Effect of low dose denosumab on bone mineral density in postmenopausal women with osteoporosis after a transition from 60 mg dose: a prospective observational study.

INTRODUCTION: Denosumab is an effective antiresorptive molecule and reduces the risk of fracture in postmenopausal osteoporosis. Cessation of denosumab therapy however is associated with rapid declines in bone mineral density (BMD), rises in bone remodeling, and an increased risk of fracture. We evaluated the effect of low dose denosumab (30 mg every 6 months) on the prevention of bone loss following a switch from standard dose (60 mg of denosumab every 6 months) in a prospective observational study. METHODS: We recruited 114 women 50-90 years of age with postmenopausal osteoporosis at a moderate fracture risk without prior fragility fractures, who had been on denosumab 60 mg every 6 month. These women switched to low dose denosumab 30 mg every 6 months. Mean percentage change in lumbar spine (LS), femoral neck (FN), total hip (TH) and 1/3 distal radius (1/3RAD) BMD at 12 and 24 months were evaluated. Predictors for change in BMD were explored. Subgroup analysis for patients on denosumab 60 mg every 6 months for <3 years and for ≥3 years before switching to low dose denosumab 30 mg was evaluated. RESULTS: At 12 months following a switch from 60 mg to 30 mg of denosumab every 6 months we observed an increase in LS BMD mean percentage change (+2.03%, 95% CI 1.18-2.88, p < 0.001). BMD was stable at the hip and radial sites. Age was found to be a predictor of the mean percentage change in LS BMD for the overall sample. At 24 months, there was a further increase in LS BMD mean percentage change (+3.44%, 95% CI 1.74-5.12, p < 0.001), with stable BMD at other skeletal sites. The 12 month mean BMD percentage change at the LS (p = 0.015), FN (p < 0.001), TH (p < 0.001), and 1/3 RAD (p < 0.001) were found to be predictors of the 24 month mean BMD percentage change. No clinical fractures were reported during 24 months of follow up. CONCLUSION: We observed stable BMD following a switch from denosumab 60 mg every 6 months to 30 mg every 6 months in this prospective observational study conducted in postmenopausal women at a moderate fracture risk.

Feasibility and Acceptability of a Telephone-Based Smoking Cessation Intervention for Qatari Residents.

The steady increase in smoking rates has led to a call for wide-reaching and scalable interventions for smoking cessation in Qatar. This study examined the feasibility and acceptability of an evidence-based smoking cessation program delivered by telephone for Qatari residents. A total of 248 participants were recruited through primary care centers and received five weekly scheduled proactive behavioral counseling calls from personnel trained in tobacco cessation and navigation to obtain cessation pharmacotherapy from clinics. Outcomes were assessed at end of treatment (EOT), and 1- and-3-month follow up. The Mann-Whitney test was used to compare the average number of participants recruited per month pre- and post-COVID. We recruited 16 participants/month, the majority (85.5%) attended at least one counselling session, and 95.4% used some of pharmacotherapy. Retention rates were 70% at EOT, 64.4% and 71.7% at 1- and 3-month follow up, respectively; 86% reported being 'extremely satisfied' by the program. Our ITT 7-day point prevalence abstinence was 41.6% at EOT, 38.4% and 39.3% at 1-and 3-month, respectively. The average number of participants recruited per month was significantly higher for pre vs. post-COVID (18.9 vs. 10.0, p-value = 0.02). Average number of participants retained at EOT per recruitment month showed a slight decrease from 8.6 pre- to 8.2 post-COVID; average number who quit smoking at EOT per recruitment month also showed a decrease from 6 to 4.6. The study results indicated that our telephone-based intervention is feasible and acceptable in this population and presents a new treatment model which can be easily disseminated to a broad population of Qatari smokers.

Factors associated with baseline smoking self-efficacy among male Qatari residents enrolled in a quit smoking study.

