Expression analysis showed that LlPGRPs of the common periwinkle were uninvolved in the immune response to infection with trematode Himasthla elongata though they might act in antibacterial defense.

Traumatic digit amputations can result in significant impairment. Optimal surgical treatment is unclear for certain digits in various amputation patterns. Our aim was to compare the contribution of revision amputation vs replantation for each particular digit to functional outcomes.

Prospective cohort study at three tertiary hospitals was conducted in China. Eligible participants were 3192 patients with traumatic digit amputations enrolled from January 1, 2014, to January 1, 2018. The primary outcome was Michigan Hand Outcomes Questionnaire (MHQ) scores 2 years after initial surgery. Secondary outcome was score on the Disabilities of the Arm, Shoulder, and Hand (DASH).

Of 3192 enrolled patients, 2890 completed the study. Main-effect linear regression showed that participants with replantation of thumb, index, long, and ring (proximal to the proximal interphalangeal [PIP] joint) fingers had significantly better MHQ scores compared to participants with the corresponding finger revision amputation. DASH re finger-finger interactions.

Replantation of the thumb, index, long, and ring (proximal to PIP joint) fingers is preferable to revision amputation, regardless of amputation pattern. Replantation of the ring finger amputated distal to PIP was beneficial only when the thumb or long finger was amputated proximal to IP/PIP joint. Replantation or revision amputation of the small finger was indistinguishable in terms of functional outcome. Future investigations and clinical decisions should take into account the role of finger-finger interactions.

COVID-19 infection is associated with a higher mortality rate in surgical patients, but surgical risk scores have not been validated in the emergency setting. We aimed to study the capacity for postoperative mortality prediction of the P-POSSUM score in COVID-19-positive patients submitted to emergency general and digestive surgery.

Consecutive patients undergoing emergency general and digestive surgery from March to June 2020, and from March to June 2019 in 25 Spanish hospitals were included in a retrospective cohort study.

30-day mortality. P-POSSUM discrimination was quantified by the area under the curve (AUC) of ROC curves; calibration was assessed by linear regression slope (β estimator); and sensitivity and specificity were expressed as percentage and 95% confidence interval (CI).

4988 patients were included 177 COVID-19-positive; 2011 intra-pandemic COVID-19-negative; and 2800 pre-pandemic. COVID-19-positive patients were older, with higher surgical risk, more advanced pathologies, and higher P-POSSUM values (1.79% vs. 1.09%, p<0.001, in both the COVID-19-negative and control cohort). 30-day mortality in the COVID-19-positive, intra-pandemic COVID-19-negative and pre-pandemic cohorts were 12.9%, 4.6%, and 3.2%. The P-POSSUM predictive values in the three cohorts were, respectively AUC 0.88 (95% CI 0.81-0.95), 0.89 (95% CI 0.87-0.92), and 0.91 (95% CI 0.88-0.93); β value 0.97 (95% CI 0.74-1.2), 0.99 (95% CI 0.82-1.16), and 0.78 (95% CI 0.74-0.82); sensitivity 83% (95% CI 61-95), 91% (95% CI 84-96), and 89% (95% CI 80-94); and specificity 81% (95% CI 74-87), 76% (95% CI 74-78), and 80% (95% CI 79-82).

The P-POSSUM score showed a good predictive capacity for postoperative mortality in COVID-19-positive patients submitted to emergency general and digestive surgery.

The P-POSSUM score showed a good predictive capacity for postoperative mortality in COVID-19-positive patients submitted to emergency general and digestive surgery.

Strengthening The Reporting Of Cohort Studies in Surgery (STROCSS) guidelines were developed in 2017 in order to improve the reporting quality of observational studies in surgery and updated in 2019. In order to maintain relevance and continue upholding good reporting quality among observational studies in surgery, we aimed to update STROCSS 2019 guidelines.

A STROCSS 2021 steering group was formed to come up with proposals to update STROCSS 2019 guidelines. An expert panel of researchers assessed these proposals and judged whether they should become part of STROCSS 2021 guidelines or not, through a Delphi consensus exercise.

42 people (89%) completed the DELPHI survey and hence participated in the development of STROCSS 2021 guidelines. All items received a score between 7 and 9 by greater than 70% of the participants, indicating a high level of agreement among the DELPHI group members with the proposed changes to all the items.

We present updated STROCSS 2021 guidelines to ensure ongoing good reporting quality among observational studies in surgery.

We present updated STROCSS 2021 guidelines to ensure ongoing good reporting quality among observational studies in surgery.

Although both vitamin D deficiency and obesity are highly prevalent in the UAE, the role of vitamin D metabolites in mediating obesity-related adverse health effects is not clear. We aimed to assess the role of vitamin D metabolites as potential mediators in the association between obesity, inflammation and metabolic risk factors.

277 participants who were part of a randomized controlled trial had their assessment that included clinical, anthropometric and physical activity data at baseline and at 6 months. Blood and urine samples were taken for measurements of serum 25(OH)D, 25(OH)D metabolites including 25(OH)D3), 25(OH)D2), 1,25(OH)2D3, 3-Epi-D3), metabolic and inflammatory markers and related biochemical variables. Multiple regression analysis used to assess the role of 25(OH)D metabolites in mediating the effect of increasing body mass index (BMI) on inflammation and metabolic risk factors.

