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Clinical Pharmacokinetics Jul 2024The interstitial fluid of tissues is the effect site for antibiotics targeting extracellular pathogens. Microdialysis studies investigating these concentrations in...
BACKGROUND AND OBJECTIVE
The interstitial fluid of tissues is the effect site for antibiotics targeting extracellular pathogens. Microdialysis studies investigating these concentrations in muscle and subcutaneous tissue have reported notable variability in tissue penetration. This study aimed to comprehensively summarise the existing data on interstitial fluid penetration in these tissues and to identify potential factors influencing antibiotic distribution.
METHODS
A literature review was conducted, focusing on subcutaneous and intramuscular microdialysis studies of antibiotics in both adult healthy volunteers and patients. Random-effect meta-analyses were used to aggregate effect size estimates of tissue penetration. The primary parameter of interest was the unbound penetration ratio, which represents the ratio of the area under the concentration-time curve in interstitial fluid relative to the area under the concentration-time curve in plasma, using unbound concentrations.
RESULTS
In total, 52 reports were incorporated into this analysis. The unbound antibiotic exposure in the interstitial fluid of healthy volunteers was, on average, 22% lower than in plasma. The unbound penetration ratio values were higher after multiple dosing but did not significantly differ between muscle and subcutaneous tissue. Unbound penetration ratio values were lower for acids and bases compared with neutral antibiotics. Neither the molecular weight nor the logP of the antibiotics accounted for the variations in the unbound penetration ratio. Obesity was associated with lower interstitial fluid penetration. Conditions such as sepsis, tissue inflammation and tissue ischaemia were not significantly associated with altered interstitial fluid penetration.
CONCLUSIONS
This study highlights the variability and generally lower exposure of unbound antibiotics in the subcutaneous and intramuscular interstitial fluid compared with exposure in plasma. Future research should focus on understanding the therapeutic relevance of these differences and identify key covariates that may influence them.
PubMed: 38955946
DOI: 10.1007/s40262-024-01394-z -
Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Jun 2024Persistent Organic Pollutants (POPs) have the characteristics of resistance to environmental degradation, bioaccumulation and long-distance migration potential. Maternal... (Review)
Review
Persistent Organic Pollutants (POPs) have the characteristics of resistance to environmental degradation, bioaccumulation and long-distance migration potential. Maternal exposure to POPs during pregnancy can enter the fetal blood circulation through the placental barrier, and have a potential impact on the functional development of the nervous system of the offspring. This in turn leads to the occurrence and development of neurological defects and diseases in adulthood. The purpose of this paper is to elucidate the effects of exposure to three major POPs (organochlorine compounds, perfluoroalkyl and polyfluoroalkyl substances, and polybrominated diphenyl ethers) during pregnancy on the functional development of the nervous system (social emotions, cognition, language, exercise, and adaptability) in children, and to provide reference for subsequent studies.
Topics: Pregnancy; Humans; Female; Prenatal Exposure Delayed Effects; Child; Nervous System; Persistent Organic Pollutants; Maternal Exposure; Halogenated Diphenyl Ethers; Hydrocarbons, Chlorinated; Child Development; Environmental Pollutants
PubMed: 38955742
DOI: 10.3760/cma.j.cn112150-20231028-00299 -
Physiological Reports Jul 2024Latent associations between low serum amylase and reduced plasma insulin levels and increased adiposity have been described previously in a small study of asymptomatic...
Latent associations between low serum amylase and reduced plasma insulin levels and increased adiposity have been described previously in a small study of asymptomatic middle-aged humans. In the present study, we sought to determine the nature of such changes during the longitudinal progression from metabolically normal to overt type 2 diabetes mellitus (T2DM) in nonhuman primates (NHPs), a disease that appears to be the same in both pathophysiology and underlying mechanisms as that which most commonly develops in middle-aged adult humans. Amylase and lipase levels were characterized in 157 unrelated adult rhesus monkeys (Macaca mulatta); 38% developed T2DM while under study. In all monkeys, multivariable linear regression analysis revealed that amylase could be negatively predicted by % body fat (β -0.29; p = 0.002), age (β -0.27; p = 0.005), and HbA1c (β -0.18; p = 0.037). Amylase levels were positively predicted by lipase levels (β = 0.19; p = -0.024) in all NHPs included in the study. Amylase was significantly lower in NHPs with metabolic syndrome (p < 0.001), prediabetes (PreDM) (p < 0.001), and T2DM (p < 0.001) compared to metabolically normal adult NHPs. Lipase increased in NHPs with PreDM (p = 0.005) and T2DM (p = 0.04) compared to normal NHPs. This is the first longitudinal study of any species, including humans, to show the dynamics of amylase and lipase during the metabolic progression from normal to metabolic syndrome, to PreDM and then to overt T2DM. The extraordinary similarity between humans and monkeys in T2DM, in pancreatic pathophysiology and in metabolic functions give these findings high translational value.
