LD Group Research Articles

Sex differences in the diathetic effects of shift work schedules on circulating cytokine levels and pathological outcomes of ischemic stroke during middle age

Shift work is associated with increased risk for vascular disease, including stroke- and cardiovascular-related mortality. However, evidence from these studies is inadequate to distinguish the effect of altered circadian rhythms in isolation from other risk factors for stroke associated with shift work (e.g., smoking, poor diet, lower socioeconomic status). Thus, the present study examined the diathetic effects of exposure to shifted LD cycles during early adulthood on circadian rhythmicity, inflammatory signaling and ischemic stroke pathology during middle age, when stroke risk is high and outcomes are more severe. Entrainment of circadian activity was stable in all animals maintained on a fixed light:dark 12:12 cycle but was severely disrupted during exposure to shifted LD cycles (12hr advance/5d). Following treatment, circadian entrainment in the shifted LD group was distinguished by increased daytime activity and decreased rhythm amplitude that persisted into middle-age. Circadian rhythm desynchronization in shifted LD males and females was accompanied by significant elevations in circulating levels of the inflammatory cytokine IL-17A and gut-derived inflammatory mediator lipopolysaccharide (LPS) during the post-treatment period. Middle-cerebral artery occlusion, 3 months after exposure to shifted LD cycles, resulted in greater post-stroke mortality in shifted LD females. In surviving subjects, sensorimotor performance, assessed 2- and 5-days post-stroke, was impaired in males of both treatment groups, whereas in females, recovery of function was observed in fixed but not shifted LD rats. Overall, these results indicate that early exposure to shifted LD cycles promotes an inflammatory phenotype that amplifies stroke impairments, specifically in females, later in life.

Effects of Stocking Density on the Growth Performance, Physiological Parameters, Redox Status and Lipid Metabolism of Micropterus salmoides in Integrated Rice-Fish Farming Systems.

Stocking density has been identified as one of the main factors affecting fish growth, welfare and behavior. However, few studies have focused on the effects of stocking density on fish health in integrated rice–fish farming systems. Thus, the aim of this study was to evaluate the effects of different stocking densities on the growth performance, physiological parameters, redox status and lipid metabolism of Micropterus salmoides in an integrated rice–fish farming system. The fish were reared at three densities: low density (LD, 40 g/m3), medium density (MD, 80 g/m3) and high density (HD, 120 g/m3) for 90 days. At the end of the experiment, fish reared in the MD and HD groups showed lower growth performance than those from the LD group. The HD treatment significantly altered the physiological parameters, including glucose and lactate. Meanwhile, the HD treatment induced oxidative stress and lipid peroxidation after 90 days of farming. Furthermore, transcriptomic analysis revealed that HD treatment led to abnormal lipid metabolism. Interestingly, we found the suppression of three key pathways related to lipid metabolism, including the PPAR, insulin and adipocytokine signaling pathways, in the HD group. Overall, our data indicated that the HD treatment inhibited growth and caused physiological responses, oxidative stress and abnormal hepatic lipid metabolism in M. salmoides in an integrated rice–fish farming system.

Comprehensive Analysis of Disease Pathology in Immunocompetent and Immunocompromised Hosts following Pulmonary SARS-CoV-2 Infection.

The Coronavirus disease 2019 (COVID-19) pandemic disproportionately affects immunocompetent and immunocompromised individuals, with the latter group being more vulnerable to severe disease and death. However, the differential pathogenesis of SARS-CoV-2 in the context of a specific immunological niche remains unknown. Similarly, systematic analysis of disease pathology in various extrapulmonary organs in immunocompetent and immunocompromised hosts during SARS-CoV-2 infection is not fully understood. We used a hamster model of SARS-CoV-2 infection, which recapitulates the pathophysiology of patients with mild-to-moderate COVID-19, to determine the dynamics of SARS-CoV-2 replication and histopathology at organ-level niches and map how COVID-19 symptoms vary in different immune contexts. Hamsters were intranasally infected with low (LD) or high (HD) inoculums of SARS-CoV-2, and the kinetics of disease pathology and viral load in multiple organs, antibody response, inflammatory cytokine expression, and genome-wide lung transcriptome by RNAseq analysis were determined and compared against corresponding responses from chemically induced immunocompromised hamsters. We observed transient body weight loss proportional to the SARS-CoV-2 infectious dose in immunocompetent hamsters. The kinetics of viral replication and peak viral loads were similar between LD and HD groups, although the latter developed more severe disease pathology in organs. Both groups generated a robust serum antibody response. In contrast, infected immunocompromised animals showed more prolonged body weight loss and mounted an inadequate SARS-CoV-2-neutralizing antibody response. The live virus was detected in the pulmonary and extrapulmonary organs for extended periods. These hamsters also had persistent inflammation with severe bronchiolar-alveolar hyperplasia/metaplasia. Consistent with the differential disease presentation, distinct changes in inflammation and immune cell response pathways and network gene expression were seen in the lungs of SARS-CoV-2-infected immunocompetent and immunocompromised animals.