Overall, 277 participants with complete 6 months follow up with a mean (±SD) age of 41 ± 12 and 204 (74%) femlites in mediating the effect of BMI on inflammatory or metabolic risk factors.Aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, first appears in lungfish, which are lobe-finned fish that are forerunners of terrestrial vertebrates. Aldosterone activation of the MR regulates internal homeostasis of water, sodium and potassium, which was critical in the conquest of land by vertebrates. We studied transcriptional activation of the slender African lungfish MR by aldosterone, other corticosteroids and progesterone and find that aldosterone, 11-deoxycorticosterone, 11-deoxycortisol and progesterone have half-maximal responses (EC50 s) below 1 nM and are potential physiological mineralocorticoids. In contrast, EC50 s for corticosterone and cortisol were 23 nM and 66 nM, respectively. Unexpectedly, truncated lungfish MR, consisting of the DNA-binding, hinge and steroid-binding domains, had a stronger response to corticosteroids and progesterone than full-length lungfish MR, indicating that the N-terminal domain represses steroid activation of lungfish MR, unlike human MR in which the N-terminal domain contains an activation function. BLAST searches of GenBank did not retrieve a GR ortholog, leading us to test dexamethasone and triamcinolone for activation of lungfish MR. At 10 nM, both synthetic glucocorticoids are about 4-fold stronger than 10 nM aldosterone in activating full-length lungfish MR, leading us to propose that lungfish MR also functions as a GR.Vitamin D3 (VD3) deficiency has been associated with increased risk for cirrhosis and hepatocellular carcinoma, a highly incident malignant neoplasia worldwide. On the other hand, VD3 supplementation has shown some beneficial effects in clinical studies and rodent models of chronic liver disease. However, preventive effects of dietary VD3 supplementation in cirrhosis-associated hepatocarcinogenesis is still unknow. To investigate this purpose, male Wistar rats submitted to a combined diethylnitrosamine- and thioacetamide-induced model were concomitantly supplemented with VD3 (5,000 and 10,000 IU/kg diet) for 25 weeks. Liver samples were collected for histological, biochemical and molecular analysis. Serum samples were used to measure 25-hydroxyvitamin D [25(OH)D] and alanine aminotransferase levels. Both VD3 interventions decreased hepatic collagen deposition and pro-inflammatory p65 protein levels, while increased hepatic antioxidant catalase and glutathione peroxidase activities and serum 25(OH)D, without a clear dose-response effect. Nonetheless, only the highest concentration of VD3 increased hepatic protein levels of VD receptor, while decreased the number of large preneoplastic glutathione-S-transferase- (>0.5 mm²) and keratin 8/18-positive lesions, as well the multiplicity of hepatocellular adenomas. Moreover, this intervention increased hepatic antioxidant Nrf2 protein levels and glutathione-S-transferase activity. In summary, dietary VD3 supplementation – in special the highest intervention – showed antifibrotic and antineoplastic properties in chemically-induced cirrhosis-associated hepatocarcinogenesis. The positive modulation of Nrf2 antioxidant axis may be mechanistically involved with these beneficial effects, and may guide future clinical studies.Spinal cord injury in fish produces fibrous scar, but spontaneous axonal regeneration beyond the scar sometimes occurs. A previous study revealed that regenerating axons enter the scar through tubular structures with laminin, and that an increased number of axons within the tube is coincident with enlargement of the tube diameter and reduction of the fibrous scar area. The present study investigated the expression of matrix metalloproteinases (MMPs) that might play a role in the degradation of the extracellular matrix in fibrous scar tissue and in the remodeling of tubular structures. Spinal hemisection produced fibrous scar tissue in the lesion center, surrounded by nervous tissue. Two weeks after spinal lesioning, MMP-9 was expressed in some regenerating axons in the fibrous scar tissue. MMP-14 was expressed in the regenerating axons, as well as in glial processes in the fibrous scar tissue. MMP-2 was suggested to be expressed in mast cells in the fibrous scar. The mast cells were in contact with fibroblasts, and in close proximity to the basement membrane of tubular structures surrounding the regenerating axons. The present findings suggest that several MMPs are involved in axon regenerating processes following spinal cord injury in goldfish. MMP-9 and MMP-14 expressed in the regenerating axons might degrade extracellular matrix and support axonal growth deep into the fibrous scar tissue. MMP-14 expressed in glial cells and MMP-2 expressed in mast cells might also provide a beneficial environment for axonal regeneration, leading to successful motor recovery.

Dilated cardiomyopathy (DCM) is a well described entity for heart failure (HF) with reduced left ventricular ejection fraction (LVEF). Recently, drugs and other substance of abuse have been recognised as potential triggers for DCM. The aim of this study was to assess the survival in patients ≤ 65 years of age with toxic cardiomyopathy (TCM). Left ventricular remodelling and the potential usefulness of left ventricular assist devices (LVADs) was also assessed.

This was a single-centre retrospective study from January 2003 to August 2019 of 553 patients ≤ 65 years old with LVEF < 40% at a tertiary-care cardiology centre.

A total of 201 patients (36%) had a diagnosis of idiopathic DCM. Further analysis identified 38 patients (19%) for which a TCM was the most likely etiology (amphetamine [50%], cocaine [37%], anabolic steroids [8%], and energy drinks [5%]). Despite a mean LVEF of 17 ± 8% at presentation, most patients (n= 27; 71%) had event-free survival with guideline-directed medical therapy, and 61% (n= 23) recovered an LVEF ≥ 40% after a median follow-up of 21 ± 23 months. Seven patients (18%) required an LVAD and 1 patient (3%) a transplantation. All LVADs were explanted or decommissioned after partial or complete LVEF recovery after a median support time of 11 ± 4 months.

TCM induced by substance abuse is a frequent cause of HF, accounting for almost 20% of patients ≤ 65 years of age with DCM of unknown etiology. Treatment must be tailored on an individual basis. Mechanical circulatory support demonstrated its usefulness in carefully selected patients.