Topics: Animals; Macaca mulatta; Diabetes Mellitus, Type 2; Lipase; Male; Metabolic Syndrome; Longitudinal Studies; Amylases; Female
PubMed: 38955666
DOI: 10.14814/phy2.16097 -
Primary Care Diabetes Jul 2024Prevalence of diabetes in Arab region has significantly increased, resulting in a significant economic burden on healthcare systems. This surge can be attributed to... (Review)
Review
Prevalence of diabetes in Arab region has significantly increased, resulting in a significant economic burden on healthcare systems. This surge can be attributed to obesity, rapid urbanization, changing dietary habits, and sedentary lifestyles. The Arab Diabetes Forum (ADF) has established localized recommendations to tackle the region's rising diabetes prevalence. The recommendations, which incorporate worldwide best practices, seek to enhance the quality of treatment for people with diabetes by raising knowledge and adherence among healthcare providers. The guidelines include comprehensive recommendations for screening, diagnosing, and treating type 1 and type 2 diabetes in children and adults for better overall health results.
PubMed: 38955658
DOI: 10.1016/j.pcd.2024.06.003 -
Obesity Research & Clinical Practice Jul 2024This study assessed whether the addition of continuous positive airway pressure (CPAP) during weight loss would enhance cardiometabolic health improvements in patients...
BACKGROUND AND AIMS
This study assessed whether the addition of continuous positive airway pressure (CPAP) during weight loss would enhance cardiometabolic health improvements in patients with obesity and Obstructive Sleep Apnoea (OSA).
METHODS AND RESULTS
Patients with overweight or obesity, pre-diabetes and moderatesevere OSA were randomised to receive CPAP therapy with a weight loss programme (CPAP+WL) or a weight loss programme alone (WL alone).
PRIMARY OUTCOME
2-hour glucose assessed by an oral glucose tolerance test.
SECONDARY OUTCOMES
24 hr blood pressure, body composition (DEXA) and fasting blood markers. 17 patients completed 3-month follow-up assessments (8 CPAP+WL and 9 WL alone). Overall, participants in both groups lost ∼12 kg which reduced polysomnography determined OSA severity by ∼45 %. In the CPAP+WL group, CPAP use (compliance 5.29 hrs/night) did not improve any outcome above WL alone. There was no improvement in 2-hour glucose in either group. However, in the pooled (n = 17) analysis there were overall improvements in most outcomes including insulin sensitivity (.000965 units, p = .008), sleep systolic BP (- 16.2 mmHg, p = .0003), sleep diastolic BP (-9.8 mmHg, p = 0.02), wake diastolic BP (- 4.3 mmHg, p = .03) and sleepiness (Epworth Sleepiness Score -3.2, p = .0003). In addition, there were reductions in glucose area under the curve (-230 units, p = .009), total (-0.86 mmol/L, p = 0.006) and LDL cholesterol (-0.58 mmol/L, p = 0.007), triglycerides (-0.75 mmol/L, p = 0.004), fat mass (-7.6 kg, p < .0001) and abdominal fat (-310 cm3, p < .0001).
CONCLUSION
Weight loss reduced OSA and improved sleepiness and cardiometabolic health. These improvements were not further enhanced by using CPAP. Results suggest weight loss should be the primary focus of treatment for patients with OSA and obesity.
PubMed: 38955574
DOI: 10.1016/j.orcp.2024.06.003 -
Obesity Research & Clinical Practice Jul 2024Revisional bariatric surgery (RBS) for insufficient weight loss/weight regain or metabolic relapse is increasing worldwide. There is currently no large multinational,...
INTRODUCTION
Revisional bariatric surgery (RBS) for insufficient weight loss/weight regain or metabolic relapse is increasing worldwide. There is currently no large multinational, prospective data on 30-day morbidity and mortality of RBS. In this study, we aimed to evaluate the 30-day morbidity and mortality of RBS at participating centres.
METHODS
An international steering group was formed to oversee the study. The steering group members invited bariatric surgeons worldwide to participate in this study. Ethical approval was obtained at the lead centre. Data were collected prospectively on all consecutive RBS patients operated between 15th May 2021 to 31st December 2021. Revisions for complications were excluded.