Smoking self-efficacy, described as confidence in one's ability to abstain from smoking in high-risk situations is a key predictor in cessation outcomes; however, there is a dearth of research on factors that influence self-efficacy surrounding smoking behavior. This study examines factors associated with baseline self-efficacy among treatment seeking participants enrolled in a pilot feasibility smoking cessation study. Participants (n = 247) were daily male smokers, residents of Doha in Qatar (18-60 years) who were enrolled in a telephone-based smoking cessation study. Baseline assessments included self-efficacy, home smoking rules, socio-demographic variables, smoking history, and psychosocial characteristics. Factors associated with self-efficacy were assessed using multiple linear regression analysis. Results showed that after controlling for relevant variables, number of cigarettes smoked ([Formula: see text] = -0.22; 95% CI: -0.37, -0.06), having at least one quit attempt in the past year ([Formula: see text] = 2.30; 95% CI: 0.27, 4.35), and reporting a complete home smoking ban ([Formula: see text] = 3.13; 95% CI: 0.56, 5.70) were significantly associated with higher self-efficacy to quit smoking. These results provide data-driven indication of several key variables that can be targeted to increase smoking self-efficacy in this understudied population.

The Influence of Rumen-Protected Choline and α-tocopherol Supplementation on Early Lactating Dairy Cows Metabolism.

It is well documented that choline is known as one of the essential ingredients of phospholipids. Choline acts as a determinative element for appropriate cell membrane functions. On the other hand α-tocopherol (Vit E) is a fat-soluble vitamin. This vitamin acts as a strong antioxidant in the living body's defense system against oxidative stress. Lipid peroxidation in peripartum and early lactating cows is significantly increased while the level of serum Vit E is decreases dramatically. These concomitant physiological changes demonstrate a higher level of oxidative stress subsequently leads to serious health issues in dairy cows. Therefore, the present research was designed to investigate the following items in dairy cattle: 1) evaluation of the possible changes in serum protein fractions, and 2) comparing the oxidative status of orally RPC and vitamin E supplementation in dairy cows in early lactation period. In the current study 30 early lactating primiparous and multiparous Holstein cows (body condition score (BCS)=2.51 ± 0.10) were used beginning five weeks postpartum. All the animals were randomly divided in to three groups (n=10) (number of lactation=2.61). The animals were randomly assigned to receive one of the following treatments. Group 1 served as control group were not received any supplement. The second group was supplemented with 90 g/d of RPC (Reashre Choline, Balchem, USA). The third group was administrated 4400 IU/d vitamin E (Roche, Vitamins Ltd; Switzerland). In the current study, serum protein electrophoresis showed four main fractions as follows: albumin, α-globulin, ß-globulin, and γ-globulin. The recorded data showed that the percentages of albumin and γ-globulin fractions were higher in treated groups compared to the control group. In the animals supplementing with RPC and vitamin E the percentages of serum albumin increased to the value of 37. 70±1.63 and 38.21±1.28 respectively compare to the control group (34.69±1.21), which were significant (P<0.05).

Cobalt and lead concentrations in cosmetic products sold at local markets in Saudi Arabia.

Cosmetics are products that can be used on the human body for cleaning, beautification or enhancing perceived attractiveness. Cosmetics may contain a variety of heavy metals such as cobalt (Co) and lead (Pb), which at high concentrations may pose adverse effects on human health. This study focuses to measure the concentration of heavy metals (Co and Pb) in some cosmetic samples of four types (foundation, skin lighteners, kajal (kohl) and lawsone (henna)) available at local markets in Saudi Arabia. The total number of all cosmetic samples understudy was 41. The samples were analysed using atomic absorption spectroscopy to measure the content of Co and Pb. Quality control of the data was performed using Standard Reference Materials [IAEA-V-10] hay powder. For all cosmetic types and qualities combined, the Co concentration range was determined to be 21.14 ± 3.70-144.91 ± 2.27 µg/g and the Pb range 0.75 ± 0.00-10.60 ± 1.24 µg/g. The Co concentration in all cosmetic types understudy was higher than the recommended level. Pb concentration was within the range recommended by the United States Food and Drug Administration in all types of cosmetics except for kohl, for which 22 % of the samples contained concentrations higher than the permissible limit. The findings of this study call for immediate and ongoing testing to monitor the concentrations of toxic metals in cosmetic products used in Saudi Arabia to ensure that established limits are respected and thereby protect consumer health.

