Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that ...a MOR-CCR5 heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED50 = 0.0146 pmol/mouse) that was 2000× greater than morphine. Moreover, MCC22 was ~3500× more potent than a mixture of mu agonist and CCR5 antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR5 heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR5 heteromer as a novel target for the treatment of chronic pain.
The low effectiveness of morphine and related mu opioid analgesics for the treatment of chronic inflammatory pain is a result of opioid-induced release of proinflammatory cytokines and glutamate that ...lower the pain threshold. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR ₅) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of adverse effects during chronic use. Given the presence of opioid receptors (MORs) and mGluR ₅ in glia and neurons, together with reports that suggest coexpressed MOR/mGluR ₅ receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR ₅ antagonist pharmacophores linked through spacers of varying length (10–24 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED ₅₀ ∼9 fmol per mouse), whereas in untreated mice its ED ₅₀ was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have ≥500-fold higher ED ₅₀ₛ in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR-mGluR ₅ heteromer. The finding that MMG22 possesses a >10 ⁶ therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration.
The inclusion of straw in high concentrate total mixed rations (TMRs) of male fattening goats can provide the necessary fiber to prevent ruminal acidosis and maintain growth. The objective of this ...study was to evaluate the effects of the physical form (PF) of the diet (pelleted vs. conventional) and the straw level (SL) of wheat straw (WS) (15% versus 25%) in total mixed rations on feed intake, growth, total tract digestibility, and blood metabolites of fattening goats. Thirty-two male Beetal goats (27.4 ± 0.28 kg body weight (BW)) were divided randomly into the following four dietary treatments with a 2 × 2 factorial arrangement (
= 8/treatment): (1) CTMR15 (conventional TMR containing 15% WS), (2) CTMR25 (conventional TMR containing 25% WS), (3) PTMR15 (pelleted TMR containing 15% WS), and (4) PTMR25 (pelleted TMR containing 25% WS). Both conventional and pelleted 15% WS TMR had 33.7% neutral detergent fiber (NDF) and 19.3% acid detergent fiber (ADF), whereas in 25% WS TMR the NDF and ADF contents were 38.7% and 22.9%, respectively. The experimental diets were formulated to be iso-nitrogenous (crude protein (CP) = 15%). The dry matter intake (DMI) (1.265 vs. 1.044 kg/day) and average daily gain (ADG) (0.176 vs. 0.143 kg/day) were higher (
< 0.05) in pelleted vs. conventional TMR-fed goats. Irrespective of the PF of the TMR, the 15% WS-fed animals had greater (
< 0.05) DMI (1.206 vs. 1.102 kg/day) and ADG (0.172 vs. 0.144 kg) when compared to those fed on 25% WS diets. Furthermore, feed-to-gain ratio (F:G) was higher (
< 0.05) in the 25% WS-fed goats when compared with the 15% WS-fed animals. Digestibility coefficients, nitrogen balancing, hepatic enzymes, blood metabolites, and hematological parameters were similar (
> 0.05) across all treatments. In conclusion, feeding pelleted TMR with WS improved DMI and growth performance as compared to those fed conventional TMR, and 15% WS performed better than 25% WS without exerting any adverse effects on blood metabolites, liver enzymes, or hematological parameters.
reaction: see text We report that "activated" dimethyl sulfoxide efficiently dehydrogenates hydrazones to the respective diazo species at -78 degrees C. Under optimized conditions, triethylamine ...hydrochloride is removed quantitatively by vacuum filtration to provide solutions of diazo compounds. Stable diazo species can be isolated in high yield, or alternatively, the direct treatment of these solutions with carboxylic acids provides esters.
