Two-week Treatment Research Articles

Dynamics of platelet hemostasis indicators in different blood pressure profiles in elderly and middle-aged hypertensive patients under combined antihypertensive treatment

In addition to achieving target blood pressure levels an equally important task is risk stratification of probable thrombotic complications in arterial hypertension in the elderly. This is reflected in the updated recommendations for implementing elderly patients with arterial hypertension. Studies of platelet activation in patients with arterial hypertension provide the implementation basis of new approaches to pharmacological prevention of complications associated with increased thrombus formation. Antihypertensive drugs have different effects on hemostasis parameters, which requires further study. Thus, this article attempts to systematise and analyse some literature data on the standard antihypertensive drugs effect. The purpose was to conduct a comparative assessment of the platelet hemostasis parameters dynamics in elderly and middle-aged hypertensive patients depending on the daily rhythm of blood pressure under combined antihypertensive treatment with enalapril and amlodipine. The work is based on the special examination of 93 elderly and 127 middle-aged hypertensive patients who were on inpatient two-week treatment. The state of spontaneous and induced platelet aggregation was determined. When analysing induced platelet aggregation a significant prolongation of time of maximal aggregation from 3.3 ± 0.9 min to 9.3 ± 0.4 min in elderly hypertensive patients with amlodipine treatment is noteworthy (p<0.05). Analysing the indicators of spontaneous platelet aggregation in elderly and middle-aged patients under combined treatment of the dipper group we established a significant decrease (p <0.05) in the amplitude of spontaneous platelet aggregation by 32% and 28%. The analysis of indicators of spontaneous aggregation of platelets showed that in the group of elderly patients of the non-dipper group, spontaneous aggregation slowed down according to the slope by 66.7% (p<0.05). Analysing the indicators of induced platelet aggregation in the elderly dipper group aggregation slope with ADP-inducer was slowed down by 37.6% (p<0.05). With insufficient nocturnal blood pressure reduction in middle-aged hypertensive patients aggregation amplitude during ADP-initiated platelet aggregation significantly decreased by 29.9% (p <0.05). There was a significant acceleration of the aggregation slope by 63.6% (p <0.05) during adrenaline-stimulated aggregation. It can be concluded that the effect of combined treatment with enalapril and amlodipine on platelet hemostasis in elderly patients depends on the initial blood pressure profile. Thus, all this confirms the reduction of thrombogenic potential in elderly patients in the dipper group under combined antihypertensive treatment with enalapril and amlodipine. Among elderly hypertensive patients according to blood pressure profile, the non-dipper group should be considered due to their involvement in a high-risk group for thrombotic events. Keywords: arterial hypertension; essential hypertension; platelet aggregation; elderly and middle-aged hypertensive patients

Multimodal ultrasound assessment of the injection therapy in lateral epicondylitis: a retrospective observational study

BackgroundAt present, there is a dearth of objective methodologies for assessing the effectiveness of treatments for Lateral Epicondylitis (LE). This study examined 73 patients suffering from tennis elbow using a multimodal ultrasound approach and investigated the correlation between pertinent indicators and clinical scores.Methods73 patients diagnosed with unilateral tennis elbow by interventional ultrasound at Zhejiang Rongjun Hospital were included in the study. Ultrasound data of the extensor tendon, as well as VAS (Visual Analog Scale) and MEPS (Mayo Elbow Performance Score) for the affected elbow, were collected before and after a two-week treatment period. The study aimed to compare the alterations in gray-scale ultrasound features, hemodynamic parameters, and elastography scores pre- and post-treatment, and to analyze the correlation between the changes in ultrasound parameters and pain scores.ResultsFollowing treatment, the effective group exhibited a reduction in both the blood flow grade and elastic score of the extensor tendon. Additionally, the extensor tendon thickness in the effective group diminished to a greater extent than in the ineffective group. The effective group also experienced a higher rate of decrease in blood flow grade and a more pronounced increase in Resistive Index (RI) compared to the ineffective group. The reduction in tendon thickness, the increase in RI, and the improvement in elastic score were all positively correlated with the reduction in VAS scores. Notably, the increase in RI demonstrated the strongest correlation with the decrease in VAS scores.ConclusionsMultimodal ultrasound plays a significant role in the clinical assessment of treatment outcomes for Lateral Epicondylitis.