Hepatic arterial infusion chemotherapy in the treatment of advanced hepatocellular carcinoma with portal vein thrombosis: a case-control study.

AIM: To study the treatment efficacy and survival of hepatic arterial infusion chemotherapy (HAIC) for patients with advanced hepatocellular carcinoma (HCC) and portal vein tumour thrombosis (PVTT) with compensated cirrhosis in comparison with sorafenib as the standard of care therapy versus best supportive care (BSC). MATERIALS AND METHODS: This case-control study included 91 patients with advanced HCC and PVTT divided into three groups: Group 1 20 treated with HAIC, (50 mg adriamycin and 50 mg cisplatin were infused in hepatic artery); Group 2, 42 patients treated with BSC; and Group 3, 29 patients treated with sorafenib. Patients were followed up for assessment and comparison of treatment outcome by modified Response Evaluation Criteria in Solid Tumours (mRECIST) and survival. RESULTS: There was no significant difference among the groups studied regarding baseline demographic and tumour characteristics. The majority of patients who received sorafenib therapy (82.8%) had stable disease. The response rate (complete response + partial response) was significantly better in the HAIC group. HAIC patients had the longest survival compared with the best supportive care and sorafenib groups, which was statistically significant (29.2 ± 21.8, 4.55 ± 11.41, and 11.52 ± 8.72 months respectively, p=0.007) CONCLUSION: HAIC is a safe procedure with a better response rate and longer survival than best supportive care or sorafenib for patients with advanced HCC and PVTT.

Correlation of the Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) with Contrast-Induced Nephropathy in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Interventions.

Introduction Contrast-induced acute nephropathy (CIN) in patients undergoing percutaneous coronary intervention (PCI) in the setting of acute coronary syndromes (ACS) is associated with adverse outcomes, including longer hospitalization and short and long-term mortality. Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are inflammatory markers that have been validated separately in prior studies as a predictor of CIN in patients with ACS who undergo a left heart catheterization. Our study aims to further investigate the role of NLR and PLR together as markers for predicting CIN in patients with ACS.  Methods A retrospective chart review was performed on a total of 1,577 patients aged 18 - 90 who presented with ACS and underwent PCI between January 2011 to December 2015 at the Florida Hospital Orlando. Cut-off values used for a high PLR and NLR were PLR > 128 and NLR > 2.6. CIN was defined as an increased serum creatinine level by ≥ 0.5 mg/dL, or ≥ 25%, over the baseline value within 72 hours after contrast agent administration. Patients with end-stage renal disease (ESRD) were excluded.  Results Of the 1,577 patients included in the study, 213 (13.51%) patients had CIN. On multivariate logistic regression analysis, high NLR showed an independent association with an elevated risk of CIN (OR 2.03, 95% CI: 1.403 - 3.176, P < 0.001). High PLR did not correlate with CIN (OR 0.831, 95% CI: 0.569 - 1.214, P = 0.339).  Conclusion Elevated NLR is an independent predictor of CIN in patients with acute myocardial infarction (AMI) and may be used to improve on current risk prediction models.

Online Reviews of American Urologists and Opportunities for Improvement.

INTRODUCTION: As patients increasingly use physician review websites as their primary source for finding new doctors, urologists must adapt and control their online presence. Herein, we identify factors that impact physician review website ratings, address opportunities to improve online presence and investigate the validity of online physician ratings by comparing their scores to quality measures. METHODS: We extracted urologist profiles from Healthgrades.com (9,902) and Vitals.com (11,670), the 2 largest physician review website platforms, using an automated web scraper. The provider profiles included demographics, rating information, patient survey data and other information provided by the physician. We also obtained rates of surgical complications, Medicare billing practices and prescribing history from public online databases and other demographic data from the 2010 U.S. Census Bureau, which was cross analyzed with physician review website data using proportional odds logistic regression. RESULTS: Ratings among urologist profiles on Healthgrades.com and Vitals.com were similar and had a correlation coefficient of 0.34 (p <0.001). We noted wait time as the most consistent theme that negatively impacted the physician ratings. For those in the group with the highest number of scores, merely correcting a profile and adding a picture was beneficial. As providers accumulated higher numbers of ratings their scores generally became increasingly positive with less variance. We did not find that physician review website ratings correlate with outcome measures. CONCLUSIONS: Urologist profiles on physician review website platforms are strongly associated with the number of reviews and wait times. Targeting these areas could improve their online presence. However online reviews do not correspond to surgical quality.