Daytime restriction of feeding prevents illuminated night-induced impairment of metabolism and sleep in diurnal zebra finches

We investigated whether nocturnal eating was causal to the impairment of metabolism and sleep disruption in diurnal animals exposed to illuminated nights. Adult zebra finches hatched and raised in 12 h light: 12 h darkness (LD) were exposed to 5-lux dim light at night (dLAN, two groups), with a control group maintained on LD. For the next 3 weeks, the food availability to one of the dLAN groups was restricted to the 12 h light period (dLAN -F); the other dLAN (dLAN +F) and LD groups were continued on ad lib feeding. In spite of similar food intakes, dLAN +F condition led to the fat accumulation and weight gain. These birds showed concurrent changes in hepatic expression of genes associated with carbohydrate and lipid metabolism, suggesting an enhanced gluconeogenesis and impaired fatty acids synthesis. Increased sirt1 mRNA levels indicated the activation of molecular mechanisms to counter-balance the metabolic damage under dLAN +F. Furthermore, reduced bout length and total duration of the nocturnal sleep suggested a poorer sleep in dLAN +F condition. Negative sleep effects of dLAN were supported by the lower hypothalamic expression of sleep promoting sik3 and camkii genes, and higher mRNA expression of awake promoting achm3 gene in dLAN +F, compared to the LD condition. Importantly, dLAN-induced negative effects in metabolism and sleep were alleviated in the dLAN –F group. These results suggest the role of timed feeding in alleviating the negative impact of illuminated nights in metabolism and sleep in diurnal zebra finches.

An Atypical Form of Diabetes Among Individuals With Low BMI.

Diabetes among individuals with low BMI (<19 kg/m2) has been recognized for >60 years as a prevalent entity in low- and middle-income countries (LMICs) and was formally classified as "malnutrition-related diabetes mellitus" by the World Health Organization (WHO) in 1985. Since the WHO withdrew this category in 1999, our objective was to define the metabolic characteristics of these individuals to establish that this is a distinct form of diabetes. State-of-the-art metabolic studies were used to characterize Indian individuals with "low BMI diabetes" (LD) in whom all known forms of diabetes were excluded by immunogenetic analysis. They were compared with demographically matched groups: a group with type 1 diabetes (T1D), a group with type 2 diabetes (T2D), and a group without diabetes. Insulin secretion was assessed by C-peptide deconvolution. Hepatic and peripheral insulin sensitivity were analyzed with stepped hyperinsulinemic-euglycemic pancreatic clamp studies. Hepatic and myocellular lipid contents were assessed with 1H-nuclear magnetic resonance spectroscopy. The total insulin secretory response was lower in the LD group in comparison with the lean group without diabetes and the T2D group. Endogenous glucose production was significantly lower in the LD group than the T2D group (mean ± SEM 0.50 ± 0.1 vs. 0.84 ± 0.1 mg/kg · min, respectively; P < 0.05). Glucose uptake was significantly higher in the LD group in comparison with the T2D group (10.1 ± 0.7 vs. 4.2 ± 0.5 mg/kg · min; P < 0.001). Visceral adipose tissue and hepatocellular lipids were significantly lower in LD than in T2D. These studies are the first to demonstrate that LD individuals in LMICs have a unique metabolic profile, suggesting that this is a distinct entity that warrants further investigation.

Ventral Attention Network Correlates With High Traits of Emotion Dysregulation in Community Women - A Resting-State EEG Study.

In recent years, many studies have focused on resting-state brain activity, and especially on functional connectivity (FC), an approach that typically describes the statistical interdependence of activity in distant brain regions through specific networks. Our aim was to study the neurophysiological correlates of emotion dysregulation. Therefore, we expected that both the Default Mode Network (DMN), and the Ventral Attention Network (VAN) would have been involved. Indeed, the latter plays a role in the automatic orienting of attention towards biologically salient stimuli and includes key regions for emotion control and modulation. Starting from a community sample of 422 female students, we selected 25 women with high traits of emotion dysregulation (HD group) and 25 with low traits (LD group). They underwent a 64-channel EEG recording during a five-minute resting state with eyes open. Seed-based FC was computed on the EEG Alpha band (8–13 Hz) as a control band, and on EEG Gamma power (30–50 Hz) as the relevant measure. The power within each network and inter-network connectivity (Inter-NC) was also calculated. Analysis of the EEG Gamma band revealed, in the HD group, higher levels of Inter-NC between the VAN and all other resting-state networks as compared with the LD group, while no differences emerged in the Alpha band. Concerning correlations, Alpha power in the VAN was negatively correlated in the HD group with affective lability (ALS-18 questionnaire), both for total score (ρ = –0.52, pFDR < 0.01) and the Depression/Elation subscale) ρ = −0.45, pFDR < 0.05). Consistent with this, in the Gamma band, a positive correlation was found between VAN spectral power and the Depression/Elation subscale of ALS-18, again in the HD group only (ρ = 0.47, pFDR < 0.05). In conclusion, both resting state FC and network power in the VAN were found to be related to high emotion dysregulation, even in our non-clinical sample with high traits. Emotion dysregulation was characterized, in the EEG gamma band, by a VAN strongly connected to all other networks, a result that points, in women prone to emotion dysregulation, to a strong automatic orienting of attention towards their internal state, bodily sensations, and emotionally intense related thoughts.