Two okra cultivars (Chinese green and Chinese red) were subjected to salt stress for 12 weeks. Salt stress treatments T1 (20.8 mM), T2 (103.3 mM), T3 (180.0 mM) and T4 (257.0 mM) were applied with ...equal proportions of NaCl and CaCl
in Hoagland nutrient solution. Salt stress significantly affects photosynthesis, transpiration, stomatal conductance, water use efficiency, water potential, plant height, root length, fresh weight and dry weight of both okra cultivars in every salt stress treatment. At T2, T3 and T4, Chinese red plants maintained their physiological and growth traits up to Weeks 9, 6 and 3, respectively; beyond these salt-stress durations, growth reductions were found. Similarly, Chinese green plants maintained their growth up to Weeks 9, 5 and 3, respectively, at T2, T3 and T4 treatments. In comparison, Chinese red showed more tolerance than Chinese green. According to the results, the third and ninth weeks are the tolerance threshold limits for both cultivars to sustain their physiological traits and growth under T4 and T2 salinity treatments. Similarly, Chinese red has the threshold limit to bear T3 treatment up to the eighth week and Chinese green, up to the fifth week. Thus, this study provides a new method to determine the threshold value of crops with respect to duration under salt stress. This finding would be useful in the field of water saving and utilisation of saline water resources.
Background Acute appendicitis remains the most common cause of lower abdominal pain leading to emergency visits. Even though the standard treatment of acute appendicitis remains appendectomy, in ...recent times, multiple randomized control trials and meta-analyses have deduced conservative treatment as a successful alternative treatment. During the coronavirus disease (COVID) pandemic, with a shortage of staff and resources, treatment with conservative management of uncomplicated acute appendicitis became very beneficial under certain circumstances and conditions. This study aimed to assess whether it is effective to manage patients with uncomplicated acute appendicitis with antibiotic therapy. Methodology This was a single hospital based retrospective, cross-sectional study from Jan 2015 to May 2020. Patients with clinical and radiological features of uncomplicated acute appendicitis with Alvarado's score >6 were included in the study. Patients were kept on antibiotics, intravenous fluids, and analgesia as part of a conservative regime. Those who failed to respond to conservative therapy were managed surgically. The follow-up period was six months. Results One hundred eighty-two cases of uncomplicated acute appendicitis were included and managed conservatively, of which 52.2% were males while 47.8% were females. The median age of the patients was 26 years. Conservative treatment was successful in 26.2% of the patients, with a recurrence of 5.5% in the six-month follow-up period. The mean number of days of hospital stay was three days in patients treated with conservative or surgical treatment. Conclusion Conservative management is gaining popularity, and many centers are inclined towards non-operative management; however, appendectomy remains the gold standard treatment for appendicitis.
In this study, hatchability characteristics and some internal egg quality characteristics of 0, 2, 3, 4, 6 and 8 d stored Fayoumi eggs were examined. It was determined that the effect of storage time ...on hatchability, hatchability of fertile eggs, embryonic mortality, hatchling weight, albumen weight, yolk weight, albumen index, yolk index and Haugh unit was significant (P<0.05). There was no positive or negative effect of storage time on the fertility rates, but there was a negative effect of storage time on egg weight, hatchability, embryonic development and hatchling weight on d 4 (P<0.05). It was determined that prolonged storage time caused a decrease in the albumen weight, yolk weight, albumen index, yolk index and Haugh unit value of Fayoumi eggs. Fayoumi eggs should not be stored more than 3 d.