Comparative Clinical Characteristics of Rheumatic Heart Disease Patients Undergoing Surgical Valve Replacement.

Background To assess the prevalence patterns of isolated/mixed rheumatic valvular lesions and associated risk factors among rheumatic heart disease (RHD) patients undergoing surgical valve replacement. Methods An analytical cross-sectional design was used. Purposive sampling was used to select 87 RHD patients who underwent a first-time valve replacement for mitral, aortic, or both valves between April 1 and October 20, 2016, at Punjab Institute of Cardiology, Lahore, Pakistan. Patients with systemic hypertension, diabetes mellitus type-II, congenital heart defects, coronary artery disease, non-rheumatic valvular degeneration, positive test for hepatitis C, or undergoing concomitant coronary artery bypass graft or a 'redo' valve replacement procedure were excluded. A proforma was used to collect preoperative data on patients' demographics, laboratory investigations, electrocardiogram (ECG), and transthoracic echocardiography reports. Results Age (mean ± S.D.) was 32.79 ± 13.06 years, which was divided into four quartile-based groups. Forty-six (52.9%) cases were males. The majority (56.3%) of patients underwent mitral valve replacement. Mitral regurgitation (MR, 80%) was the most common lesion. Of 71 available ECGs, atrial fibrillation was observed in 46.5% cases. Increasing age group was negatively correlated with MR severity (τc = -0.188, p-value = 0.033) and positively with aortic stenosis (AS) severity (τc = 0.141, p-value = 0.010). No significant elevations were observed for anti-streptolysin O titer, C-reactive protein, and leukocyte count, though the erythrocyte sedimentation rate was abnormally high in 46.94% cases. Conclusions MR was the most common lesion. MR was more severe in younger patients whilst AS was more severe in older cases. There is little evidence of ongoing residual inflammation.

Omega-3 fatty acids protects against chronic sleep-deprivation induced memory impairment.

AIMS: The current study aims to evaluate the possible protective effect of omega-3 fatty acids on memory impairment induced by sleep-deprivation in rats. MATERIALS AND METHODS: Animals were chronically sleep deprived using the modified multiple platform model (8 h/day for 8 weeks). Omega-3 fatty acids were administered as fish oil via oral gavage at a daily dose of 100 mg omega-3 PUFA/100 g BWT. The spatial learning and memory were evaluated using the radial arm water maze (RAWM). Additionally, the following oxidative stress biomarkers were measured in the hippocampus: glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG, glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD), and thiobarbituric acid reactive substance (TBARS). KEY FINDINGS: Animals in the SD group committed significantly more errors in both short- and long- term memory tests of the RAWM compared to other groups. On the other hand, animals that were sleep deprived and treated with omega-3 fatty acids committed similar number of errors compared to the control group. This indicates that SD impaired both short- and long- term memories, and that chronic omega-3 fatty acids administration prevented these effects. Omega-3 fatty acids also prevented the decreases in hippocampal GPx, catalase and GSH/GSSG ratio and normalized the increases in GSSG levels, which were impaired by SD model. No changes were observed on hippocampal TBARS levels, or activity of SOD among experimental groups. SIGNIFICANCE: In conclusion, a protective effect of omega-3 fatty acids administration has been observed against chronic SD-induced memory impairment probably via improving hippocampus antioxidant effects.

The initial experience of safety and efficacy of argon plasma coagulation (APC) in the primary prevention of variceal bleeding.