Effects of Taraxacum mongolicum Hand.-Mazz. (dandelion) on growth performance, expression of genes coding for tight junction protein and mucin, microbiota composition and short chain fatty acids in ileum of broiler chickens

BackgroundDandelion is becoming an exploitable alternative to the widely prohibited antibiotics in the poultry production. This research aimed to investigate the effects of dandelion on the growth performance and intestinal barrier function of broiler chickens maintained under standard condition of management. One-hundred and sixty 1-day-old Arbor Acres (AA) male broiler chickens were randomly divided into four groups, with five replicates of eight birds each. The birds were fed a basal diet supplemented without (control group, [CON]) or with 500 (low dose [LD]) or 1000 (high dose [HD]) mg/kg dandelion or with 250 mg/kg chlortetracycline 20% premix (CTC) for 42 days, including the starter phase (d 1 to 21) and the grower phase (d 22 to 42). Body weight (BW) of each bird and feed consumption of each replicate were measured at d 21 and d 42. The ileal tissues were collected on day 21 and 42 to determine expression of genes coding for tight junction protein and mucin as well as ELISA analysis for immune factor. The ileal digesta was collected for microbiota and short chain fatty acids analysis.ResultsCompared with CON group, during day 1–21, the average daily feed intake (ADFI) and feed/gain ratio (F/G) of LD group were lower (P < 0.05); during day 22–42, the F/G of LD and CTC group tended to be lower (P = 0.07); during the overall phase, the ADFI of HD and CTC groups were decreased (P < 0.05), and the F/G of dandelion and CTC groups tended to be decreased (P = 0.07). On day 21, the relative mRNA expression of claudin, occludin-1 and mucin1 in dandelion groups were up-regulated (P < 0.05), and the ZO-1 mRNA expression in CTC group was increased (P < 0.05); on day 42, the claudin and mucin1 transcripts in LD group and ZO-1 transcripts in HD and CTC group were up-regulated (P < 0.05), while the occludin-1 and mucin1 transcripts in CTC group was significantly down-regulated (P < 0.05). In addition, the contents of TNF-α in dandelion groups were lower than that in CTC group (P < 0.05). In the analysis of ileal microbiota, on day 21, decreased α-diversity was observed in HD and CTC groups (P < 0.05). Meanwhile, on day 21, the relative abundance of Firmicutes in dandelion groups tended to be higher (P = 0.09), the relative abundance of Lactobacillus in LD and CTC group were increased (P < 0.05), while Bacteroidete, Bacteroides, and Alistipes relative abundance in dandelion and CTC groups were decreased (P < 0.05). On day 42, the Actinobacteriota relative abundance in CTC group tended to be higher (P = 0.05), and Lysinibacillus relative abundance of CTC group was higher (P = 0.02). Compared with CON group, on day 21, the propionic acid and butyric acid content in CTC group were higher, the butyric acid content in HD group was lower (P < 0.10).ConclusionIn summary, dietary dandelion supplementation at 500 mg/kg of diet enhanced growth performance of broilers by improving the intestinal barrier function. Dandelion can be supplemented in the diet as an antibiotics alternative to enhance production in poultry industry.

Alcohol binge drinking decreases brain glucose metabolism and functional connectivity in adolescent rats.

Alcohol misuse represents a serious health concern, especially during adolescence, with approximately 18% of high school students engaging in binge drinking. Despite widespread misuse of alcohol, its effects on how the brain functions is not fully understood. This study utilized a binge drinking model in adolescent rats to examine effects on brain function as measured by brain glucose metabolism (BGluM). Following an injection of [18 FDG] fluro-2-deoxy-D-glucose, rats had voluntary access to either water or various concentrations of ethanol to obtain the following targeted doses: water (no ethanol), low dose ethanol (0.29 ± 0.03g/kg), moderate dose ethanol (0.98 ± 0.05), and high dose ethanol (2.19 ± 0.23g/kg). Rats were subsequently scanned using positron emission tomography. All three doses of ethanol were found to decrease BGluM in the restrosplenial cortex, visual cortex, jaw region of the somatosensory cortex, and cerebellum. For both the LD and MD ethanol dose, decreased BGluM was seen in the superior colliculi. The MD ethanol dose also decreased BGluM in the subiculum, frontal association area, as well as the primary motor cortex. Lastly, the HD ethanol dose decreased BGluM in the hippocampus, thalamus, raphe nucleus, inferior colliculus, and the primary motor cortex. Similar decreases in the hippocampus were also seen in the LD group. Taken together, these results highlight the negative consequences of acute binge drinking on BGluM in many regions of the brain involved in sensory, motor, and cognitive processes. Future studies are needed to assess the long-term effects of alcohol binge drinking on brain function as well as its cessation.