TCM induced by substance abuse is a frequent cause of HF, accounting for almost 20% of patients ≤ 65 years of age with DCM of unknown etiology. Treatment must be tailored on an individual basis. Mechanical circulatory support demonstrated its usefulness in carefully selected patients.

Whether low-density lipoprotein (LDL) receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL cholesterol (LDL-C) reductions in HeFH.

A total of 615 individuals with HeFH (receptor-defective [RD] genotype n= 226; receptor-negative [RN] genotype n= 389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared with the use of linear models.

There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with an RN genotype untreated RN 7.24 (95% confidence interval [CI] 6.98-7.50) mmol/L vs RD 6.70 (95% CI 6.41-6.98) mmol/L (P= 0.0002); on-statin RN 4.50 (95% CI 4.31-4.70) vs RD 4.05 (95% CI 3.84-4.26) mmol/L (P= 0.0004). After adjustments for age, sex, smoking status, untreated LDL-C concentrations, statin type and dose, as well as the clinic where the patients were treated, the LDL-C-lowering effect of statins was significantly weaker for individuals with an RN mutation than for individuals with an RD mutation RN-31.1% (95% CI-34.7% to-27.4) vs RD-36.5% (95% CI-40.4% to-32.6%); P < 0.0001. The LDLR genotype was the strongest nonmodifiable independent correlate of statin-induced LDL-C reductions (R

= 2.3%; P= 0.0001).

The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.

