Medicinal potential of embelin and its nanoformulations: An update on the molecular mechanism and various applications.

Natural herbs have garnered significant research recently as their components target multiple disease signaling pathways, making them highly potential for various disease prevention and treatment. Embelin, a naturally occurring benzoquinone isolated from Embelia ribes, has shown promising biological activities such as antitumor, antidiabetic, anti-oxidant, and antimicrobial. Various mechanisms have been reported, including monitoring genes that synchronize the cell cycle, up-regulating multiple anti-oxidant enzymes, suppressing genes that prevent cell death, influencing transcription factors, and preventing inflammatory biomarkers. However, the hydrophobic nature of embelin leads to poor absorption and limits its therapeutic potential. This review highlights a wide range of nanocarriers used as delivery systems for embelin, including polymeric nanoparticles, liposomes, nanostructured lipid carriers, micelles, nanoemulsion, and metallic nanoparticles. These embelin nanomedicine formulations have been developed in preclinical studies as a possible treatment for many disorders and characterized using various in vitro, ex vivo, and in vivo models.

Predicting repurposed drugs targeting the NS3 protease of dengue virus using machine learning-based QSAR, molecular docking, and molecular dynamics simulations.

Dengue fever, prevalent in Southeast Asian countries, currently lacks effective pharmaceutical interventions for virus replication control. This study employs a strategy that combines machine learning (ML)-based quantitative-structure-activity relationship (QSAR), molecular docking, and molecular dynamics simulations to discover potential inhibitors of the NS3 protease of the dengue virus. We used nine molecular fingerprints from PaDEL to extract features from the NS3 protease dataset of dengue virus type 2 in the ChEMBL database. Feature selection was achieved through the low variance threshold, F-Score, and recursive feature elimination (RFE) methods. Our investigation employed three ML models - support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost) - for classifier development. Our SVM model, combined with SVM-RFE, had the best accuracy (0.866) and ROC_AUC (0.964) in the testing set. We identified potent inhibitors on the basis of the optimal classifier probabilities and docking binding affinities. SHAP and LIME analyses highlighted the significant molecular fingerprints (e.g. ExtFP69, ExtFP362, ExtFP576) involved in NS3 protease inhibitory activity. Molecular dynamics simulations indicated that amphotericin B exhibited the highest binding energy of -212 kJ/mol and formed a hydrogen bond with the critical residue Ser196. This approach enhances NS3 protease inhibitor identification and expedites the discovery of dengue therapeutics.

Posaconazole-hemp seed oil loaded nanomicelles for invasive fungal disease.

Invasive fungal infections (IFI) pose a significant health burden, leading to high morbidity, mortality, and treatment costs. This study aims to develop and characterize nanomicelles for the codelivery of posaconazole and hemp seed oil for IFI via the oral route. The nanomicelles were prepared using a nanoprecipitation method and optimized through the Box Behnken design. The optimized nanomicelles resulted in satisfactory results for zeta potential, size, PDI, entrapment efficiency, TEM, and stability studies. FTIR and DSC results confirm the compatibility and amorphous state of the prepared nanomicelles. Confocal laser scanning microscopy showed that the optimized nanomicelles penetrated the tissue more deeply (44.9µm) than the suspension (25µm). The drug-loaded nanomicelles exhibited sustained cumulative drug release of 95.48 ± 3.27% for 24 h. The nanomicelles showed significant inhibition against Aspergillus niger and Candida albicans (22.4 ± 0.21 and 32.2 ± 0.46 mm, respectively). The pharmacokinetic study on Wistar rats exhibited a 1.8-fold increase in relative bioavailability for the nanomicelles compared to the suspension. These results confirm their therapeutic efficacy and lay the groundwork for future research and clinical applications, providing a promising synergistic antifungal nanomicelles approach for treating IFIs.

Serum pentraxin 3 levels in term neonates with persistent pulmonary hypertension.