RESULTS
A total of 65 global centres submitted data on 750 patients. Sleeve gastrectomy (n = 369, 49.2 %) was the most common primary surgery for which revision was performed. Revisional procedures performed included Roux-en-Y gastric bypass (RYGB) in 41.1 % (n = 308) patients, One anastomosis gastric bypass (OAGB) in 19.3 % (n = 145), Sleeve Gastrectomy (SG) in 16.7 % (n = 125) and other procedures in 22.9 % (n = 172) patients. Indications for revision included weight regain in 615(81.8 %) patients, inadequate weight loss in 127(16.9 %), inadequate diabetes control in 47(6.3 %) and diabetes relapse in 27(3.6 %). 30-day complications were seen in 80(10.7 %) patients. Forty-nine (6.5 %) complications were Clavien Dindo grade 3 or higher. Two patients (0.3 %) died within 30 days of RBS.
CONCLUSION
RBS for insufficient weight loss/weight regain or metabolic relapse is associated with 10.7 % morbidity and 0.3 % mortality. Sleeve gastrectomy is the most common primary procedure to undergo revisional bariatric surgery, while Roux-en-Y gastric bypass is the most commonly performed revision.
PubMed: 38955573
DOI: 10.1016/j.orcp.2024.06.001 -
Saudi Medical Journal Jul 2024To evaluate the correlation between different attributes, levels of biomarkers, and the probability of developing cardiorenal syndrome (CRS) in patients who have been...
OBJECTIVES
To evaluate the correlation between different attributes, levels of biomarkers, and the probability of developing cardiorenal syndrome (CRS) in patients who have been diagnosed with type 2 diabetes mellitus (T2DM) and liver cirrhosis (LC). The hypothesis suggests that liver illness may be linked to renal impairment, cardiac dysfunction, and the development of cardiorenal syndrome METHODS: The current study retrospectively assessed the medical records of patients who had LC and T2DM diagnoses and were hospitalized at Al Madina Al Munwara hospitals in 2022 and 2023.
RESULTS
This research investigated T2DM patients with physician-confirmed to have LC. Poor glycemic control is indicated by high blood glucose and glycated hemoglobin (HbA1c) readings in research participants. High blood pressure, atherogenic plasma indicator (AIP), and obesity plagued most of these individuals. High creatinine, moderate estimated Glomerular Filtration Rate (eGFR) decline, and a modest urinary albumin-to-creatinine (UACR) rise were the most prevalent variables in LC and T2DM patients. Cardiorenal syndrome risk factors, including elevated blood pressure, triglyceride levels, body mass index (BMI), and high-sensitivity C-reactive protein (hs-CRP) concentrations, were identified through logistic regression. It has been demonstrated that the prevalence of these risk factors increases with age; women may be at a greater risk for developing CRS. Specific biomarker evaluations classified 108 (22.6%) LC and T2DM patients at high risk for chronic kidney disease (CKD), 100 (20%) at risk for cardiovascular disease (CVD), and 91 (18.2%) at risk for CRS.
CONCLUSION
The current assessment included 500 patients with T2DM and LC. The risk factors for CRS identified in this study included elevated cholesterol and triglyceride levels, high BMI, and elevated blood pressure, with age being a significant factor, particularly in female patients. Early identification of these characteristics in patients with LC and T2DM could aid in mitigating the progression of chronic illnesses and their associated complications.
Topics: Humans; Diabetes Mellitus, Type 2; Female; Liver Cirrhosis; Male; Biomarkers; Saudi Arabia; Middle Aged; Cardio-Renal Syndrome; Risk Factors; Retrospective Studies; Aged; Adult; Body Mass Index; C-Reactive Protein; Glomerular Filtration Rate; Glycated Hemoglobin; Creatinine
PubMed: 38955454
DOI: 10.15537/smj.2024.45.7.20240156 -
Journal of Sleep Research Jul 2024Since the first description of narcolepsy at the end of the 19th Century, great progress has been made. The disease is nowadays distinguished as narcolepsy type 1 and... (Review)
Review
Since the first description of narcolepsy at the end of the 19th Century, great progress has been made. The disease is nowadays distinguished as narcolepsy type 1 and type 2. In the 1960s, the discovery of rapid eye movement sleep at sleep onset led to improved understanding of core sleep-related disease symptoms of the disease (excessive daytime sleepiness with early occurrence of rapid eye movement sleep, sleep-related hallucinations, sleep paralysis, rapid eye movement parasomnia), as possible dysregulation of rapid eye movement sleep, and cataplexy resembling an intrusion of rapid eye movement atonia during wake. The relevance of non-sleep-related symptoms, such as obesity, precocious puberty, psychiatric and cardiovascular morbidities, has subsequently been recognized. The diagnostic tools have been improved, but sleep-onset rapid eye movement periods on polysomnography and Multiple Sleep Latency Test remain key criteria. The pathogenic mechanisms of narcolepsy type 1 have been partly elucidated after the discovery of strong HLA class II association and orexin/hypocretin deficiency, a neurotransmitter that is involved in altered rapid eye movement sleep regulation. Conversely, the causes of narcolepsy type 2, where cataplexy and orexin deficiency are absent, remain unknown. Symptomatic medications to treat patients with narcolepsy have been developed, and management has been codified with guidelines, until the recent promising orexin-receptor agonists. The present review retraces the steps of the research on narcolepsy that linked the features of the disease with rapid eye movement sleep abnormality, and those that do not appear associated with rapid eye movement sleep.
