Purpose
Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral ...testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model.
Methods
Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson’s trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining.
Results
Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (
p
< 0.05) and 1144 + ALPHA (
p
= 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions.
Conclusions
Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.
Around 60% dairy animals developed moderate to severe hepatic lipidosis at the time of parturition or during early lactation stage. Most of clinician suspect the hepatic lipidosis during above time ...window only. However, negative energy balance or feeding of high concentrate diet can lead to hepatic lipidosis at any phase of life. The aim of the present study was to evaluate the potential for diagnosis of hepatic lipidosis by means of hemato-biochemical parameters and ultrasonography of the liver at any stage of life. Here, ultrasonographic back fat thickness measurement was correlated with ultrasonographic features of hepatic lipidosis. A total 60 buffaloes were included under the study and sampled for hematological and biochemical parameters. Hematological parameters did not exhibit any significant difference between healthy and hepatic lipidosis-affected buffaloes. Biochemical parameters like beta hydroxy butyric acid, non esterified fatty acid, aspartate amino transferase, gamma glutamyl transferase and alkaline phosphatase revealed a significant increase, while triglyceride, cholesterol, and glucose declined significantly in hepatic lipidosis-affected buffaloes. Total protein, albumin, and total bilirubin levels did not exhibit any significant difference. Based on ultrasonographic findings, the hepatic lipidosis-affected buffaloes were further sub divided into mild, moderate, and severe groups. Portal vein diameter and depth of portal vein were also estimated in current study. Ultrasonographic examination could diagnose 53.33% hepatic lipidosis cases in buffaloes. Among it, 37.50% buffalo had mild hepatic lipidosis, 33.33% had moderate hepatic lipidosis, and 29.16% had severe hepatic lipidosis. Depth of portal vein significantly increased in hepatic lipidosis cases. However, portal vein diameter exhibited a non-significant difference in mild, moderate, and severe groups of hepatic lipidosis. Back fat thickness also revealed a non-significant difference in mild, moderate, and severe hepatic lipidosis. Above study indicate that B mode ultrasonography of the liver can be employed to differentiate various grades of hepatic lipidosis in buffaloes. Biochemical parameters like NEFA, BHBA, AST, GGT, ALP, TG, cholesterol, and glucose can be helpful to screen the hepatic lipidosis at farm level.
Graphical abstract
Tobacco smoking is associated with chronic obstructive pulmonary disease (COPD) in more than 80% of cases. Our aim was to investigate the effect of sustained-release bupropion (amfebutamone) (SR) in ...promoting abstinence from smoking in patients with COPD.
In a double-blind, randomised, placebo-controlled trial 404 individuals with mild or moderate COPD who smoked 15 or more cigarettes per day, were assigned bupropion SR (150 mg twice daily) or placebo for 12 weeks. All patients received smoking cessation counselling. Study medication was taken for 1 week before patients attempted to stop smoking. The primary efficacy endpoint was the complete and continuous abstinence from smoking from the beginning of week 4 to the end of week 7. Participants were followed up at month 6. Analysis was by intention to treat.
All patients were chronic smokers with a smoking history of about 51 pack-years. Continuous smoking abstinence rates from week 4 to 7 were significantly higher in participants receiving bupropion SR than in those receiving placebo (28% 57/204 vs 16% 32/200, p=0·003). Continuous abstinence rates from weeks 4 to 12 (18% 36/204 vs 10% 20/200) and weeks 4 to 26 (16% 32/204 vs 9% 18/200) were also higher in participants receiving bupropion SR than in those taking placebo (p<0·05). Furthermore, symptoms of tobacco craving and withdrawal were attenuated in those receiving bupropion SR. Seven individuals discontinued study medication because of adverse events.
Bupropion SR is a well-tolerated and effective aid to smoking cessation in people with mild to moderate COPD.
To investigate machine learning based models combining clinical, radiomic, and molecular information to distinguish between early true progression (tPD) and pseudoprogression (psPD) in patients with ...glioblastoma.
A retrospective analysis was undertaken of 76 patients (46 tPD, 30 psPD) with early enhancing disease following chemoradiotherapy for glioblastoma. Outcome was determined on follow-up until 6 months post-chemoradiotherapy. Models comprised clinical characteristics, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and 307 quantitative imaging features extracted from enhancing disease and perilesional oedema masks on early post-chemoradiotherapy contrast-enhanced T1-weighted imaging, T2-weighted imaging (T2WI), and apparent diffusion coefficient (ADC) maps. Feature selection was performed within bootstrapped cross-validated recursive feature elimination with a random forest algorithm. Naive Bayes five-fold cross-validation was used to validate the final model.