Kinetics of the inflammatory response during experimental Babesia rossi infection of beagle dogs

Babesia rossi causes severe morbidity and mortality in dogs in sub-Saharan Africa, and the complications associated with this disease are likely caused by an unfocused, excessive inflammatory response. During this experimental B. rossi study we investigated inflammatory marker and cytokine kinetics during infection and after treatment. We aimed to determine whether infectious dose and treatment would influence the progression of the inflammatory response and clinical disease. Six healthy male beagle dogs formed the study population, one was used to raise the infectious inoculum, three were administered a high B. rossi infectious dose (HD group) and two a low infectious dose (LD group). Clinical examination, complete blood count (CBC) and C-reactive protein (CRP) were determined daily. Cytokines were quantified on stored plasma collected during the study, using a canine specific cytokine magnetic bead panel (Milliplex©). The experiment was terminated and treatment administered when predetermined experimental or humane endpoints were reached. Parasitemia occurred on day 1 and 3 in the HD and LD groups respectively. The rate of increase in parasitemia in the HD group was significantly faster than that seen in the LD group. Significant differences were found in heart rate, blood pressure, interferon gamma (INFγ), keratinocyte chemoattractant (KC), INFγ-induced protein 10 (IP10), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP1), tumor necrosis factor alpha (TNFα), interleukin 2 (IL-2), IL-6, IL-7, IL-8, IL-10 IL-15, IL-18, CRP, neutrophils and monocytes between groups at multiple time points during the course of the infection. Our findings suggest that the initiation of inflammation occurs before the onset of clinical disease in B. rossi infection and infectious dose influences the onset of the inflammatory response. Treatment enhances the inflammatory response in the immediate post-treatment period which may contribute to disease associated complications. Finally, we found that there is an imbalance in pro/anti-inflammatory cytokine concentrations during infection which may promote parasite replication.

Exploration of a panel of urine biomarkers of kidney disease in two paediatric cohorts with Type 1 diabetes mellitus of differing duration

BackgroundThe pathogenesis of diabetic kidney disease (DKD) is complex and involves both glomerular and tubular dysfunction. A global assessment of kidney function is necessary to stage DKD, a progressive kidney disease that is likely to begin in childhood. The present study evaluated whether kidney injury biomarkers identified as early DKD biomarkers in adults have any prognostic value in the very early stages of childhood diabetes.MethodsWe measured urine free Retinol-binding protein 4 (UfRBP4), albumin (UAlb), Kidney injury molecule-1 (KIM-1) and the microRNAs miR-155, miR-126 and miR-29b in two cohorts of paediatric T1DM patients without evidence of DKD, but with diabetes of short-duration, ≤ 2.5 years (SD, n = 25) or of long-duration, ≥ 10 years (LD, n = 29); non-diabetic siblings (H, n = 26) were recruited as controls. A p value < 0.05 was considered significant for all results.ResultsUfRBP4 and UAlb were not significantly different across the three groups. No differences were found in KIM-1 excretion between any of the three groups. UfRBP4 was correlated with UAlb in all three groups (r 0.49; p < 0.001), whereas KIM-1 showed no correlation with albumin excretion. Among microRNAs, miR-29b was higher in all diabetic children compared with the H control group (p = 0.03), whereas miR-155 and miR-126 were not significantly different. No differences were found between the SD and LD groups for all three microRNAs. No associations were identified between these biomarkers with sex, age, BMI, eGFR, T1DM duration or glycaemic control.ConclusionsUfRBP4, KIM-1, miR-155, and miR-126 were unaffected by the presence and duration of diabetes, whereas miR-29b showed a modest elevation in diabetics, regardless of duration. These data support the specificity of a panel of urine biomarkers as DKD biomarkers, rather than any relationship to diabetes per se or its duration, and not as early DKD biomarkers in a paediatric setting.