Longitudinal study on the effects of a synbiotic supplement to Atlantic salmon diets on performance, gut microbiota and immune responses during antibiotic treatment and subsequent recovery

BackgroundAntibiotic use has undesirable side-effects on the host, including perturbations of gut microbiota, immunity, and health. Mammalian studies have demonstrated that concomitant/post antibiotic use of pro-, pre-, and synbiotics could re-establish gut microbiota and prevent detrimental host effects. However, studies evaluating similar effects in fish are scanty. This study evaluated the effects of dietary supplementation with a synbiotic mixture on the post-smolt Atlantic salmon gut microbiota, growth performance, and health during antibiotic treatment and subsequent recovery. Fish in five tanks each were fed either a commercial control diet or a synbiotic diet containing Pediococcus acidilactici and fructo-oligosaccharides, for 6 weeks (S1). Then, fish in three tanks per treatment were fed with medicated diets, containing 3500 ppm florfenicol coated onto the control or synbiotic diets, for 2 weeks (S2) and refed with the respective nonmedicated diets for another 3 (S3) and 5 (S4) weeks of recovery period. The fish not subjected to medication were fed the control or synbiotic diets throughout the experimental period. Samples were collected at S1-S4 from both the nonmedicated and medicated fish.ResultsFlorfenicol decreased the feed intake in control group. It reduced the growth rate in both control and synbiotic groups with lesser reduction in synbiotic group. Florfenicol did not significantly affect observed taxa and Shannon indexes. Bacterial composition before and after medication clustered distinctly in control and clustered together in synbiotic groups. Lactobacillus dominated in control while Lactobacillus and Pediococcus dominated in synbiotic group during medication and recovery. Florfenicol did not significantly influence the immune or stress response marker gene expressions, though the expression patterns differed between diet groups. Florfenicol did not cause inflammation in the distal intestine or change hepatosomatic index.ConclusionsThis study highlighted the negative impact of a two-week florfenicol treatment on feed intake and growth performance in Atlantic salmon, with moderate effects on gut microbiota and gene expression. Concomitant use of a synbiotic diet helped to maintain the gut microbial composition and influenced the performance positively and immune gene expressions differently during medication. This study indicates the importance of nutritional interventions through synbiotic supplementation as a possible strategy for managing Atlantic salmon during antibiotic treatment.

Esculetin improves inflammation of the kidney via gene expression against doxorubicin-induced nephrotoxicity in rats: In vivo and in silico studies

Examining the preventive potential and underlying mechanisms of Esculetin (E) in mitigating kidney damage induced by doxorubicin (DOX) in rats, this study also assessed the nephrotoxic effects when DOX was administered in combination with E. The experimental protocol involved a two-week treatment period with cumulative DOX doses (5 mg/kg), daily administration of E (50 mg/kg and 100 mg/kg), and the combined treatment of DOX with E50 and E100. The study delved into the gene expression levels of key regulatory factors associated with inflammation and apoptosis. Molecular analyses revealed that E effectively ameliorated the dysregulations induced by DOX at gene levels in the kidneys. Notably, the concurrent administration of E was observed to counteract the alterations in gene expressions induced by DOX significantly. E treatment decreased serum creatinine, albumin, and urea nitrogen levels in DOX-induced kidney damage. Furthermore, the docking analysis revealed that pi–cation, pi–pi stacking, and hydrogen bond interactions were the predominant molecular interactions within the binding pockets of these genes. This suggests that the nephroprotection provided by E involves the remodeling of inflammation and apoptosis pathways affected by DOX.

Treatment with oclacitinib, a Janus kinase inhibitor, down-regulates and up-regulates CD25 and Foxp3 expression, respectively, in peripheral blood T cells of dogs with atopic dermatitis