PubMed: 38955433
DOI: 10.1111/jsr.14277 -
Beneficial Microbes Jul 2024Previous studies reporting the association between gut microbiota dysbiosis and maternal obesity were mostly confined at the phylum level or at postpartum period. This...
Previous studies reporting the association between gut microbiota dysbiosis and maternal obesity were mostly confined at the phylum level or at postpartum period. This study aimed to investigate the dynamic changes in gut microbial communities associated with maternal obesity at different time points of pregnancy. We performed 16S rRNA gene V3-V4 amplicon sequencing on stool samples from 110 women in all three trimesters and 1-month postpartum. Maternal gut microbial communities associated with maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) were explored. The influence of maternal obesity on gut microbiota trajectories was determined based on longitudinal shifts in community clusters across the trimesters. The richness index of alpha diversity decreased with the progression of pregnancy, particularly in women with excessive GWG. The evenness index in 2nd trimester was found inversely associated with GWG. Various taxonomic differences in 1st trimester were associated with excessive GWG, whereas limited taxonomic differences in 2nd and 3rd trimesters were associated with pre-pregnancy BMI or GWG. Meanwhile, the gut microbiota trajectory with especially depleted genus Faecalibacterium in 1st trimester was associated with excessive GWG (adjusted odds ratio 5.7, 95% confidence interval 1.2-28.1). Moreover, the longitudinal abundances of genus Lachnospiraceae ND3007 group across gestations were depleted in women with overweight/obese pre-pregnancy BMI, while genus Bifidobacterium enriched in women with excessive GWG. Our study shows that dysbiosis of the gut microbiota in early pregnancy may have a significant impact on excess GWG. The abundance of the genus Faecalibacterium in 1st trimester may be a potential risk factor. Clinical trial number: NCT03785093 (https://classic.clinicaltrials.gov/ct2/show/NCT03785093).
PubMed: 38955351
DOI: 10.1163/18762891-bja00018 -
Current Biology : CB Jun 2024Organisms experience constant nutritional flux. Mechanisms at the interface of opposing nutritional states-scarcity and surplus-enable organismal energy homeostasis....
Organisms experience constant nutritional flux. Mechanisms at the interface of opposing nutritional states-scarcity and surplus-enable organismal energy homeostasis. Contingent on nutritional stores, adipocytes secrete adipokines, such as the fat hormone leptin, to signal nutrient status to the central brain. Increased leptin secretion underlies metabolic dysregulation during common obesity, but the molecular mechanisms regulating leptin secretion from human adipocytes are poorly understood. Here, we report that Atg8/LC3 family proteins, best known for their role in autophagy during nutrient scarcity, play an evolutionarily conserved role during nutrient surplus by promoting adipokine secretion. We show that in a well-fed state, Atg8/LC3 promotes the secretion of the Drosophila functional leptin ortholog unpaired 2 (Upd2) and leptin from human adipocytes. Proteomic analyses reveal that LC3 directs leptin to a secretory pathway in human cells. We identified LC3-dependent extracellular vesicle (EV) loading and secretion (LDELS) as a required step for leptin release, highlighting a unique secretory route adopted by leptin in human adipocytes. In Drosophila, mutations to Upd2's Atg8 interaction motif (AIM) result in constitutive adipokine retention. Atg8-mediated Upd2 retention alters lipid storage and hunger response and rewires the bulk organismal transcriptome in a manner conducive to starvation survival. Thus, Atg8/LC3's bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively. We posit that decoding how bidirectional molecular switches-such as Atg8/LC3-operate at the nexus of nutritional scarcity and surplus will inform therapeutic strategies to tackle chronic metabolic disorders.
PubMed: 38955177
DOI: 10.1016/j.cub.2024.06.005