The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.Due to its complexity and its ubiquitous nature the ageing process remains an enduring biological puzzle. Many molecular mechanisms and biochemical process have become synonymous with ageing. However, recent findings have pinpointed epigenetics as having a key role in ageing and healthspan. In particular age related changes to DNA methylation offer the possibility of monitoring the trajectory of biological ageing and could even be used to predict the onset of diseases such as cancer, Alzheimer’s disease and cardiovascular disease. At the molecular level emerging evidence strongly suggests the regulatory processes which govern DNA methylation are subject to intracellular stochasticity. It is challenging to fully understand the impact of stochasticity on DNA methylation levels at the molecular level experimentally. An ideal solution is to use mathematical models to capture the essence of the stochasticity and its outcomes. In this paper we present a novel stochastic model which accounts for specific methylation levels within a gene promoter. Uncertainty of the eventual site-specific methylation levels for different values of methylation age, depending on the initial methylation levels were analysed. Our model predicts the observed bistable levels in CpG islands. In addition, simulations with various levels of noise indicate that uncertainty predominantly spreads through the hypermethylated region of stability, especially for large values of input noise. A key outcome of the model is that CpG islands with high to intermediate methylation levels tend to be more susceptible to dramatic DNA methylation changes due to increasing methylation age.The oral bioavailability and efficacy of baicalein is dramatically limited by its low solubility and effect of efflux. In our study, we chose PVP-VA64 as a carrier and TPGS as a plasticizer and efflux inhibitor to prepare a solid dispersion of baicalein using hot-melt extrusion technology to improve its solubility and bioavailability. The hot-melt process and formulation were optimized, and a BAC-PVP VA64-TPGS solid dispersion (BPT-SD) was prepared. BAC exists in an amorphous or molecular state in BPT-SD. BPT-SD comprised irregular lumps and small particles without BAC or carrier characteristics. The dissolution efficiency of BPT-SD improved under sink conditions. FTIR showed a strong hydrogen bond between BAC and PVP-VA64 in BPT-SD. BPT-SD maintained good physical stability for 6 months. The apparent permeability coefficient of BAC in the Caco-2 cell model confirmed that BPT-SD had higher gastrointestinal membrane permeability. A rat pharmacokinetic study showed that BPT-SD had higher Cmax and AUC0-24h, shorter Tmax, and 2.88-fold higher bioavailability than BAC. A behavioral experiment in chronic unpredictable mild stress (CUMS) mice confirmed the antidepressant efficacy of BAC. BPT-SD reversed depression-like behavior in CUMS mice and improved BAC bioavailability. BAC preparation into a solid dispersion significantly enhanced dissolution performance and bioavailability.Formulation design for colon-specific delivery of 5-aminosalicylic acid (5-ASA) could bring some therapeutic benefits in the treatment of ulcerative colitis (UC). In the current study, a 32 full factorial design was used to predict optimum coating composed of two enteric (poly methacrylic acid, methyl methacrylates 12 and 11) and time-dependent (poly ethyl acrylate, methyl methacrylate, trimethylammonio ethyl methacrylate chloride 120.1) polymethacrylates for colon-specific delivery of 5-ASA pellets. A unique coating composition and coating level predicted by the model was applied onto either inulin-free 5-ASA pellets or inulin-bearing 5-ASA pellets and the coated pellets were examined by dissolution test in-vitro. The coated pellets were also tested in a rat model of UC and compared with the a commercially available colonic delivery system of 5-ASA. The ratio of the two enteric polymethacrylates and time-dependet polymethacrylate of 166420 w/w at a coating level of 15% was discovered as the optimum coating for delivery of 5-ASA pellets to the colon. In general, the coated pellets offered a better therapeutic outcome compared to commercially available colonic delivery system of 5-ASA and uncoated pellets in terms of colitis activity index and the colon’s tissue enzymes of MDA and GSH. It seems that the coating composed of enteric and pH-dependent polymethacrylates could tune up the rate of drug release from 5-ASA-coated pellets and trigger drug release based on pH and time.Morphine is an opioid drug often used in treating moderate to severe pain. However, morphine tolerance in patients limits its used in clinical settings. Our previous study showed that a cannabinoid type 2 (CB2) receptor agonist attenuated morphine tolerance. However, the exact mechanism by which CB2 agonists reduce morphine tolerance remains unclear. In this study, we investigated the effect of mitogen activated protein kinase (MAPK) and mitogen activated protein kinase phosphatases 1 and 3 (MKP-1 and MKP-3) on the regulation of morphine tolerance by CB2 receptor agonist. Chronic morphine treatments for 7 days reduced the protein expression of MKP-1 and MKP-3 in the spinal cord and increased the phosphorylation of p38, ERK1/2 and the level of proinflammatory mediator, such as IL-1β, IL-6 and TNF-α. Coadministration of CB2 receptor agonist AM1241 alleviated the inhibition of MKP-1 and MKP-3 by chronic morphine administration and reduced the expression of phosphorylated MAPK and proinflammatory factors. The effect of the CB2 receptor agonist on morphine-induced downregulation of MKP-1 and MKP-3 was reversed by the MKP-1 and MKP-3 antagonist triptolide. Our findings suggested that CB2 receptor agonist may induce the expression of MKP-1 and MKP-3 to promote MAPK dephosphorylation and reduce the production of downstream cytokine, thereby reducing morphine tolerance. This finding suggested that MKPs may serve as a new target for alleviating morphine tolerance.The prospect of exploiting memory reconsolidation to treat mental health disorders has received great research interest, particularly following demonstrations that the β-adrenergic receptor antagonist propranolol, which is safe for use in humans, can disrupt the reconsolidation of pavlovian conditioned fear memories. However, recent studies have failed to replicate the effects of propranolol on fear memory reconsolidation, and have questioned whether treatments based upon reconsolidation blockade would be robust enough for clinical translation. It remains possible, though, that studies reporting no effect of propranolol on memory reconsolidation could be due to a failure to engage the memory destabilisation process, which is necessary for the memory to become susceptible to disruption with amnestic agents. Demonstrating that memory destabilisation has not been engaged is challenging when only using behavioural measures, but there are molecular correlates of memory destabilisation that can be used to determine whether memory lability has been induced. Here, we attempted to replicate the classic finding that systemic administration of propranolol disrupts the reconsolidation of a pavlovian auditory fear memory. Following a failure to replicate, we manipulated the parameters of the memory reactivation session to enhance prediction error in an attempt to overcome the boundary conditions of reconsolidation. On finding no disruption of memory despite these manipulations, we examined the expression of the post-synaptic density protein Shank in the basolateral amygdala. Degradation of Shank has been shown to correlate with the induction of memory lability, but we found no effect on Shank expression, consistent with the lack of observed behavioural effects.Individuals with Highly Superior Autobiographical Memory (HSAM) provide the opportunity to investigate the neurobiological substrates of enhanced memory performance. While previous studies started to assess the neural correlates of memory retrieval in HSAM, here we assessed for the first time the intrinsic connectivity of a core memory region, the hippocampus, with the whole brain, in 8 HSAM subjects (HSAMs) and 21 controls during resting-state functional neuroimaging. We found in HSAMs vs. controls disrupted hippocampal resting-state functional connectivity (rsFC) with high-level control regions belonging to the saliency network (the anterior cingulate cortex and the left and right insulae), and to the ventral fronto-parietal attentional network (the temporo-parietal junction and the inferior frontal gyrus), also involved with salience detection. Conversely, HSAMs showed enhanced hippocampal rsFC with sensory regions along the fusiform gyrus and the inferior temporal cortex. This altered pattern of hippocampal rsFC might be interpreted as a reduced capability of HSAMs to discriminate and select salient information, with a subsequent increase in the probability to encode and consolidate sensory information irrespective of their task-relevancy. Ultimately, these findings provide evidence that HSAM might be paradoxically enabled by an altered hippocampal rsFC that bypasses regions involved with salience detection in favor of specialized sensory regions.Affective disorders (i.e. anxiety and depression) are commonly observed in patients with epilepsy and induce seizure aggravation. Animal models of epilepsy that exhibit affective disorder features are essential in developing new neuromodulatory treatments. GEAS-W rats (Generalized Epilepsy with Absence Seizures, Wistar background) are an inbred model of generalized epilepsy showing spontaneous spike-wave discharges concomitant with immobility. Transcranial Direct Current Stimulation (tDCS) is a safe non-invasive neuromodulatory therapy used to modulate dysfunctional circuitries frequently and successfully applied in affective disorders for symptom alleviation. Here we investigated anxiolytic and antidepressant effects of tDCS in GEAS-W rats and the role of corticosterone as a possible mechanism of action. GEAS-W and Wistar rats were randomly divided into control, sham-tDCS and active-tDCS groups. Both tDCS groups received 15 sessions of sham or active-tDCS (1 mA, cathode). Behavioural tests included the Open Field and Forced Swimming tests followed by corticosterone analysis. We observed a main effect of treatment and a significant treatment by strain interaction on anxiety-like and depressive-like behaviours, with active-tDCS GEAS-W rats entering the center of the open field more often and showing less immobility in the forced swimming test. Furthermore, there was a main effect of treatment on corticosterone with active-tDCS animals showing marked reduction in plasmatic levels. This study described preclinical evidence to support tDCS treatment of affective disorders in epilepsy and highlights corticosterone as a possible mechanism of action.The endocannabinoid system within the periaqueductal grey (PAG) has been implicated in fear-conditioned analgesia (FCA), the profound suppression of pain upon re-exposure to a context previously paired with an aversive stimulus. Since the endocannabinoid and nociceptive systems exhibit sexual dimorphism, the aim of the present study was to assess possible sex differences in the expression of FCA, fear in the presence of nociceptive tone, and associated sex-dependent alterations in the endocannabinoid system within the PAG. Male and female Sprague-Dawley rats received footshock (10 × 1s; 0.4 mA; every 60 s) or no-footshock in a conditioning arena and 23.5 h later received intraplantar injection of formalin (2.5%) under brief isoflourane anaesthetic into the right hind paw. Nociceptive and fear-related behaviours were assessed 30 min later. Levels of endocannabinoids, N-acylethanolamines and neurotransmitters in the PAG were assessed by LC-MS/MS and expression of endocannabinoid system-related proteins by Western immunoblotting. Male, but not female, rats exhibited robust FCA and greater expression of fear-related behaviours than females. Fear-conditioned formalin-treated males, but not females, had higher levels of N-oleoylethanolamine (OEA) and γ-aminobutyric acid (GABA) in the PAG, compared with non-fear-conditioned controls. There was no effect of fear conditioning on the levels of FAAH or CB1 receptor expression (CB1R) in the PAG of male or female formalin-treated rats. Non-fear-conditioned females had higher levels of CB1R and PPARγ expression than non-fear-conditioned male counterparts. In summary, our results provide evidence of sexual dimorphism in the expression of FCA and fear-related behaviours, and associated alterations in components of the endocannabinoid system and GABA within the PAG.