BackgroundOclacitinib (OCL), a Janus kinase inhibitor, is a novel immunomodulatory/immunosuppressive agent which is an approved as the first-line treatment for atopic dermatitis (AD) in dogs. The aim of the study was to investigate the effects of OCL on CD4+ and CD8+ T cells and their selected subsets under clinical conditions, i.e. in dogs suffering from AD, in terms of both safety and immune mechanisms underlying its therapeutic actions. Eight dogs were treated for 28 days with OCL at the recommended dose. Blood samples were taken at day 0, 7, 14 and 28.ResultsThe study showed that the mean percentage and absolute count of CD4+ and CD8+ T cells on the 14th and 28th day of the treatment with OCL did not differ from the corresponding baseline values, i.e. those before the treatment. On the 7th day of the treatment, the mean absolute count of CD4+ T cells and the mean percentage and absolute count of CD8+ T cells were significantly increased. The research found that on the 14th day of the treatment, the mean percentage and absolute count of CD25+CD4+ and CD25+CD8+ T cells were significantly decreased; the reduction in the percentage of CD25+CD4+ T cells persisted on 28th day of the treatment. A two-week treatment with OCL resulted in an increase in the mean percentage of Foxp3+CD4+ T cells, and this effect was sustained at the last time point. The treatment with OCL decreased the eosinophil level but does not affect the absolute counts of basophils, monocytes and neutrophils.ConclusionsThe findings of the study strongly suggest that: (a) in terms of the impact of OCL on the number of PB CD4+ and CD8+ T cells, monthly treatment with the drug should be considered as a relatively safe; (b) the eosinophil-reducing effect and the down-regulation of the AD up-regulated CD25 expression on CD4+ Teff cells may constitute significant elements of the mechanism of action underlying the therapeutic effects of the drug in the treatment of canine AD; (c) the generation of inducible Foxp3-expressing CD4+ regulatory T cells - resulting in the shift of the CD4+ Treg cell (i.e. Foxp3+CD4+)/activated Teff (i.e. CD25+CD4+) cell balance toward an increased proportion of Treg cells - may be considered as additional mechanism involved in producing the immunomodulatory/immunosuppressive properties of OCL.

Aging by autodigestion.

The mechanism that triggers the progressive dysregulation of cell functions, inflammation, and breakdown of tissues during aging is currently unknown. We propose here a previously unknown mechanism due to tissue autodigestion by the digestive enzymes. After synthesis in the pancreas, these powerful enzymes are activated and transported inside the lumen of the small intestine to which they are compartmentalized by the mucin/epithelial barrier. We hypothesize that this barrier leaks active digestive enzymes (e.g. during meals) and leads to their accumulation in tissues outside the gastrointestinal tract. Using immune-histochemistry we provide evidence in young (4 months) and old (24 months) rats for significant accumulation of pancreatic trypsin, elastase, lipase, and amylase in peripheral organs, including liver, lung, heart, kidney, brain, and skin. The mucin layer density on the small intestine barrier is attenuated in the old and trypsin leaks across the tip region of intestinal villi with depleted mucin. The accumulation of digestive enzymes is accompanied in the same tissues of the old by damage to collagen, as detected with collagen fragment hybridizing peptides. We provide evidence that the hyperglycemia in the old is accompanied by proteolytic cleavage of the extracellular domain of the insulin receptor. Blockade of pancreatic trypsin in the old by a two-week oral treatment with a serine protease inhibitor (tranexamic acid) serves to significantly reduce trypsin accumulation in organs outside the intestine, collagen damage, as well as hyperglycemia and insulin receptor cleavage. These results support the hypothesis that the breakdown of tissues in aging is due to autodigestion and a side-effect of the fundamental requirement for digestion.

Nasal administration of polysaccharides-based nanocarrier combining hemoglobin and diferuloylmethane for managing diabetic kidney disease

The management of diabetic kidney disease (DKD) faces challenges stemming from intricate pathologies and suboptimal biodistributions during drug delivery. Although clinically available anti-inflammatory agents hold considerable promise for treating DKD, their therapeutic effectiveness is limited when utilized in isolation. To address this limitation, we introduced a novel self-oriented nanocarrier termed F-GCS@Hb-DIF, designed to synergistically integrate the therapeutic diferuloylmethane (DIF), the polysaccharide fucoidan/glycol chitosan (F-GCS), and phototherapeutic hemoglobin (Hb). F-GCS@Hb-DIF demonstrated the capability to autonomously navigate toward diseased renal sites and directly release drugs into the cytoplasm of target cells following intranasal administration. This self-directed drug delivery system increased the accumulation of Hb and DIF at the target site as per biodistribution data. This enhancement allowed F-GCS@Hb-DIF to adopt a synergistic approach in treating the complex pathologies of DKD during the two-week treatment period. This approach entails modulating immunity, promoting renal functional recovery with a tissue-protective effect, and alleviating renal inflammation. These results underscore the promising therapeutic potential of F-GCS@Hb-DIF in managing DKD and other degenerative diseases associated with diabetes.