Top selected features included age, MGMT promoter methylation status, two shape-based features from the enhancing disease mask, three radiomic features from the enhancing disease mask on ADC, and one radiomic feature from the perilesional oedema mask on T2WI. The final model had an area under the receiver operating characteristics curve (AUC) of 0.80, sensitivity 78.2%, specificity 66.7%, and accuracy of 73.7%.
Incorporating a machine learning-based approach using quantitative radiomic features from standard-of-care magnetic resonance imaging (MRI), in combination with clinical characteristics and MGMT promoter methylation status has a complementary effect and improves model performance for early prediction of glioblastoma treatment response.
•Early assessment of treatment response in glioblastoma is a key clinical issue.•Contrast-enhanced MRI cannot differentiate early true- and pseudo-progression.•Quantitative imaging-based radiomic features can be used as potential biomarkers.•We used radiomic, clinical and molecular features in machine learning-based models.•A combined clinico-radiomic model demonstrated the highest performance.
Bisphenol-A (BPA) is a polymerizing agent used in plastic bottles and several routinely used consumer items. It is classified among endocrine disrupting chemicals suspected to cause adverse health ...effects in mammals ranging from infertility and cancer to behavioral disorders. Work with the invertebrate lab model Caenorhabditis elegans has shown that BPA affects germ cells by disrupting double-stranded DNA break repair mechanisms. The current study utilizes this model organism to provide insight into low-dose and long-term behavioral effects of BPA and bisphenol-S (BPS), a supposed safer replacement for BPA.
Experiments presented in our report demonstrate that the effects of embryonic exposure to considerably low levels of BPA persist into adulthood, affecting neural functionality as assayed by measuring habituation to mechano-sensory stimuli in C. elegans. These results are noteworthy in that they are based on low-dose exposures, following the rationale that subtler effects that may not be morphologically apparent are likely to be discernible through behavioral changes. In addition, we report that embryonic exposure to BPS follows a pattern similar to BPA.
Building upon previous observations using the C. elegans model, we have shown that exposure of embryos to BPA and BPS affects their behavior as adults. These long-term effects are in line with recommended alternate low-dose chemical safety testing approaches. Our observation that the effects of BPS are similar to BPA is not unexpected, considering their structural similarity. This, to our knowledge, is the first reported behavioral study on low-dose toxicity of any endocrine disrupting chemical in C. elegans.
A series of 2,5,6-trisubstituted imidazo2,1-
b1,3,4-thiadiazole derivatives
4(
a–
k) have been prepared by reaction of 2-amino-5-cyclopropyl-1,3,4-thiadiazole and an appropriate phenacyl bromide. ...Further 5-bromo
5(
a–
k) and 5-thiocyanato
6(
a–
k) derivatives were synthesized in order to study the effect of these substituents on antitumor activity. Structures of these compounds were established by IR,
1H NMR,
13C NMR and Mass spectroscopy. Seven compounds were granted NSC code at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10
−5 M) in full NCI 60 cell panel. Among the compounds tested, 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo2,1-
b1,3,4thiadiazole
5b (
NSC
D-
96022/
1) was found to be the most active candidate of the series at five dose level screening with degree of selectivity toward Leukemic cancer cell line.
The 2,5,6-trisubstituted imidazo2,1-
b1,3,4-thiadiazole derivatives and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated.
Display omitted
► Synthesis and biological evaluation of 2,5,6-trisubstituted imidazo2,1-
b1,3,4thiadiazole derivatives as antitumor investigated. ► 5-Bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo2,1-
b1,3,4thiadiazole
5b (
NSC D-
96022/
1) was the most active candidate. ► It shown degree of selectivity toward Leukemic cancer cell line (MG MID ratio: 3.6).
Objective: To study clinical characters and outcomes in patients of malignant ovarian germ cell tumor (MOGCT) undergoing surgery following neoadjuvant chemotherapy (NACT).
Methods: Retrospective ...study of patients undergoing surgery following NACT for MOGCT at our institute. Platinum based chemotherapy was given in all patients in NACT.
Results: Between March 2013 and February 2023, 30 patients had surgery after NACT. Patient’s median age was 22 years (range, 12 to 35 years) and median follow up 42months (range, 6 to 132 months). Majority had endodermal sinus tumor (n=12), dysgerminoma (n=9) and mixed GCT (n=7). All had either International Federation of Gynecology and Obstetrics (FIGO) stage 3 (n=19) or FIGO stage 4 disease (n=11). Complete response to NACT seen in 5 patients and 23 patients had partial response. Fertility sparing surgery in 18 patients and complete surgery in 12 patients. Suboptimal surgery was seen in 4 patients. Currently, 20 of 30 patients are alive and disease free, 3 lost for follow up and 7 patients had progression after adjuvant therapy. Five patients had mortality―4 with progression and 1 with bleomycin toxicity. Fifteen of 17 eligible patients have resumed menstruation and one had successful pregnancy. Prognostic factors noted in study are stage, optimal surgery and viable tumor in histopathology. Dysgerminoma had better outcome than other histology.