Systems for smartphone dispatch of lay responders to perform cardio-pulmonary resuscitation (CPR) and bring automated external defibrillators to out-of-hospital cardiac arrests (OHCAs) are advocated by recent international guidelines and emerging worldwide.

This study aimed to investigate the emotional responses, posttraumatic stress reactions and levels of wellbeing among smartphone-alerted lay responders dispatched to suspected OHCAs.

Lay responders were stratified by level of exposure unexposed (Exp-0), tried to reach (Exp-1), and reached the suspected OHCA (Exp-2). Participants rated their emotional responses online, at 90 minutes and at 4-6 weeks after an incident. Level of emotional response was measured in two dimensions of core affect „alertness” – from deactivation to activation, and „pleasantness” – from unpleasant to pleasant. At 4-6 weeks, WHO wellbeing index and level of posttraumatic stress (PTSD) were also rated.

Altogether, 915 (28%) unexposed and 1471 (64%) exposed responders completed the survey. Alertness was elevated in the exposed groups Exp-0 6.7 vs. Exp-1 7.3 and Exp-2 7.5, (p<0.001) and pleasantness was highest in the unexposed group 6.5, vs. Exp-1 6.3, and Exp-2 6.1, (p<0.001). Mean scores for PTSD at follow-up was below clinical cut-off, Exp-0 9.9, Exp-1 8.9 and Exp-2 8.8 (p=0.065). Wellbeing index showed no differences, Exp-0 78.0, Exp-1 78.5 and Exp-2 79.9 (p=0.596).

Smartphone dispatched lay responders rated the experience as high-energy and mainly positive. No harm to the lay responders was seen. The exposed groups had low posttraumatic stress scores and high-level general wellbeing at follow-up.