Topiramate and Acetazolamide Combination a Comparative Study between High and Low Dose Profile of Side Effects on Metabolism

Background: Topiramate, with multiple putative anticonvulsant pathways, is a relatively recent antiepileptic drug. The ability to inhibit carbonic anhydrase, a property common with the acetazolamide anticonvulsant, is among them. Aim: The study refers to compare between the use of combinations of topiramate and acetazolamide high and low doses of drugs and which one is safer for the patients. Methods: Twenty stable adult males wistar rats three weeks after acclimatization and uniformly split into two groups (10 rats in each group) and 60 days of treatment: 9 mg/kg/B.W of Topiramate and 30 mg/kg/B.W of Acetazolamide in the high dose (Hd) group and 5 mg/kg B.W of Topiramate and 30 mg/kg B.W of Acetazolamide in the low dose (Ld) group, orally/day in the high dose (Hd) group. Results: No major differences in mean Glutamate pyruvate transaminase, Glutamic oxaloacetic transaminase, Alkaline phosphatase concentration were found in the statistical analysis of the results in all experimental groups compared with each other at the pretreated period, also revealed that intubation of rats in the 60-days Hd induced a substantial (P&gt;0.05) rise in the mean Glutamate Pyruvate Transaminase and Glutamic Oxaloacetic Transaminase serum concentrations relative to the control and Ld classes. Treatment of low-dose rats showed a substantial (P&lt;0.05) decrease in serum alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen and creatinine enzyme concentrations at 30 and 60 days of the trial compared with the T1 group. Conclusion: The study showed that high-dose combinations of topiramate and acetazolamide had the same adverse effect somewhat in low-dose combinations.

Ameliorative effects of Liv-52 on doxorubicin-induced oxidative damage in rat liver

ABSTRACT Hepatotoxicity is a common side effect of doxorubicin (Dox) treatment of cancer. Liv-52 is an ayurvedic medicine that is reported to ameliorate liver injury due to oxidative stress. We investigated the effects of Liv-52 on Dox induced oxidative damage to liver tissues of rats using biochemical and histopathological techniques. Thirty male rats were assigned randomly into three equal groups: control (CG), Dox group (DG) Liv-52 + Dox group (LD). Rats in the LD group received 50 mg/kg Liv-52 in distilled water via gastric gavage. Distilled water was given via the same route to the rats in the DG and CG groups. Rats in the LD and DG groups were injected intraperitoneally with 5 mg/kg Dox 1 h after administration of Liv-52 or distilled water. The procedure was repeated daily for 7 days. On day 8, the animals were sacrificed, and serum and tissue biochemical and histopathological assays were performed. The malondialdehyde level was increased significantly in the DG group, while glutathione and superoxide dismutase levels were significantly lower in the DG group compared to the LD and CG groups. The highest levels of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase were found in the DG group, while the lowest levels were found in the CG group, which exhibited levels similar to those of the LD group. Treatment with Liv-52 prior to Dox treatment reduced the histopathologic changes in the Dox group. Therefore, pre-treatment with Liv-52 protected against Dox induced oxidative stress and hepatotoxicity.

Preliminary study for the application of Raman spectroscopy for the identification of Leishmania infected dogs.

Raman spectroscopy is a rapid qualitative and quantitative technique that allows the simultaneous determination of several components in biological fluids. This methodology concerns an alternative technique to distinguish between non-healthy and healthy subjects. Leishmaniasis is a zoonosis of world interest, the most important agent is L. infantum. Dogs are the principal reservoirs affected by a broad spectrum of clinical features. During a clinical exam, blood samples were collected in tubes without anticoagulants, from twenty two dogs. One aliquot was used for serological test for Leishmaniasis, one aliquot was subjected to the Raman spectroscopic analysis. Animals were divided into two groups of equal subjects, Leishmania group (LG) constituted by infected dogs, and control group (CG) constituted by healthy dogs. The acquired spectra were different in the region 1200–1370 cm−1, in which it is possible to distinguish the amide III vibration (~ 1300 cm−1). In LG, an evident shift to the shortwave region is observed in spectral frequencies of the band centered at ~ 1250 cm−1. Our results distinguished between LD group and CG. Further studies are necessary to exclude the effect of metabolic modification due to disease on the recorded spectra changes and to consolidate the achievability of Raman spectroscopy as rapid and less expensive diagnosis of Leishmaniasis.

The effect of density on sex differentiation, sexual dimorphism, stress, and related gene expression in yellow perch.