IntroductionSuicide by self-poisoning is a common cause of death, especially in the younger population. More specifically, hair-dye poisoning is being increasingly used for suicide. ...Paraphenylenediamine (PPD), also known as “Kala pathar”, is a highly toxic ingredient present in hair-dye that can cause death. Therefore, this study is designed to assess the demographics, clinical features, laboratory findings, and outcomes of PPD poisoning in patients admitted to the National Poison Control Center in Karachi, Pakistan.Materials and methodsWe conducted a prospective study for a period of six months at the National Poison Control Center, Karachi, Pakistan. A total of eight patients with PPD poisoning with no cardiac, liver, or renal co-morbidities were included in this study. The demographic characteristics, clinical features, laboratory findings, mode of intoxication, and route of intoxication were noted in a proforma. Furthermore, hospitalization time, tracheostomy status, mechanical ventilation status, and mortality rates were also recorded. For continuous variables, the means and SDs were calculated. Whereas for categorical data, percentages were calculated.ResultsIn our study, the mean age of the patients was estimated at 25.38 ± 3.77 years. It was deemed that the majority of poisoning cases were intentional in nature (75%). These suicide cases were more commonly observed in young females (75%) who belonged to a low socioeconomic class (87.5%). The preferred route of administration was oral (87.5%). In 87.5% of the patients, the characteristic clinical features such as cervicofacial edema, dysphagia, dysphonia, and stridor were noted. During the later clinical stages of poisoning, clinical features such as rhabdomyolysis (62.5%), chocolate-colored urine (87.5%), hepatitis (75%), and acute renal failure (12.5%) were noteworthy. The mean ± SD of total leukocyte count (TLC), creatine phosphokinase (CPK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine and serum potassium were, respectively, noted at 10,500 ± 3,854.4 cells/mm3, 32.87 ± 11.36 IU/L, 1,239.1 ± 1,106.2 IU/L, 776.8 ± 1,149.8 IU/L, 2.125 ± 2.275 mg/dL, and 4.9 ± 1.094 mmol/L. In our patients, the mean intensive care unit stay was 8.25 ± 3.99 days. Emergency tracheostomy was performed in 25% of patients. Mechanical ventilation was required for 50% of our patients. Overall, the mortality rate observed in our study stands at 25%.ConclusionPPD poisoning is associated with a high rate of morbidity and mortality. Therefore, it is imperative for physicians to be mindful of the clinical characteristics and treatment options in order to optimally manage such cases of poisoning. In addition, the use of hair-dyes composed of highly lethal PPD should also be banned.
Introduction Hyperhomocysteinemia is associated with atherosclerosis, as it can be seen in inborn errors of methionine metabolism. Likewise, many studies have also reported more modest increases in ...serum homocysteine levels in other atherosclerotic disorders like cardiovascular disease and all types of stroke with a positive correlation with age. But overall literature is controversial. Therefore, this study is being conducted to further investigate the relationship between homocysteine levels and age in patients, especially those with ischemic stroke. Material and methods This cross-sectional study is conducted at a major hospital in Karachi in which all patients with ischemic stroke, diagnosed within 24 hours on CT, and age 40-75 years of both genders were enrolled for six months. Other demographics were also noted like gender, smoking status, and comorbidities (diabetes mellitus DM, hypertension HTN). The homocysteine level was also checked by collecting non-fasting blood. Vitamin B12 level was not checked. The age, weight, height, body mass index (BMI), and homocysteine level's means and standard deviations and the gender, DM, hypertension, and smoking status frequencies and percentages were calculated. The correlation coefficient of homocysteine level and age was also calculated. Stratification was done to see the effects of gender, BMI, DM, and HTN on homocysteine levels by applying the chi-square test. Results The mean age of the patients was 55.60 ± 11.45 years. Gender distribution showed that 111 (62.40%) patients were male, and 67 (37.60%) patients were female. Diabetic, hypertensive, and smoking status of the patients was 58 (32.60%), 96 (53.90%), and 53 (29.80%), respectively. The mean homocysteine level was 14.61, with a standard deviation of 1.47. Pearson's correlation test showed that there is no statistically significant correlation between homocysteine levels and age. But a significant linear relationship was found of homocysteine levels with DM and HTN. Conclusion Further investigation of the relationship of homocysteine levels with age, diabetes mellitus, and hypertension, and the role of homocysteine as a risk factor for ischemic stroke should be carried out on a larger scale to prove its accuracy. The benefits of screening for homocysteine levels also need to be studied in the elderly, especially those with diabetes mellitus and hypertension, which can lead to timely prevention of strokes and ischemic heart disease with vitamin B supplements, and other appropriate interventions.
Bicyclic diazenium salts were efficiently prepared by a Lewis acid mediated intramolecular cycloaddition. Terminal olefins provided mixtures of fused and bridged bicyclic diazenium salts. The ...alpha-chloroazo cycloaddition precursors were conveniently prepared from the corresponding phenyl hydrazones by treatment with chlorodimethylsulfonium chloride.
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