Smartphone dispatched lay responders rated the experience as high-energy and mainly positive. No harm to the lay responders was seen. The exposed groups had low posttraumatic stress scores and high-level general wellbeing at follow-up.Pantoea Natural Product 3 (PNP-3) is an antibiotic produced by Pantoea agglomerans that is effective against a broad range of multi-drug resistant bacteria. PNP-3 is encoded by a unique, eight-gene biosynthetic gene cluster composed of predicted enzymes (pnp3b, pnp3e-h), a regulator (pnp3d), and two Major Facilitator Superfamily transporters (pnp3a and pnp3c). To better characterize the role of the transporters, we generated pnp3a and pnp3c mutants and evaluated PNP-3 production. Disruption of pnp3a in Pantoea results in impaired growth and loss of antibiosis, suggesting a role in PNP-3 export and resistance. In contrast, pnp3c mutants display only reduced antibiotic production/export, suggesting a minor role for Pnp3c. Expression of pnp3a in susceptible Erwinia amylovora led to increased PNP-3 tolerance, while co-expression of pnp3a and pnp3e-h resulted in the production and export of PNP-3. Comparative genomic analyses identified pnp3a in 12 other Pantoea strains, eight of which carry a complete or nearly complete PNP-3 biosynthetic cluster. The four other Pantoea strains that carry pnp3a lack most of the PNP-3 cluster; however, they are PNP-3 tolerant. These results suggest Pnp3a plays an essential role in PNP-3 export and resistance in Pantoea.In this study, we investigated the action of varespladib (VPL) alone or in combination with a coral snake antivenom (CAV) on the local and systemic effects induced by Micrurus corallinus venom in rats. Adult male Wistar rats were exposed to venom (1.5 mg/kg – i.m.) and immediately treated with CAV (antivenomvenom ratio 11.5 'v/w’ – i.p.), VPL (0.5 mg/kg – i.p.), or both of these treatments. The animals were monitored for 120 min and then anesthetized to collect blood samples used for haematological and serum biochemical analysis; after euthanasia, skeletal muscle, renal and hepatic tissue samples were collected for histopathological analysis. M. corallinus venom caused local oedema without subcutaneous haemorrhage or apparent necrosis formation, although there was accentuated muscle morphological damage; none of the treatments prevented oedema formation but the combination of CAV and VPL reduced venom-induced myonecrosis. Venom caused neuromuscular paralysis and respiratory impairment in approximately 60 min following envenomation; CAV alone did not prevent the neurotoxic action, whereas VPL alone prevented neurotoxic symptoms developing as did the combination of CAV and VPL. Venom induced significant increase of serum CK and AST release, mostly due to local and systemic myotoxicity, which was partially prevented by the combination of CAV and VPL. The release of hepatotoxic serum biomarkers (LDH and ALP) induced by M. corallinus venom was not prevented by CAV and VPL when individually administered; their combination effectively prevented ALP release. The venom-induced nephrotoxicity (increase in serum creatinine concentration) was prevented by all the treatments. VPL alone or in combination with CAV significantly prevented the venom-induced lymphocytosis. In conclusion, VPL shows to be effective at preventing the neurotoxic, nephrotoxic, and inflammatory activities of M. corallinus venom. In addition, VPL acts synergistically with antivenom to prevent a number of systemic effects caused by M. corallinus venom.Chronic stress is a potential problem associated with anxiety, depression, and cognitive dysfunction. Bee pollen, a powerful antioxidant, has many therapeutic effects. In this study, we aimed to examine the effects of one of the Anatolian bee pollens on depression/anxiety. 24 male Sprague Dawley rats were divided into 3 groups as control, stress, and bee pollen + stress. Bee pollen (200 mg/kg/day) was given to rats exposed to physical stress for 10 days. Open field test (OFT) and forced swimming test (FST) were applied to monitor the behavioral changes of the rats. After behavioral tests, the rats were euthanized. Brain-derived neurotrophic factor (BDNF), interleukin 1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels were measured by ELISA to evaluate neurological and biochemical changes in rat hippocampal tissue. In addition, malondialdehyde (MDA) and glutathione (GSH) levels in the brain were evaluated. According to the behavioral test results, bee pollen reduced anxiety-like behavior but did not affect depression-like behavior. We also found that bee pollen suppressed neuroinflammation while reducing oxidative stress and lipid peroxidation in hippocampal tissues. Moreover, bee pollen significantly increased the level of BDNF in the hippocampus. In conclusion, bee pollen reduced oxidative damage and neuroinflammation caused by immobilization stress in rat brain tissue. Therefore, we suggest that bee pollen may be an effective natural compound in alleviating the negative effects caused by immobilization stress.Recent reports have implied that aberrant biochemical processes in the brain are frequently accompanied by subtle shifts in the cellular epigenetic profile that might underlie the pathogenic progression of psychiatric disorders. The aim of the present study was to examine the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 240 min/day for 14 days. We applied dosing schedules. In one schedule, from the 3rd day of stress exposure, mice were treated with TSA (1650 μM/4 μL, i.c.v.) immediately after the daily exposure to restraint stress. In the other schedule, from the 1st day of stress exposure, mice were treated with TSA 2 h before exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using the hole-board test. Mice that were exposed to restraint stress for 240 min/day for 14 days showed a decrease in head-dipping behavior. This decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with TSA 2 h before daily exposure to restraint stress, which confirmed the development of stress adaptation. On the other hand, no such stress adaptation was observed under chronic treatment with TSA immediately after daily stress exposure. A biochemical study showed that tryptophan hydroxylase, the rate-limiting enzyme in serotonin (5-HT) synthesis, was increased in midbrain containing raphe nuclei obtained from stress-adapted mice that were chronically treated with TSA 2 h before daily stress exposure. These findings suggest that an HDAC inhibitor may have a beneficial effect on stress adaptation by affecting 5-HT neural function in the brain and alleviate the emotional abnormality under conditions of excessive stress.Candida auris is an emerging multidrug resistant fungal pathogen, which represents a major challenge for newborns systemic infections worldwide. Management of C. auris infections is complicated due to its intrinsic antifungal resistance and the limited information available on its pathogenesis, particularly during neonatal period. In this study, we developed a murine model of C. auris neonatal invasive infection. C. auris dissemination was evaluated by fungal burden and histopathological analysis of lung, brain, liver, kidney, and spleen at different time intervals. We found fungal cells in all the analyzed