A 180-day experiment was conducted to evaluate the effects of density on sex differentiation, sexual dimorphism, cortisol level, and stress related gene expression. Yellow perch, Perca flavescens, with initial mean body weight of 0.03 ± 0.001 g were reared in three different stocking densities: 1, 2, and 4 fish/L, termed as low (LD), moderate (MD), and high (HD) density, respectively, in a flow-through tank system. Results showed no significant differences in sex ratio in all density groups compared to normal population 1:1, and sexual size dimorphism (SSD) appeared when male and female were as small as the mean size reaching 11.5 cm and 12.3 cm in total length (TL) or 13.2g and 16.9g in body weight (BW), respectively. This female-biased sexual growth dimorphism was more pronounced in LD, although it was observed across all density groups. A significantly higher condition factor (K) of females than males in the LD group, and significantly higher R values of LD and MD than HD with the length/weight (L/W) linear relationships in females, were observed. Parallelly, fish reared in LD showed significantly higher mean body weight than those in the MD and HD groups, but there were no significant differences between the MD and HD. Similar results were also observed in all the other parameters of weight gain, specific growth rate (SGR), condition factor (K), and survival. These findings suggested that high density not only affected growth itself, but also affected SSD, growth trajectory or body shape, and general wellbeing in fish, especially in females. There were no significant differences in gonadosomatic index (GSI) and viscerosomatic index (VSI) among all the density groups; however, the hepatosomatic index (HSI) of LD was significantly higher than MD and HD, suggesting high density affected liver reserves or functions. Physiologically, plasma cortisol level was significantly highest in the LD among all groups, followed by MD, and lowest in HD. At the molecular level, the expression of the 70-kDa heat shock protein (Hsp70), glutathione peroxidase (GPx), and superoxide dismutase (SOD) genes involved in cellular stress were significantly upregulated in the HD group. The most significantly downregulated expression of these genes was consistently observed in the MD when compared to the LD and HD groups. In conclusion, increasing density induced chronic stress in yellow perch without affecting sex differentiation, but negatively affected expression of stress-related genes and mobilization of liver reserve, resulting in poorer wellbeing and reduced SSD, growth, and survival.

Acetyl-L-carnitine improves erectile function in bilateral cavernous nerve injury rats via promoting cavernous nerve regeneration

ABSTRACT Introduction Acetyl-L-carnitine (ALCAR), an acetyl derivative of L-carnitine, has been proven to promote nerve repair and regeneration in a variety of neurodegenerative diseases. Neurogenic erectile dysfunction (NED) caused by CN injury is a common complication after radical prostatectomy, which lacks efficient curative treatments. Objective Although attempts have been made to apply ALCAR to treatment of peripheral neuropathy, the effects of ALCAR on NED remain unknown. Therefore, we intend to explore the potential role of ALCAR in the treatment of NED. Methods A rat model of bilateral cavernous nerve injury (BCNI) was established by crushing the CN 5 millimeters distal to the major pelvic ganglion (MPG). Twenty-four BCNI rats were randomly divided into BCNI group, BCNI+ALCAR-LD (50 mg/kg/day) group, and BCNI+ALCAR-HD (100 mg/kg/day) group, whereas the remaining eight age-matched rats were sham-operated as controls. Fourteen days after intraperitoneal injection of ALCAR, erectile function was evaluated by measuring intracavernosal pressure and mean arterial pressure. The penile tissues and CNs at the distal damage point were collected from each group of rats for subsequent histological and molecular biological analysis. Rat Schwann cell line S16 was used for CCK-8 and wound healing assay, and the expressions of SC markers Pmp22 and nerve growth factor (NGF) were verified by PCR. Results First, we found that the erectile function of rats in the BCNI model group was severely impaired, which was improved considerably in both BCNI+ALCAR-LD and BCNI+ALCAR-HD groups. Then, we observed that the penis was fibrotic after denervation in the BCNI group, which was manifested as decreased smooth muscle content and increased collagen content in the corpus cavernosum, and high expression of fibrosis indicators including TGF-beta, CTGF, and Smad 2/3. The above changes were alleviated after the administration of low and high-dose ALCAR. Meanwhile, our results also showed that after ALCAR treatment, the NO/cGMP pathway was promoted and the RhoA/ROCK pathway was inhibited in the corpus cavernosum of BCNI rats. Further, rats treated with ALCAR had high expression of ATF3 and S100 in the distal nerve tissues of the CN extrusion site, indicating the repairing effect of ALCAR on the CN. In vitro experiments showed that ALCAR promoted the proliferation and migration of SC, and increased the expression of Pmp22 and NGF. Conclusions ALCAR could boost CN repair and regeneration, thereby suppressing penile fibrosis and improving penile erection. ALCAR could inhibit penile fibrosis and improve penile erection by promoting proliferation and migration of SC and secretion of NGF to promote nerve repair and regeneration. Our study provides new insight into the therapeutic effect of ALCAR and preclinical evidence for a potential treatment strategy for NED. Disclosure Work supported by industry: no.