BACKGROUND AND STUDY AIMS: The well-known complications of variceal bleeding together with the high mortality rate mandate effective prophylaxis. Because of the intolerance, failure of response and lack of compliance related to B blockers and because of the high incidence of variceal recurrence after endoscopic variceal ligation (EVL), other alternatives should be investigated. As APC provides coagulation at a shallow depth, it has been considered an ideal procedure to promote mucosal fibrosis for oesophageal varices. This study aims to investigate the safety and effectiveness of APC application to the oesophagus post-variceal obliteration in an attempt to decrease variceal recurrence and bleeding, as compared to EVL. PATIENTS AND METHODS: This study included 60 patients with chronic liver disease and portal hypertension referred to the Gastrointestinal Endoscopy Unit, Kasr Al-Aini Hospital, Cairo University, during the period from August 2008 till January 2010. Patients had to have large-sized varices (F3), without history of bleeding, portal hypotensive drugs or intervention. Patients were allocated into either group I that included 30 patients for whom EVL was performed and sequentially followed by one session of APC or group II that included 30 patients for whom EVL alone was done. Patients underwent surveillance endoscopy at 3 and 6months to evaluate variceal recurrence (F1 or more). RESULTS: Both groups were comparable in terms of the demographic features, hepatic functional reserve and endoscopic findings. Post-APC, fever was reported in 6.7%, dysphagia in 3.3%, procedure-related bleeding in 0% and stricture in 3.3%. At 3 and 6months follow-up, both groups were comparable in terms of variceal recurrence and none of the patients in both groups developed variceal bleeding. CONCLUSION: Although, APC application to the oesophageal mucosa is a safe technique, its additive benefit in terms of variceal recurrence and re-bleeding is comparable to EVL alone. This is encountered when only a single session of APC is applied. A more beneficial effect of multiple sessions of APC awaits further studies.

The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis.

Copper plays a fundamental role in the biochemistry of all aerobic organisms. The delivery of this metal to specific intracellular targets is mediated by metallochaperones. To elucidate the role of the metallochaperone Atox1, we analyzed mice with a disruption of the Atox1 locus. Atox1(-/-) mice failed to thrive immediately after birth, with 45% of pups dying before weaning. Surviving animals exhibited growth failure, skin laxity, hypopigmentation, and seizures because of perinatal copper deficiency. Maternal Atox1 deficiency markedly increased the severity of Atox1(-/-) phenotype, resulting in increased perinatal mortality as well as severe growth retardation and congenital malformations among surviving Atox1(-/-) progeny. Furthermore, Atox1-deficient cells accumulated high levels of intracellular copper, and metabolic studies indicated that this defect was because of impaired cellular copper efflux. Taken together, these data reveal a direct role for Atox1 in trafficking of intracellular copper to the secretory pathway of mammalian cells and demonstrate that this metallochaperone plays a critical role in perinatal copper homeostasis.

Structure, expression, and chromosomal localization of the mouse Atox1 gene.

Copper trafficking in eukaryotes involves small proteins termed metallochaperones, which mediate copper delivery to specific intracellular sites. Previous studies in yeast and human cell lines have suggested that Atox1 plays a critical role in copper delivery to the secretory pathway. In the present study, a mouse Atox1 (mAtox1) cDNA was cloned and shown to encode an open reading frame with 85% amino acid identity to human Atox1. RNA blot analysis revealed that mAtox1 was expressed as a single transcript in multiple tissues, and immunoblotting indicated that the relative abundance of mAtox1 mRNA directly correlated with mAtox1 protein. Analysis of the mAtox1 gene locus revealed a genomic structure with four exons encompassing a total of 14.5 kb. RFLP and haplotype analyses indicated that the mAtox1 locus was tightly linked to the Trhr and D15Bir7 loci on mouse chromosome 15. Taken together, these data reveal marked evolutionary conservation of Atox1 structure and provide a genomic organization and localization that will aid in the genetic deciphering of the molecular role of this protein in copper homeostasis.

Heme is an effector molecule for iron-dependent degradation of the bacterial iron response regulator (Irr) protein.