tissues, neonatal liver and brain were the most susceptible tissues to fungal invasion. This model will help to better understand pathogenesis mechanisms and facilitate strategies for control and prevention of C. auris infections in newborns.Leptospirosis, caused by pathogenic Leptospira, is a global critical zoonotic disease in terms of mortality and morbidity. Vaccines are often used to prevent leptospirosis. However, few studies have reported the therapeutic effect of a vaccine against Leptospira infection. This study demonstrates the efficacy of the emergency vaccine immunization against acute leptospirosis in hamsters. Treatment with a whole-cell vaccine (Leptospira interrogans serovar Lai) at 24 h post-infection improved the survival rate of hamsters with lower leptospiral burden and minor pathological damage to organs. The vaccine also protected against multiple Leptospira serotypes acute infection. However, the protective effect of the vaccines was lost when beginning treatment at 36 h or 48 h post-infection. These results indicated that vaccines could treat acute leptospirosis in hamsters, but only if immunization is within 24 h after infection.Although the follicle-stimulating hormone (FSH) plays a vital role in male reproduction, the molecular relationships among FSH, autophagy, and the secretory function of Sertoli cells remain largely undetermined. In this study, we sought to investigate the effects of FSH on dairy goat Sertoli cell autophagy and the role of autophagy in protein clearance. FSH treatment of primary Sertoli cells was found to enhance the expression level of LC3-II, reduce p62 degradation and the number of lysosomes, and downregulate the levels of LAMP2 protein and lysosomal gene mRNAs. Further analyses revealed that starvation-induced autophagy promotes the translocation of transcription factor EB (TFEB) from the cytoplasm to nucleus and its binding to the promoter region of LAMP2, whereas FSH suppresses the nuclear translocation of TFEB. Moreover, we found that the FSH-mediated inhibition of autophagy extends the biological half-lives of androgen-binding protein (ABP), glial-derived neurotrophic factor (GDNF), and stem cell factor (SCF) and promotes the secretion of these proteins. Collectively, these observations indicate that FSH inhibits autophagy by reducing lysosomal biogenesis, which is associated with the suppression of TFEB nuclear translocation via activation of the PI3K/Akt/mTOR pathway, thereby extending the biological half-lives and enhancing the expression of ABP, GDNF, and SCF in dairy goat Sertoli cells.Hepatocyte necroptosis is a core pathogenetic event during alcoholic liver disease. This study was aimed to explore the potential of tetramethylpyrazine (TMP), an active hepatoprotective ingredient extracted from Ligusticum Wallichii Franch, in limiting alcohol-triggered hepatocyte necroptosis and further specify the molecular mechanism. Results revealed that TMP reduced activation of receptor-interacting protein kinase 1 (RIPK1)/RIPK3 necrosome in ethanol-exposed hepatocytes and phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which thereby diminished necroptosis and leakage of damage-associated molecular patterns. Suppression on mitochondrial translocation of p-MLKL by TMP contributed to recovery of mitochondrial function in ethanol-damaged hepatocytes. TMP also disrupted necroptotic signal loop by interrupting mitochondrial reactive oxygen species (ROS)-dependent positive feedback between p-MLKL and RIPK1/RIPK3 necrosome. Further, TMP promoted clearance of impaired mitochondria in ethano liver disease.Personalised orodispersible films (ODFs) manufactured at the point of care offer the possibility of adapting the dosing requirements for individual patients. Inkjet printing was extensively explored as a tool to produce personalised ODFs, but it is extensively limited to dispensing liquid with low viscosity and the interaction between ink and edible substrate complicates the fabrication process. In this study, we evaluated the feasibility of using a micro-dispensing (MD) jet system capable of accurately dispensing viscous liquid to fabricate substrate-free ODFs on-demand. The model inks containing hydroxypropyl methylcellulose (HPMC) and paracetamol were used to prepare personalised ODFs by expanding the film area. Cast films were used as the control sample to benchmark the mechanical properties, disintegration time, and dosing accuracy of MD printed ODFs. Both the cast and printed films showed smooth surface morphology without any bubbles. No significant difference was found in the disintegration time of the MD printed films compared to the cast films. High precision in dosing by MD printing was achieved. The dose of paracetamol had a linear correlation with the dimension of the printed films (R2 = 0.995). The results provide clear evidence of the potential of MD printing to fabricate ODFs and the knowledge foundation of advancing MD printing to a point-of-care small-batch manufacturing technology of personalised ODFs.Methotrexate (MTX) is a common drug used for rheumatoid arthritis (RA) treatment; however, a series of adverse effects associated with its oral or subcutaneous administration is reported. Transdermal delivery of MTX is an alternative to abate these issues, and the use of drug delivery systems (DDS) based on polymeric films presents an impressive potential for this finality. Based on this, in this study, we report the preparation of films made by cationic starch (CSt), poly(vinyl alcohol) (PVA), and chondroitin sulfate (ChS) to incorporate and release MTX, as well as the in vivo evaluation in model of rheumatoid arthritis in mice. CSt/PVA and CSt/PVA/ChS-based films (with and without MTX) were prepared using a simple protocol under mild conditions. The films loaded with 5 w/w-% of MTX exhibited appreciable drug loading efficiency and distribution. The MTX permeation through the layers of porcine skin demonstrated that most of the drug permeated was detected in the medium, suggesting that the formulation can provide a systemic absorption of the MTX. In vivo studies performed in an arthritis-induced model in mice demonstrated that the MTX-loaded films were able to treat and attenuate the symptoms and the biochemical alterations related to RA (inflammatory process, oxidative stress, and nociceptive behaviors). Besides, the pharmacological activity of MTX transdermally delivery by the CSt/PVA and CSt/PVA/ChS films was comparable to the MTX orally administered. Based on these results, it can be inferred that both films are prominent materials for incorporation and transdermal delivery of MTX in a practical and non-invasive manner.The present paper serves as a demonstration how an in-line PAT tool can be used for rapid and efficient process development in a fully continuous powder to granule line consisting of an interconnected twin-screw wet granulator, vibrational fluid bed dryer, and a regranulating mill. A new method was investigated for the periodic in-line particle size measurement of high mass flow materials to obtain real-time particle size data of the regranulated product. The system utilises a vibratory feeder with periodically altered feeding intensity in order to temporarily reduce the mass flow of the material passing in front