Effects of stocking density on growth performance, digestive function and immune performance of Matou goats

The objective of this study was to examine the effects of different stocking densities on Matou goats. Thirty-six female Matou goats were randomly assigned into three experimental treatments including the low density (LD, 0.67 goat/m2), the medium density (MD, 1 goat/m2) and the high density (HD, 2 goats/m2) group. Compared with LD group, the average daily weight gain (ADG) of HD group decreased (p < .05). The length of duodenal and ileal villi in HD group was significantly lower than that in LD group (p < .05). The rumen pH and concentration of total volatile fatty acid (VFA), propionate butyrate and ammonia-nitrogen increased in HD group (p < .05). The acetate/propionate ratio was the highest in MD group (p < .05). The mRNA expression level of agouti-related protein gene (AgRP) in hypothalamus of LD was higher than that in HD group (p < 0.05). Proopiomelanocortin (POMC) mRNA expression level was the highest in MD group (p<.05) and the lowest in HD group (p < .05). An increase in growth hormone receptor (GHR), insulin-like growth factor 1 (IGF1) and claudin-1 mRNA expression level were noticed in HD group (p<.05). Compared with LD group, the serum total protein (TP), albumin (Alb), globulin (Glb) IgA and IgG levels in HD group decreased (p < .05). Glucocorticoid (GCS), β-endorphin (β-EP) and cortisol levels in serum were also significantly increased in HD group compared with LD group (p < .05). These results showed that stocking density affected rumen environment and high stocking density resulted in a decrease in growth, digestive and immune function of Matou goats.

Prospective randomized controlled trial on the effectiveness of low-dose and high-dose intravenous tranexamic acid in reducing perioperative blood loss in single-level minimally invasive transforaminal lumbar interbody fusion

A prospective randomized controlled trial was conducted to study the effectiveness and safety of intravenous different doses tranexamic acid (TXA) in single-level unilateral minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). The patients treated with single-level unilateral MIS-TLIF between September 2019 and October 2020 were enrolled and randomly classified into low-dose TXA (LD) group (n=39), high-dose TXA (HD) group (n=39), and placebo-controlled (PC) group (n=38). The LD, HD, and PC groups received intravenous TXA 20 mg/kg, TXA 50 mg/kg, the same volume of normal saline at 30 minute before skin incision after general anesthesia, respectively. There was no significant difference on baseline characteristics and preoperative laboratory results among 3 groups (P>0.05), including age, gender, body mass index, surgical segments, hematocrit (HCT), hemoglobin (HGB), prothrombin time (PT), international normalized ratio (INR), D-dimer, fibrin degradation products (FDP), activated partial prothromboplastin time (APTT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea. The intraoperative blood loss (IBL), postoperative drainage volume, operation time, total blood loss (TBL), hidden blood loss (HBL), blood transfusion, hematological examination indexes on the first day after operation, and the incidence of complications within 1 month were compared among the 3 groups. There were 3, 2, and 4 patients in the LD, HD, and PC groups who underwent autologous blood transfusion, respectively, and there was no allogeneic blood transfusion patients in the 3 groups. There was no significant difference in IBL, postoperative drainage volume, and operation time between groups (P>0.05). The TBL, HBL, and the decreased value of HGB in LD and HD groups were significantly lower than those in PC group (P<0.05), and TBL and HBL in HD group were significantly lower than those in LD group (P<0.05); the decreased value of HGB between LD group and HD group showed no significant difference (P>0.05). On the first day after operation, D-dimer in LD and HD groups were significantly lower than that in PC group (P<0.05); there was no significant difference between LD and HD groups (P>0.05). There was no significant difference in other hematological indexes between groups (P>0.05). All patients were followed up 1 month, and there was no TXA-related complication such as deep venous thrombosis of lower extremity, pulmonary embolism, and epilepsy in the 3 groups. Intravenous administration of TXA in single-level unilateral MIS-TLIF is effective and safe in reducing postoperative TBL and HBL within 1 day in a dose-dependent manner. Also, TXA can reduce postoperative fibrinolysis markers and do not increase the risk of thrombotic events, including deep venous thrombosis and pulmonary embolism.

The effect of a loading dose of meropenem on outcomes of patients with sepsis treated by continuous renal replacement: study protocol for a randomized controlled trial

BackgroundSepsis and continuous renal replacement therapy (CRRT) are both responsible for the alterations of the pharmacokinetics of antibiotics. For patients with sepsis receiving CRRT, the serum concentrations of meropenem in the early phase (< 48 h) was significantly lower than that in the late phase (> 48 h). This current trial aimed to investigate whether administration of a loading dose of meropenem results in a more likely achievement of the pharmacokinetic (PK)/pharmacodynamics (PD) target (100% fT > 4 × MIC) and better therapeutic results in the patients with sepsis receiving CRRT.MethodsThis is a single-blinded, single-center, randomized, controlled, two-arm, and parallel-group trial. This trial will be carried out in Guangzhou First People’s Hospital, School of Medicine, South China University of Technology Guangdong, China. Adult patients (age ≥ 18 years) with critical sepsis or sepsis-related shock receiving CRRT will be included in the study. The subjects will be assigned to the control group and the intervention group (LD group) randomly at a 1:1 ratio, the estimated sample size should be 120 subjects in each group. In the LD group, the patient will receive a loading dose of 1.5-g meropenem resolved in 30-ml saline which is given via central line for 30 min. Afterward, 0.75-g meropenem will be given immediately for 30 min every 8 h. In the control group, the patient will receive 0.75-g meropenem for 30 min every 8 h. The primary objective is the probabilities of PK/PD target (100% fT > 4 × MIC) achieved in the septic patients who receive CRRT in the first 48 h. Secondary objectives include clinical cure rate, bacterial clearance rate, sepsis-related mortality and all-cause mortality, the total dose of meropenem, duration of meropenem treatment, duration of CRRT, Sequential Organ Failure Assessment (SOFA), C-reactive protein levels, procalcitonin levels, white blood cell count, and safety.DiscussionThis trial will assess for the first time whether administration of a loading dose of meropenem results in a more likely achievement of the PK/PD target and better therapeutic results in the patients with sepsis receiving CRRT. Since CRRT is an important therapeutic strategy for sepsis patients with hemodynamic instability, the results from this trial may help to provide evidence-based therapy for septic patients receiving CRRT.Trial registrationChinese Clinical Trials Registry, ChiCTR2000032865. Registered on 13 May 2020, http://www.chictr.org.cn/showproj.aspx?proj=53616.