Efficacy and safety of intra-articular-only meropenem after one-stage revision for treating Escherichia coli-induced periprosthetic joint infection in a rat model.

The optimum type of antibiotics and their administration route for treating Gram-negative (GN) periprosthetic joint infection (PJI) remain controversial. This study aimed to determine the GN bacterial species and antibacterial resistance rates related to clinical GN-PJI, and to determine the efficacy and safety of intra-articular (IA) antibiotic injection after one-stage revision in a GN pathogen-induced PJI rat model of total knee arthroplasty. A total of 36 consecutive PJI patients who had been infected with GN bacteria between February 2015 and December 2021 were retrospectively recruited in order to analyze the GN bacterial species involvement and antibacterial resistance rates. Antibiotic susceptibility assays of the GN bacterial species were performed to screen for the most sensitive antibiotic, which was then used to treat the most common GN pathogen-induced PJI rat model. The rats were randomized either to a PJI control group or to three meropenem groups (intraperitoneal (IP), IA, and IP + IA groups). After two weeks of treatment, infection control level, the side effects, and the volume of antibiotic use were evaluated. Escherichia coli was the most common pathogen in GN-PJI, and meropenem was the most sensitive antibiotic. Serum inflammatory markers, weightbearing activity, and Rissing score were significantly improved by meropenem, especially in the IA and IP + IA groups ( p < 0.05). Meropenem in the IA group eradicated E. coli from soft-tissue, bone, and prosthetic surfaces, with the same effect as in the IP + IA group. Radiological results revealed that IA and IP + IA meropenem were effective at relieving bone damage. Haematoxylin and eosin staining also showed that IA and IP + IA meropenem improved synovial inflammation and bone destruction. No pathological changes in the main organs or abnormal serum markers were observed in any of the meropenem-treated rats. The IA group required the lowest amount of meropenem, followed by the IP and IP + IA groups. IA-only meropenem with a two-week treatment course was effective and safe for PJI control following one-stage revision in a rat model, with less meropenem use.

Late development of OCD-like phenotypes in Dlgap1 knockout mice

RationaleDespite variants in the Dlgap1 gene having the two lowest p-value in a genome-wide association study of obsessive compulsive disorder (OCD), previous studies reported the absence of OCD-like phenotypes in Dlgap1 knockout (KO) mice. Since these studies observed behavioral phenotypes only for a short period, development of OCD-like phenotypes in these mice at older ages was still plausible.ObjectiveTo examine the presence or absence of development of OCD-like phenotypes in Dlgap1 KO mice and their responsiveness to fluvoxamine.Methods and resultsNewly produced Dlgap1 KO mice were observed for a year. Modified SHIRPA primary screen in 2-month-old homozygous mutant mice showed only weak signs of anxiety, stress conditions and aggression. At older ages, however, these mutant mice exhibited excessive self-grooming characterized by increased scratching which led to skin lesions. A significant sex difference was observed in this scratching behavior. The penetrance of skin lesions reached 50% at 6–7 months of age and 90% at 12 months of age. In the open-field test performed just after the appearance of these lesions, homozygous mutant mice spent significantly less time in the center, an anxiety-like behavior, than did their wild-type and heterozygous littermates, none and less than 10% of which showed skin lesions at 1 year, respectively. The skin lesions and excessive self-grooming were significantly alleviated by two-week treatment with fluvoxamine.ConclusionUsefulness of Dlgap1 KO mice as a tool for investigating the pathogenesis of OCD-like phenotypes and its translational relevance was suggested.

Abstract Tu068: Calmodulin Kinase II is a Mutation-Specific Driver of Disease in Hypertrophic Cardiomyopathy

