ carcinoma. The modification involved extending the polyurethane coating of the stent to 8 cm below the lower edge. In dogs, significantly more reflux episodes occurred with the regular stent (mean, 197 episodes) than with the modified stent (mean, 16 episodes; P = 0.03). In patients who received the modified stent, dysphagia scores were significantly reduced (mean baseline score, 3.4; mean end point score, 1.1; P <0.001). The modified stent prevented GER while allowing belching and vomiting.

A simple method of assessment of gestational age in newborn infants.

A simple method of assessment of gestational age based on only four characteristics, namely, the anterior vascular capsule of the lens, plantar creases, breast nodule, and ear firmness, is presented. Critical evaluation by appropriate statistical analyses has shown this to be a useful method of practical value with 95% confidence limits of 11 days. It is applicable to newborn infants, including sick babies, at any time within the first 2 days of life.

Effect of ageing on the upper and lower oesophageal sphincters.

OBJECTIVE: To determine the effect of ageing on length and resting pressure of the upper and lower oesophageal sphincters (UOSs, LOSs). BACKGROUND: The effectiveness of upper and lower oesophageal sphincters (UOSs and LOSs, respectively) in the control of retrograde trans-sphincteric flow is influenced by sphincteric pressure and length. METHODS: Nine young and nine elderly healthy volunteers were studied. Resting UOS and LOS pressures were measured by sleeve devices and lengths were measured by the station pull-through technique. RESULTS: The length of the UOS high pressure zone in the elderly (2.1 +/- 0.7 cm posterior; 1.9 +/- 0.1 cm anterior) was significantly shorter than that of the young (2.9 +/- 0.1 cm posterior; 3.1 +/- 0.2 cm anterior) (P< 0.01). Resting UOS pressure in the elderly (42 +/- 5 mmHg) was significantly lower than that of the young (62 +/- 7 mmHg) (P< 0.05). The intersphincteric length of the oesophagus in the elderly (21 +/- 0.2 cm) was similar to that of the young (21 +/- 0.4 cm). Total length of the LOS high pressure zone in the young (4.0 +/- 0.1 cm) was similar to that of the elderly (4.1 +/- 0.1 cm). LOS resting pressure was similar between young and elderly subjects (17 +/- 5 mmHg and 15 +/- 3 mmHg, respectively). CONCLUSIONS: Ageing affects the UOS and LOS differently. With regard to resting pressure and length, ageing weakens the UOS, but has no significant effect on the LOS.

Effect of pharyngeal stimulation on the motor function of the esophagus and its sphincters.

OBJECTIVE/HYPOTHESIS: Sensory impulses from the pharynx induce contraction of the upper esophageal sphincter (UES), relaxation of the lower esophageal sphincter (LES), and inhibition of peristalsis. To determine 1) the magnitude of UES contractile response to threshold volume of fluid that induces LES relaxation and 2) the effect of rapid pharyngeal air stimulation on LES resting pressure and its concurrent influence on the UES and progression of esophageal peristalsis. METHODS: Eleven healthy volunteers (age, 31 +/- 2 y) were studied by concurrent UES, esophagealbody, and LES manometry. RESULTS: At a threshold volume of 0.3 +/- 0.05 mL, injections of water into the pharynx directed posteriorly, resulted in complete LES relaxation. Duration of these relaxations averaged 19 +/- 1 seconds. In 10 of 11 subjects, these relaxations were accompanied by a simultaneous increase in UES resting tone that averaged 142% +/- 27% above preinjection values. Pharyngeal stimulation by rapid air injection resulted in complete LES relaxation in 8 of the 11 subjects (threshold volume, 14 +/- 6 mL). Five of 8 developed a concurrent mild increase in resting UES pressure (17% +/- 6% above preinjection values) (P < .05). Pharyngeal water injection inhibited the progression of the peristaltic pressure wave at all tested sites and in all subjects, but pharyngeal air injection in only 2 of the 11 studied subjects. CONCLUSIONS: The inhibitory effect of pharyngeal water injection on LES resting pressure is accompanied by a substantial contractile effect on the UES. Although stimulation of the pharynx by rapid air injection may induce LES relaxation, its inhibitory effect on esophageal peristalsis and stimulatory effect on UES pressure are negligible compared with that of water injection.

Lack of effect of quinidine on divalent mineral absorption from the reticulorumen of sheep.

The effects of quinidine on divalent mineral absorption were studied using normal and high potassium intraruminal buffers with the in vivo isolated washed rumen technique. A concentration of 1 mmol litre-1 quinidine in the intraruminal buffer decreased the absorption rates of Na+ and C1- from the rumen but had no significant effect on the absorption rates of Mg2+, Ca2+ and K+. Prolonged oral administration of quinidine had no significant effect on the absorption of any of these ions from either a normal or a high potassium ruminal solution.

Secretion of magnesium and calcium in the total saliva of sheep and its relevance to hypomagnesaemia.

The rate of total secretion of saliva was measured over a 3-h period, under steady state conditions, in conscious sheep. The rates of secretion of magnesium and calcium in saliva represented 25-30% of the magnesium and calcium in the extracellular fluid. Since the large stores of intracellular magnesium are not readily mobilizable, the only readily available reserve of magnesium to maintain magnesium homeostasis is a little in bone. Thus, if magnesium ions from food and saliva are not adequately reabsorbed in the fore-stomachs, their loss could contribute significantly to the failure of homeostasis noted in acute ruminant hypomagnesaemia. Studies of the salivary clearance of 28 Mg showed a delay of 5-13 h in the time course of the salivary specific activity of 28 Mg, relative to that in plasma. This delay is indicative of transcellular interchange between magnesium ions in the central compartment, represented by the extracellular fluid, and an outer compartment which includes the salivary epithelial cells. Prolonged hypercalcaemia, caused by injections of 1 alpha (OH) cholecalciferol, was accompanied by a significant increase in the secretion rate of calcium in saliva but the secretion rate of magnesium was unchanged.

The role of phosphate on the rates of mineral absorption from the forestomach of sheep.

Phosphorus plays an important role in calcium and magnesium homeostasis in ruminants. In five trained sheep, each with a large rumen cannula, the isolated rumen wash technique was used to measure the magnesium and calcium absorption rates from the rumen. After one control period of measurement, the intra-ruminal phosphate concentration was increased from 2 to 10 mmol/L, and there was a significant increase in the calcium and magnesium absorption rates. The same technique was also used to demonstrate the effect of hyperphosphatemia on the absorption rates of magnesium and calcium from the forestomach. Although the absorption rates of magnesium and calcium tended to increase, the changes were not statistically significant. It is concluded that intra-ruminal phosphate concentration plays a role in the absorption of magnesium and calcium ions from the forestomach of sheep.