Influence of definitive and interim restorative materials and surface finishing on the scanning accuracy of an intraoral scanner

PurposeTo analyze the influence of the restorative material type (definitive and interim) and its surface treatment (polished or glazed) on the scanning accuracy of an intraoral scanner. Material and methodsA mandibular dental typodont containing 3 typodont teeth (left second premolar and left first and second molars) was used for testing. Ten groups were created based on the crown material: typodont tooth (control group), gold (G group), zirconia (Z group), lithium disilicate (LD group), hybrid ceramic (HC group), composite resin (CR group), conventional PMMA (CNV-PMMA group), bis-acryl composite resin (CNV-BA group), milled PMMA (M-PMMA group), and additively manufactured bis-acryl-based polymer (AM-BA group). Except the G group, groups were subdivided into polished (P subgroups) or glazed (G subgroups). Each specimen was digitized by using an extraoral scanner (D1000; 3Shape A/G) and an intraoral scanner (TRIOS 4; 3Shape). Each reference scan was used to measure the discrepancy with the corresponding 15 intraoral scans by calculating the root mean square (RMS) error (Geomagic; 3D Systems). The Welch ANOVA and Games-Howell tests were selected to examine trueness (α=0.05). The F-test with Bonferroni correction was used to evaluate precision. ResultsSignificant trueness and precision differences were found (P<.001). The G-P subgroup had the lowest trueness values, while the CNV-PMMA-P, M-PMMA-P, and AM-BA-P subgroups had the highest trueness values. Significant RMS mean discrepancies were computed when comparing polished and glazed specimens fabricated with the same material (P<.001). The CNV-PMMA-G subgroup had the lowest precision values, while the CNV-BA-P subgroup had the highest precision values (P<.001). ConclusionsThe type and surface finishing of the restorative materials tested influenced the scanning accuracy of the IOS tested. The lowest trueness values were found in the high noble alloy specimens, while the highest trueness values were measured in conventional and milled PMMA and additively manufactured bis-acryl-based polymer polished specimens. Except for zirconia crowns, higher trueness values were found in polished specimens when compared with glazed crowns. The CNV-PMMA-G subgroup had the lowest precision values, while the highest precision values were measured in the CNV-BA-P subgroup. CLINICAL SIGNIFICANCEDefinitive and interim materials tested decrease intraoral scanning accuracy. Furthermore, polishing instead of glazing definitive and interim material assessed might be preferable to maximize intraoral scanning accuracy.

Lower versus higher starting tacrolimus dosing in kidney transplant recipients.

Achieving therapeutic tacrolimus levels is an essential component of balancing immunosuppression in kidney transplantation. At our institution, the starting tacrolimus dose was reduced from .075 mg/kg BD (higher dose [HD]) to .050 mg/kg BD (lower dose [LD]), to better achieve our target level of 6–10 μg/L in the early posttransplant period. Kidney transplant recipients (KTRs) transplanted 1‐year before (HD: n = 64) and after (LD: n = 63) the starting dose reduction were retrospectively compared. Achieved tacrolimus levels were significantly lower in the LD group during the first 14 days posttransplant, but not at day 21 or day 28. A higher proportion of LD KTRs achieved therapeutic levels (day 1–3: 36.1% vs. 18.8%; day 4–7: 50.8% vs. 40.6%, day 8–14: 83.6% vs. 71.7%), while the HD KTRs were more likely to have supratherapeutic levels. Tacrolimus dose was significantly lower on day 5 compared to day 0 in the HD group but similar in the LD group. Rates of delayed graft function, posttransplant diabetes, and treated rejection at 6 months and graft outcomes at 3 years were all similar. Lowering the starting tacrolimus dose increased the proportion of KTRs achieving therapeutic range and minimized dose changes early posttransplant without an impact on clinical outcomes.