In the heart, Ca/Calmodulin Kinase IIδ (CaMKIIδ) functions to maintain electromechanical and calcium homeostasis. Post-translational modifications (PTMs) of CaMKIIδ render its activity autonomous of Ca/CaM. In hypertrophic cardiomyopathy (HCM), increased levels of autonomous CaMKIIδ are linked to disease progression. We have shown that the pathogenic role of CaMKIIδ in HCM is mutation-specific: autonomous CaMKIIδ is elevated in cardiac troponin T (cTnT)-R92W mice, but not in cTnT-R92L mice. These results pose a clinically relevant and critical question: what is the trigger for CaMKIIδ dysregulation in HCM, such that it is only found with certain mutations? We hypothesize that CaMKIIδ dysregulation results from distinct modifications in thin filament (TF) biophysical properties altered by point mutations. cTnT-R92W TFs display faster calcium dissociation kinetics compared to wild type TFs, whereas cTnT-R92L TFs have slower dissociation kinetics, thus we propose accelerated calcium dissociation kinetics as a mutation-specific trigger of CaMKIIδ dysregulation. To test this, we will use mass spectrometry following CaMKIIδ immunoprecipitation to assess the levels of phosphorylation at Thr-287 and oxidation at Met-281/282 in mice expressing the R94H, I79N, or R92W mutations in cTnT, which exhibit differing calcium dissociation kinetics. Preliminary data shows that CaMKIIδ PTMs can be readily detected. We will also use the CaMKIIδ biosensor CaMKAR in cardiomyocytes isolated from these mice to evaluate CaMKIIδ activity. We have shown that genetic inhibition of CaMKIIδ in cTnT-R92W mice improves diastolic function and atrial remodeling. We also aim to test the efficacy of the small molecule CaMKIIδ inhibitor ruxolitinib (rux) in cTnT-R92W mice. Two-week treatment of these mice with rux improves systolic and diastolic function, and has no effect in nontransgenic controls, implicating small molecule inhibition of CaMKIIδ as a potential therapeutic option in HCM. To continue these studies, we will explore changes in calcium handling in the three mouse models to further establish potential mechanistic pathways for CaMKIIδ dysregulation in HCM and will extend rux treatment to longer timepoints to further evaluate its efficacy as an HCM therapeutic.

Efficacy and safety of elobixibat in combination with or switched from conventional treatments of chronic constipation: A retrospective observational study.

Elobixibat is a triple mode of action laxative that increases water secretion into the colon, promotes colonic motility, and reestablishes the defecation desire. This study aims to evaluate the effectivity and safety of elobixibat in chronic constipation (CC) patients refractory to conventional laxatives. A single-center retrospective observational study was conducted in refractory CC patients diagnosed according to the Rome IV criteria and received elobixibat between April 2018 and June 2022 at Osaka Saiseikai Nakatsu Hospital. Data were collected for spontaneous bowel movement (SBM), Bristol stool form scale (BSFS) scores, abdominal symptoms, and adverse events. Eligible 311 patients were selected for the analysis. Two-week Elobixibat treatment significantly increased SBM (times/week) from 2.9 ± 1.9 to 4.3 ± 1.9 (P < 0.0001). The BSFS score improved significantly from 3.2 ± 1.7 to 4.4 ± 1.4 (P < 0.0001). The percentages of patients with hard stool were decrease and that with normal stools were increase. Improvements in abdominal symptoms (sensation of incomplete bowel evacuation, straining, abdominal pain and distention, and difficulty defecating) were also significant (P < 0.05). These constipation symptoms were improved irrespective of patient characteristics or previous laxatives. The 43.9% of previous laxatives were discontinued at the start of or after starting elobixibat treatment. A few adverse events were observed, elobixibat was well tolerated. Elobixibat was effective in patients who were refractory to other laxatives, irrespective of previous therapy or patient characteristics. Elobixibat may contribute to resolving polypharmacy with single mode of action laxatives.

Is Botulinum Toxin Type A Safe for Gummy Smile Treatment in Bronchial Asthma Patients? A Case Report

Background and Aim: The increasing demand for aesthetic enhancements has led to the widespread use of Botox for various facial concerns, including gummy smiles. While its efficacy in treating gummy smiles is established, the safety profile of Botox in patients with underlying medical conditions, such as asthma, remains relatively unexplored. This case report presents a patient with asthma who underwent Botox treatment to correct excessive gingival display. The study aims to demonstrate the potential of Botox for aesthetic improvement in this patient population while emphasizing the need for further research to assess its safety profile. Results: A two-week Botox treatment course successfully eliminated the patient's gummy smile without inducing any asthma-related complications or adverse effects. Conclusion: Although this case suggests the potential of Botox for treating gummy smiles in patients with asthma, it is essential to conduct larger studies to establish its safety and efficacy. A comprehensive medical evaluation is crucial before considering Botox treatment for individuals with underlying health conditions.