Conclusion: NACT may be a reasonable option in patients with extensive unresectable disease or in whom fertility sparing is not possible or in the poor general condition. Fertility sparing surgery can be attempted post neoadjuvant chemotherapy without adversely affecting prognosis.
Pancreaticopleural Fistula (PPF), a rare occurrence, is characterised by an abnormal connection between pleural and peritoneal cavity. It forms usually due to the rupture of pancreatic pseudocyst. ...Pancreatic pseudocyst is formed due to the repeated episodes of acute or chronic pancreatitis. Most pancreatic pathologies, such as acute and chronic pancreatitis, cause clinically insignificant effusions that resolve with disease control, whereas PPF causes massive effusion and is thus rarely considered as a cause of massive pleural effusion due to its low incidence. PPF are most common in middle-aged alcoholic males and typically present as massive recurrent left-sided pleural effusions. In the present case, a 50-year-old male presented to the Department of Respiratory Medicine with the complaint of right-sided chest pain, progressive breathlessness, abdominal pain and loss of appetite. Patient was labourer by occupation, chronic alcoholic, non diabetic. Contrast Enhanced Computed Tomography (CECT) thorax with abdomen showed massive right-sided pleural effusion and pancreatitis. A diagnosis of PPF was confirmed as its cause. Pleural fluid analysis for elevated amylase, confirms the diagnosis and investigations such as CECT thorax and abdomen, Endoscopic Retrograde Cholangiopancreatography (ERCP), or Magnetic Resonance Cholangiopancreatography (MRCP) may be used to establish the fistulous communication between the pancreas and the pleural cavity. PPF should always be considered as a differential diagnosis while finding a cause for right-sided pleural effusion.
Purpose The goal of this systematic review was to present the current best evidence for clinical outcomes of osteochondral autograft transplantation to elucidate the efficacy of this procedure. ...Methods PubMed, CINAHL, and the Cochrane Central Register of Controlled Trials were searched (key terms “knee,” “osteochondral autograft transfer,” or “mosaicplasty”) to identify relevant literature between 1950 and 2013 in the English language. This evaluation included studies in pediatric and adult patients with grade 3 or 4 articular cartilage injuries; the studies had a minimum of 25 patients and at least 12 months of follow-up and compared osteochondral autograft transfers/mosiacplasty with another treatment modality. Articles were limited to full-text randomized controlled trials or cohort studies. Main outcomes studied were patient-reported and functional outcome, with secondary outcomes including effect of lesion size, return to sport and sport function, radiographic outcomes, and reoperation rates. Results There were a total of 9 studies with 607 patients studied in this systematic review. When osteochondral autologous transfer/mosaicplasty (OATM) was compared with microfracture (MF), patients with OATM had better clinical results, with a higher rate of return to sport and maintenance of their sports function from before surgery. Meanwhile, patients who underwent MF trended toward more reoperations, with deterioration around 4 years after surgery. When compared with autologous chondrocyte implantation (ACI), clinical outcome improvement was not conclusive; however, at 10-year follow-up, a greater failure rate was found to be present in the OATM group. Conclusions Current evidence shows improved clinical outcomes with OATM when compared with preoperative conditions. These patients were able to return to sport as early as 6 months after the procedure. It could be suggested from the data that OATM procedures might be more appropriate for lesions that are smaller than 2 cm2 with the known risk of failure between 2 and 4 years. Further high-quality prospective studies into the management of these articular cartilage injuries are necessary to provide a better framework within which to target intervention. Level of Evidence Level II, systematic review of Level I and II studies.
Chronic kidney disease (CKD) impacts over 10% of the global population. Adults with CKD face significant morbidity and mortality. As kidney disease progresses, the risk of adverse outcomes increases. ...Here, we present an overview of strategies to care for adults with advanced CKD (stage 4–5 CKD, not receiving kidney replacement therapy). We aim to guide clinicians through several aspects of CKD care, ranging from recommended laboratory assessments to interdisciplinary support for patients as they plan for kidney replacement therapy (dialysis, transplantation, or conservative management). We incorporate considerations of health equity and person-centered care, empowering clinicians to deliver high-quality care to people with CKD.
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