BACKGROUND: Persistent pulmonary hypertension of the neonate (PPHN) is a serious disorder. The long pentraxin 3 (PTX3) plays an important role in angiogenesis, cell proliferation, tissue repair and cell regulation. The present study aims to assess the diagnostic and clinical value of PTX3 in PPHN. METHODS: The present case-control 60 full-term neonates diagnosed with PPHN by echocardiography within 72 hours of birth. In addition, there were 30 age and sex-matched healthy neonates who served as controls. All participants were subjected to careful history taking and complete clinical examination, Laboratory investigations included complete blood count, C-reactive protein (CRP), blood culture and PTX3 level. Radiological investigations included plain X- ray and two-dimensional transthoracic echocardiography (TTE). RESULTS: Comparison between patients and controls revealed that patients had significantly higher CRP (6.12±2.18 versus 3.69±1.25 mg/dl, p < 0.001) and PTX3 levels (2.07±0.67 versus 0.96±0.21, p < 0.001) when compared with controls. Patients with associated PDA had significantly higher PTX3 levels when compared with patients without (2.58±0.5 versus 2.02±0.51 ng/ml, p = 0.002). Also, patients with associated PFO had significantly higher PTX3 levels when compared with patients without (2.12±1.05 versus 2.05±0.46, p = 0.002). ROC curve analysis identified good performance of CRP and PTX3 levels in diagnosis of PPHN with PTX3 showing better performance. CONCLUSIONS: There is a significant association between serum PTX3 levels and PPHN particularly those with associated PDA or PFO.

Role of Polyphenols, Their Nano-formulations, and Biomaterials in Diabetic Wound Healing.

A diabetic wound is one of the major complications arising from hyperglycemia, neuropathy, and oxidative stress in diabetic patients. Finding effective treatments for diabetic wounds has been difficult owing to the complex pathophysiology of diabetic wound environments. Chronic wounds are notoriously difficult to treat with conventional wound care methods. In recent years, polyphenols found in plants have received much interest as a potential treatment for diabetic wounds. Their key benefits are their safety and the fact that they act through many molecular routes to treat diabetic wounds. However, problems with their formulation development, including lipophilicity, light sensitivity, limited membrane permeability, rapid systemic elimination, and enzymatic degradation, prevented them from gaining clinical attention. This article highlights and discusses the mechanism of polyphenols and various polyphenol-based drug delivery systems used till now to treat diabetic wounds. The consideration that should be taken in polyphenols-based nano-formulations and their prospect for diabetic wounds are also discussed briefly.

Omega-3 fatty acid-based self-microemulsifying drug delivery system (SMEDDS) of pioglitazone: Optimization, in vitro and in vivo studies.

Pioglitazone (PGL) is an effective insulin sensitizer, however, side effects such as accumulation of subcutaneous fat, edema, and weight gain as well as poor oral bioavailability limit its therapeutic potential for oral delivery. Recent studies have shown that combination of both, PGL and fish oil significantly reduce fasting plasma glucose, improve insulin resistance, and mitigate pioglitazone-induced subcutaneous fat accumulation and weight gain. Nevertheless, developing an effective oral drug delivery system for administration of both medications have not been explored yet. Thus, this study aimed to develop a self-micro emulsifying drug delivery system (SMEDDS) for the simultaneous oral administration of PGL and fish oil. SMEDDS was developed using concentrated fish oil,Tween® 80, and Transcutol HP and optimized by central composite design (CCD). The reconstituted, optimized PGL-SMEDDS exhibited a globule size of 142 nm, a PDI of 0.232, and a zeta potential of -20.9 mV. The in-vitro drug release study of the PGL-SMEDDS showed a first-order model kinetic release and demonstrated remarkable 15-fold enhancement compared to PGL suspension. Additionally, following oral administration in fasting albino Wistar rats, PGL-SMEDDS exhibited 3.4-fold and 1.4-fold enhancements in the AUC0-24h compared to PGL suspension and PGL marketed product. The accelerated stability testing showed that the optimized SMEDDS formulation was stable over a three-month storage period. Taken together, our findings demonstrate that the developed fish oil-based SMEDDS for PGL could serve as effective nanoplatforms for the oral delivery of PGL, warranting future studies to explore its synergistic therapeutic potential in rats.

Effect of amla and ginger powders on quality criteria of African catfish (Clarias gariepinus) fingers.

Catfish (Clarias gariepinus) meat isn't preferred by consumers in compared to other fish species meat, thus to enhance the use of catfish meat, ready to eat catfish fingers were prepared with some plants additives (amla and ginger powder). The mean objective of this study was to assess the impact of amla and ginger powder on catfish finger qualities in terms of physical, chemical, microbiological, and sensorial parameters under stored at a low temperature (5 ± 1 °C). The obtained results were compared with those of a control sample (basic formula) and a sample containing the synthetic antioxidant. During the storage period, the levels of pH, thiobarbituric acid, total volatile basic nitrogen, trimethylamine, total bacteria count, psychrophilic bacteria, molds and yeasts counts increased dramatically, although the values remained within acceptable ranges. The findings also revealed, that amla and ginger powder considerably (p < 0.05) reduced the changes in quality parameters, as well as there was a considerable increase in the quality parameter in all treated samples than in the control. Finally, amla and ginger powder can be a substitute for synthetic antioxidants and antimicrobials. These findings suggest that the powder of amla and ginger are suitable for use as a natural antioxidants and antimicrobials to extend the shelf-life of animal products.