Efficacy of fexuprazan compared with rebamipide in Korean patients with gastritis: A matching-adjusted indirect comparison.

Gastritis is one of the most frequently diagnosed diseases requiring medical treatment in South Korea. Fexuprazan, a novel potassium-competitive acid blocker, has been approved for treating gastritis and erosive esophagitis. Meanwhile, rebamipide is the most commonly used mucoprotective agent for acute and chronic gastritis in real-world settings in South Korea. However, there have been no studies comparing the efficacy of these two drugs yet. To compare the efficacy of fexuprazan with that of rebamipide for acute and chronic gastritis. This was a matching-adjusted indirect comparison. Individual patient data from a phase III study of fexuprazan (10 mg BID) were compared with cumulative data from two matching studies of rebamipide (100 mg TID). Erosion improvement and healing rates were compared between two weeks of fexurapan, two weeks of rebamipide, and four weeks of rebamipide. The two main outcome variables were presented as percentages, and the risk differences (RD) and 95% confidence intervals (CI) were calculated for the relative treatment effects. In the primary analysis, the erosion improvement and healing rates after a two-week treatment with fexuprazan were 64.5% and 53.2%, respectively, while a two-week treatment with rebamipide resulted in erosion improvement and healing rates of 43.6% (RD: 21.0%; 95%CI: 9.6-32.3; P < 0.01) and 35.6% (RD: 17.6%; 95%CI: 6.1-29.2; P = 0.003), respectively. In the additional analysis, the erosion improvement and healing rates for the two-week fexuprazan treatment (64.2% and 51.2%, respectively) were similar to those obtained during a four-week treatment with rebamipide (60.6%; RD: 3.6%; 95%CI: -9.8, 17.0; P = 0.600 and 53.5%; RD: -2.3%; 95%CI: -16.1, 11.5; P = 0.744, respectively). The two-week fexuprazan treatment was superior to the two-week rebamipide treatment and similar to the four-week rebamipide treatment for patients with gastritis.

Transcutaneous auricular vagus nerve stimulation improves anxiety symptoms and cortical activity during verbal fluency task in Parkinson's disease with anxiety

ObjectiveTo investigate the effect of 20/4Hz transcutaneous auricular vagus nerve stimulation (taVNS) on anxiety symptoms in Parkinson's disease (PD) and the potential neural mechanism. MethodsIn the current randomized, double-blind, sham-controlled trial, 30 PD patients with anxiety (PD-A), 30 PD patients without anxiety (PD-nA), and 30 healthy controls (HCs) were enrolled. PD-A patients were randomly (1:1) allotted to real taVNS stimulation group (RS) or sham stimulation group (SS) to explore the efficacy of a two-week treatment of taVNS to promote anxiety recovery. Simultaneously, all participants were measured activation in the bilateral prefrontal cortex during verbal fluency task (VFT) using functional near-infrared spectroscopy. ResultsPD-A patients showed significantly decreased oxyhemoglobin in the left triangle part of the inferior frontal gyrus (IFG) during VFT, which was negatively related to the severity of anxiety symptoms. After two-week treatment of taVNS, the interaction of group and time had significant effect on HAMA scores (F = 18.476, p < 0.001, η2 = 0.398). In RS group, compared with baseline, HAMA scores decreased significantly in the post-treatment and follow-up condition (both p < 0.001). Meanwhile, in RS group, HAMA scores were lower than those in SS group in the post-treatment and follow-up condition (p = 0.006, <0.001, respectively). Furthermore, the 20/4Hz taVNS remarkably ameliorated anxiety symptoms in PD patients, directly correlated with the increased activation of the left triangle part of the IFG during VFT in RS group. ConclusionOur results depicted that taVNS could ameliorate the anxiety symptoms of PD-A patients and regulated the function of the left triangle part of the IFG.

Impact of SMAASH-C, a novel nutritional supplement, on drug-seeking and toxicity in female and male rats.