The bacterial iron response regulator (Irr) protein mediates iron-dependent regulation of heme biosynthesis. Pulse-chase and immunoprecipitation experiments showed that Irr degraded in response to 6 microM iron with a half-life of approximately 30 min and that this regulated stability was the principal determinant of control by iron. Irr contains a heme regulatory motif (HRM) near its amino terminus. A role for heme in regulation was implicated by the retention of Irr in heme synthesis mutants in the presence of iron. Addition of heme to low iron (0.3 microM) cultures was sufficient for the disappearance of Irr in cells of the wild-type and heme mutant strains. Spectral and binding analyses of purified recombinant Irr showed that the protein bound heme with high affinity and caused a blue shift in the absorption spectrum of heme to a shorter wavelength. A Cys(29) --> Ala substitution within the HRM of Irr (IrrC29A) abrogated both high affinity binding to heme and the spectral blue shift. In vivo turnover experiments showed that, unlike wild-type Irr, IrrC29A was stable in the presence of iron. We conclude that iron-dependent degradation of Irr involves direct binding of heme to the protein at the HRM. The findings implicate a regulatory role for heme in protein degradation and provide direct evidence for a functional HRM in a prokaryote.

Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis.

The delivery of copper to specific sites within the cell is mediated by distinct intracellular carrier proteins termed copper chaperones. Previous studies in Saccharomyces cerevisiae suggested that the human copper chaperone HAH1 may play a role in copper trafficking to the secretory pathway of the cell. In this current study, HAH1 was detected in lysates from multiple human cell lines and tissues as a single-chain protein distributed throughout the cytoplasm and nucleus. Studies with a glutathione S-transferase-HAH1 fusion protein demonstrated direct protein-protein interaction between HAH1 and the Wilson disease protein, which required the cysteine copper ligands in the amino terminus of HAH1. Consistent with these in vitro observations, coimmunoprecipitation experiments revealed that HAH1 interacts with both the Wilson and Menkes proteins in vivo and that this interaction depends on available copper. When these studies were repeated utilizing three disease-associated mutations in the amino terminus of the Wilson protein, a marked diminution in HAH1 interaction was observed, suggesting that impaired copper delivery by HAH1 constitutes the molecular basis of Wilson disease in patients harboring these mutations. Taken together, these data provide a mechanism for the function of HAH1 as a copper chaperone in mammalian cells and demonstrate that this protein is essential for copper homeostasis.

Identification of a functional fur gene in Bradyrhizobium japonicum.

The recent identification of the iron response regulator (Irr) in Bradyrhizobium japonicum raised the question of whether the global regulator Fur is present in that organism. A fur gene homolog was isolated by the functional complementation of an Escherichia coli fur mutant. The B. japonicum Fur bound to a Fur box DNA element in vitro, and a fur mutant grown in iron-replete medium was derepressed for iron uptake activity. Thus, B. japonicum expresses at least two regulators of iron metabolism.

The bacterial irr protein is required for coordination of heme biosynthesis with iron availability.

Heme is a ubiquitous macromolecule that serves as the active group of proteins involved in many cellular processes. The multienzyme pathway for heme formation culminates with the insertion of iron into a protoporphyrin ring. The cytotoxicity of porphyrins suggests the need for coordination of its biosynthesis with iron availability. We isolated a mutant strain of the bacterium Bradyrhizobium japonicum that, under iron limitation, accumulated protoporphyrin and showed aberrantly high expression of hemB, an iron-regulated gene encoding the heme synthesis enzyme delta-aminolevulinic acid dehydratase. The strain carries a loss of function mutation in irr, a newly described gene that encodes a putative member of the GntR family of bacterial transcriptional regulators. Irr accumulated only under iron limitation, and turned over rapidly upon an increase in iron availability. A separate role for Irr in controlling the cellular iron level was inferred based on a deficiency in high affinity iron transport activity in the irr strain, and suggests that regulation of the heme pathway is coordinated with iron homeostasis. A high level of protoporphyrin accumulation is not a normal consequence of nutritional iron deprivation, thus a mechanism for iron-dependent control of heme biosynthesis may be present in other organisms.