of the camera. This results in the drastic reduction of particle overlapping in the images, making image analysis a viable tool for the in-line particle size measurement of high mass-flow materials. To evaluate the performance of the imaging system, the effect of several milling settings and the liquid-to-solid ratio was investigated on the product’s particle size in the span of a few hours. The particle sizes measured with the in-line system were in accordance with the expected trends as well as with the results of the off-line reference particle size measurements. Based on the results, the in-line imaging system can serve as a PAT tool to obtain valuable real-time information for rapid process development or quality assurance.This work describes the application of liquisolid technique to enhance cannabinoid dissolution from Cannabis sativa L. (CS) compacts. Effects of five vehicles, namely, volatile (ethanol) and nonvolatile (caprylocaproyl macrogolglycerides, polyethylene glycol 400, oleoyl macrogolglycerides and polysorbate 20) liquids, on tablet properties, dissolution and stability were investigated. The viscid oleoresin CS extract was mixed with vehicles before being transformed into free-flowing powder by the use of microcrystalline cellulose and colloidal silica as carrier and coating materials. Liquid vehicles had a nonsignificant effect on liquid load factor of CS extract. CS liquisolid compacts had acceptable tableting properties in terms of weight variation, friability, hardness, content uniformity and disintegration time. Different vehicles affected the hardness, disintegration, and wettability of CS compacts and thus the dissolution behaviors of cannabinoids to different extents. Dissolutions of cannabinoids from CS compacts were rate-limited by the disintegration process. Liquisolid formulations using nonvolatile liquids with low polarity or high hydrophilic-lipophilic balance yielded more than 90% cannabinoid dissolution. Stability studies revealed nonsignificant changes in tablet characteristics, cannabinoid content and dissolutions of CS compacts when stored at 5 ± 3 °C for 3 months. This work presents a general concept of how to successfully formulate CS extract with cannabinoid dissolution enhancement characteristics.Oral delivery of nanoparticles possesses many advantages for delivery of active pharmaceutical ingredients (APIs) to the gastrointestinal tract. However, the poor physical stability of nanoparticles in liquid state is often a challenge. Removing water from the nanosuspensions and transforming the nanoparticles into solid particulate matter in the form of, e.g., tablets could be a potential approach to increase the stability of nanoparticles. The aim of this study was to transform nanoparticles into compacts and to investigate the redispersion of nanoparticles from compacts as well as the dissolution behavior of these compacts. DL-lactide-co-glycolide copolymer (PLGA) nanoparticles and celecoxib (CLX) nanoparticles were used as two model nanoparticle systems and fabricated into nano-embedded microparticles (NEMs) and subsequently compressed into compacts. The compacts were evaluated with respect to the redispersibility of the nanoparticles, as well as the dissolution characteristics of CLX. The results showed ticle within oral drug delivery of nanoparticles.The formimidoyltransferase cyclodeaminase (FTCD) gene encodes an enzyme required for the catabolism of histidine and tetrahydrofolate (THF). Previous studies showed that FTCD plays a role as a tumour suppressor gene in hepatocellular carcinoma (HCC). It is unknown whether the restoration of functional FTCD may exhibit an anti-tumour effect on HCC. This study constructed a delivery system based on hollow mesoporous organosilica nanotheranostics (HMON) capable of efficiently loading Mn ions and FTCD plasmids. This study showed that the Mn-doped and FTCD-loaded nanoparticles (HMON@Mn-PEI@FTCD) could efficiently induce the expression of FTCD and achieve enhanced magnetic resonance imaging. In vitro results demonstrated that the upregulation of FTCD induced by HMON@Mn-PEI@FTCD nanoparticles dramatically reduced intracellular THF levels, inhibited of NADPH/NADP+ and GSH/GSSG ratios, and induced reactive oxygen species generation and mitochondrial oxidative stress. As a result, cytochrome c release increased with the opening of the mitochondrial permeability transition pore, which finally activated the caspase-dependent cell apoptosis pathway. Therefore, our designed HMON@Mn-PEI@FTCD could induce apoptosis by activating the mitochondria-mediated apoptosis signalling pathway, and finally significantly suppressed the proliferation of HCC both in vitro and in vivo, which provides an effective strategy for the treatment of HCC.The characteristics of oocytes, which are female germ cells, have not been studied using optical materials. The structural layers (zona pellucida, ZP) around oocytes make it difficult to deliver drugs aimed at treating infertility. Here, we investigated whether the fluorescent probes sulforhodamine, fluorescein 5(6)-isothiocyanate, tetramethylrhodamine isothiocyanate, cyanine 3 carboxylic acid, and cyanine 5 carboxylic acid penetrate oocytes. By targeting the ZP layer of the oocyte, the characteristics of the model drug, a fluorescent probe, were analyzed, and the position of the probe in the oocyte was confirmed for differences in the characteristics. Penetration of the ZP and delivery into the cytoplasm differed between the fluorescent probes. This was due to their different physiochemical properties, including hydrophobicity (contact angle and surface tension), surfactant activity, and electrical charge. Among the fluorescent probes delivered to cytoplasm, unlike TRITC, Cy3 and Cy5 perturbed oocyte development. These results suggest that in oocytes with high physical barriers (cell membrane, zona pellucida), the delivery efficiency can be estimated by considering the properties (molecular weight and structure, solubility and functional structure, etc.) of the drug. In addition, it suggests that an encapsulated or bound carrier of a drug with properties similar to that of a fluorescent probe can be efficiently delivered into oocytes.

A systematic review and meta-analysis were performed to evaluate the necessity for compression therapy with elastic stockings following endovenous thermal ablation (EVTA) for chronic venous insufficiency.

MedLine, ScienceDirect and the Cochrane Library were searched for the relevant literature according to the inclusion and exclusion criteria. Two researchers independently extracted data and assessed the quality of the literature. Randomized controlled trials comparing the use of elastic stockings for compression therapy versus no compression therapy following RFA or EVLA for varicose veins were included in this study. The primary outcome of postoperative pain was assessed using the visual analogue pain scale. Secondary outcomes included the bruising score, quality of life, venous clinical severity score, time to return to normal activities, complications, and the rate of saphenous vein occlusion. The mixed effect model or random effect model was used to calculate relative risk (RR), mean difference (MD) or standardized mean difference following the heterogeneity test.