Relapse to drug use after abstinence is a major challenge in treating substance use disorder. Exposure to drug-associated cues during abstinence can trigger intense craving and precipitate relapse. New and more effective anti-relapse interventions are critically needed, particularly for cocaine use disorder since no effective pharmacological intervention is available. We discovered that a nutritional supplement we developed as part of a nutritional approach for managing patients with substance use disorder reduced patient reports of drug craving and relapse. The goal of this study was to determine the efficacy of this supplement, SMAASH-C, at reducing drug-craving/relapse vulnerability in males and females in rat models with cocaine. Effects were determined following extended-access cocaine self-administration (24-hr/day for 10 days) and a two-week treatment regimen at a moderate and moderate-to-high dose (0.4 and 0.8 g/kg/day) as well as a 6-week regimen at a moderate dose (0.4 g/kg/day; Experiment 2). We also determined its efficacy to offset serum markers of organ toxicity in response to chronic cocaine self-administration and abstinence (aspartate transaminase, alanine transaminase, amylase; urea nitrogen). In females, both the 2- and 6-week SMAASH-C treatment regimens reduced cocaine-seeking (extinction or cue-induced reinstatement), particularly when drug-seeking was heightened (e.g., during estrus). Despite a lack of efficacy to reduce drug-seeking in males, SMAASH-C treatment normalized cocaine/abstinence-induced increases in serum levels of aspartate transaminase and amylase, which are markers of liver and pancreatic toxicity respectively. Thus, the beneficial effects of oral SMAASH-C treatment over abstinence following chronic cocaine self-administration appears to be sex-specific.

Longitudinal changes in the PTSD symptom network following trauma-focused treatment in military populations: Identifying central symptoms and the role of military sexual trauma

Posttraumatic stress disorder (PTSD) is a debilitating condition affecting military populations, with a higher prevalence compared to the general population. Despite the development of first-line trauma-focused treatments such as Cognitive Processing Therapy (CPT) and Prolonged Exposure Therapy (PE), a significant proportion of patients continue to experience persistent PTSD symptoms following treatment. This study utilized network analysis to explore the PTSD symptom network's dynamics pre- and post- trauma-focused treatment and investigated the role of military sexual trauma (MST) history in shaping the network. Network analysis is a novel approach that can guide treatment target areas. The sample was comprised of 1648 service members and veterans who participated in a two-week intensive PTSD treatment program, which included completion of evidenced-based individual therapy as well as skill-building focused group therapy. PTSD severity was assessed using the PTSD Checklist for DSM-5 at baseline and post-treatment. Network analyses revealed strong connections within symptom clusters, with negative emotions emerging as one of the most central symptoms. Interestingly, the symptom network's overall structure remained stable following treatment, whereas global strength significantly increased. MST history did not significantly impact the network's structure or its change relative to treatment. Future research should further examine whether targeting negative emotions optimizes PTSD treatment outcomes for military populations.

Bu zhong Yiqi Decoction ameliorates mild cognitive impairment by improving mitochondrial oxidative stress damage via the SIRT3/MnSOD/OGG1 pathway

Ethnopharmacological relevanceBu-Zhong-Yi-Qi Decoction(BZYQD) is a traditional formula commonly used in China, known for its effects in tonifying Qi and raising Yang. It can relieve symptoms of cognitive impairment such as forgetfulness and lack of concentration caused by qi deficiency, which is common in aging and debilitating. However, much of the current research on BZYQD has been focused on its impact on the digestive system, leaving its molecular mechanisms in improving cognitive function largely unexplored. Aim of the studyCognitive decline in the aging central nervous system is intrinsically linked to oxidative damage. This study aims to investigate the therapeutic mechanism of BZYQD in treating mild cognitive impairment caused by qi deficiency, particularly through repair of mitochondrial oxidative damage. Materials and methodsA rat model of mild cognitive impairment (MCI) was established by administering reserpine subcutaneously for two weeks, followed by a two-week treatment with BZYQD/GBE. In vitro experiments were conducted to assess the effects of BZYQD on neuronal cells using a H2O2-induced oxidative damage model in PC12 cells. The open field test and the Morris water maze test evaluated the cognitive and learning memory abilities of the rats. HE staining and TEM were employed to observe morphological changes in the hippocampus and its mitochondria. Mitochondrial activity, ATP levels, and cellular viability were measured using assay kits. Protein expression in the SIRT3/MnSOD/OGG1 pathway was analyzed in tissues and cells through western blotting. Levels of 8-OH-dG in mitochondria extracted from tissues and cells were quantified using ELISA. Mitochondrial morphology in PC12 cells was visualized using Mito Red, and mitochondrial membrane potential was assessed using the JC-1 kit. ResultsBZYQD treatment significantly improved cognitive decline caused by reserpine in rats, as well as enhanced mitochondrial morphology and function in the hippocampus. Our findings indicate that BZYQD mitigates mtDNA oxidative damage in rats by modulating the SIRT3/MnSOD/OGG1 pathway. In PC12 cells, BZYQD reduced oxidative damage to mitochondria and mtDNA in H2O2-induced conditions and was associated with changes in the SIRT3/MnSOD/OGG1 pathway. ConclusionBZYQD effectively counteracts reserpine-induced mild cognitive impairment and ameliorates mitochondrial oxidative stress damage through the SIRT3/MnSOD/OGG1 pathway.

BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Transcranial alternating current stimulation improves quality of life in Parkinson’s disease: study protocol for a randomized, double-blind, controlled trial

BackgroundThe neural cells in the brains of patients with Parkinson’s disease (PWP) display aberrant synchronized oscillatory activity within the beta frequency range. Additionally, enhanced gamma oscillations may serve as a compensatory mechanism for motor inhibition mediated by beta activity and also reinstate plasticity in the primary motor cortex affected by Parkinson’s disease. Transcranial alternating current stimulation (tACS) can synchronize endogenous oscillations with exogenous rhythms, thereby modulating cortical activity. The objective of this study is to investigate whether the addition of tACS to multidisciplinary intensive rehabilitation treatment (MIRT) can improve symptoms of PWP so as to enhance the quality of life in individuals with Parkinson’s disease based on the central-peripheral-central theory.MethodsThe present study was a randomized, double-blind trial that enrolled 60 individuals with Parkinson’s disease aged between 45 and 70 years, who had Hoehn-Yahr scale scores ranging from 1 to 3. Participants were randomly assigned in a 1:1 ratio to either the tACS + MIRT group or the sham-tACS + MIRT group. The trial consisted of a two-week double-blind treatment period followed by a 24-week follow-up period, resulting in a total duration of twenty-six weeks. The primary outcome measured the change in PDQ-39 scores from baseline (T0) to 4 weeks (T2), 12 weeks (T3), and 24 weeks (T4) after completion of the intervention. The secondary outcome assessed changes in MDS-UPDRS III scores at T0, the end of intervention (T1), T2, T3, and T4. Additional clinical assessments and mechanistic studies were conducted as tertiary outcomes.DiscussionThe objective of this study is to demonstrate that tACS can enhance overall functionality and improve quality of life in PWP, based on the framework of MIRT. Additionally, it seeks to establish a potential correlation between these therapeutic effects and neuroplasticity alterations in relevant brain regions. The efficacy of tACS will be assessed during the follow-up period in order to optimize neuroplasticity and enhance its potential impact on rehabilitation efficiency for PWP.Trial registrationChinese Clinical Trial Registry ChiCTR2300071969. Registered on 30 May 2023.

Urogenital Myiasis Caused by Psychoda albipennis Larvae (Diptera: Psychodidae) in Ahvaz, South Western Iran: A Case Report

Urogenital myiasis is a rare parasitic infestation caused by larvae Psychoda albipennis. The settlement, feeding, and activity of larvae in urogenital tracts lead to disorders of the urinary and reproductive systems. This study presents a 36-year-old man with the main complaint of dysuria, hematuria, urethral discharge, and abdominal flank pain. He observed some black-grayish-colored mobile particles in his urine three times over eight months period. He was referred to the urology outpatient clinic and received anti-cystitis and/or urethritis treatment. But his symptoms did not improve and observed some larvae in his urine. After investigations of his urine under the light microscope, some alive, stirring, and hairy larvae (approximately 1 cm in length) were identified as the fourth-stage larvae of the moth fly, Psychoda Albipennis based on morphological characteristics. Human urogenital myiasis caused by Psychoda Albipennis is an infrequent infection disease in Iran. It seems that urinating in poor hygiene environments, sleeping without a blanket in traveling to the countryside on the banks of the Dez River, in the north of Khuzestan province, and urination in unsanitary toilets were the main risk factors of urogenital myiasis inrecent case. The use of appropriate antiseptic medication, and drinking plenty of water improved patient complaints following the two-week treatment period. The urogenital myiasis is an uncommon occurrence and comprises only 0.7% of all cases of human myiasis based on a few publication reports in Iran and the world. It`s the first report of urogenital myiasis caused by P. albipennis from Khuzestan province, South Western Iran.