Palatable Levocetirizine Dihydrochloride Solid Dispersed Fast-Dissolving Films: Formulation and In Vitro and In Vivo Characterization.

One of the most important issues for bitter-tasting drugs such as levocetirizine dihydrochloride (LCD) is the production of palatable dosage forms. LCD also has a delayed onset of action following oral administration. In this study, solid dispersed fast-dissolving films (FDFs) of LCD using the solvent casting method for oral application were prepared and evaluated. The FDF is composed of HPMC as the film forming polymer and different types of superdisintegrants (sodium starch glycolate, croscarmellose sodium, or crospovidone). FDF containing crospovidone showed the highest percentage release of the drug (100.54% ± 1.47 within 3 min.) and was chosen for fabricating into palatable solid dispersed FDFs using different ratios of gelatine. The results of Raman and FTIR revealed that the drug's crystalline structure has been disrupted, and the drug has intermolecular hydrogen bonds with gelatine. The solid dispersed FDF (LF-7), which contained the drug in the form of a 1 : 1 solid dispersion with gelatine, showed a rapid in vitro disintegration (25 seconds) and a burst release of the drug (99.22% ± 2.22 within one min). The in vivo studies were conducted on human participants and showed a significant (p < 0.05) reduction in disintegration time (9.43 ± 2.16 sec.) and higher taste masking ability of the solid dispersed FDF (LF-7) compared to the nonsolid dispersed FDF (LF-4). The stability studies indicated that the prepared FDF remained stable over three months. Overall, FDFs of levocetirizine dihydrochloride with a palatable and rapid onset of action were developed to relieve allergic symptoms.

Brain targeted delivery of carmustine using chitosan coated nanoparticles via nasal route for glioblastoma treatment.

This study aims to develop chitosan-coated PLGA nanoparticles intended for nose-to-brain delivery of carmustine. Formulations were prepared by the double emulsion solvent evaporation method and optimized by using Box-Behnken Design. The optimized nanoparticles were obtained to satisfactory levels in terms of particle size, PDI, entrapment efficiency, and drug loading. In vitro drug release and ex-vivo permeation showed sustained release and enhanced permeability (approx. 2 fold) of carmustine compared to drug suspension. The AUC0-t of brain obtained with carmustine-loaded nanoparticles via nasal administration in Albino Wistar rats was 2.8 and 14.7 times that of intranasal carmustine suspension and intravenous carmustine, respectively. The MTT assay on U87 MG cell line showed a significant decrease (P < 0.05) in the IC50 value of the formulation (71.23 µg ml-1) as compared to drug suspension (90.02 µg ml-1).These findings suggest chitosan coated nanoparticles could be used to deliver carmustine via intranasal administration to treat Glioblastoma multiforme.

A laser wakefield acceleration facility using SG-II petawatt laser system.

Laser wakefield acceleration (LWFA) using PW-class laser pulses generally requires cm-scale laser-plasma interaction Rayleigh length, which can be realized by focusing such pulses inside a long underdense plasma with a large f-number focusing optic. Here, we present a new PW-based LWFA instrument at the SG-II 5 PW laser facility, which employs f/23 focusing. The setup also adapted an online probing of the plasma density via Nomarski interferometry using a probe laser beam having 30 fs pulse duration. By focusing 1-PW, 30-fs laser pulses down to a focal spot of 230 µm, the peak laser intensity reached a mild-relativistic level of 2.6 × 1018 W/cm2, a level modest for standard LWFA experiments. Despite the large aspect ratio of >25:1 (transverse to longitudinal dimensions) of the laser pulse, electron beams were observed in our experiment only when the laser pulse experienced relativistic self-focusing at high gas-pressure thresholds, corresponding to plasma densities higher than 3 × 1018 cm-3.

Early inflammation dysregulates neuronal circuit formation in vivo via upregulation of IL-1ß.

Neuro-immune interaction during development is strongly implicated in the pathogenesis of neurodevelopmental disorders, but the mechanisms that cause neuronal circuit dysregulation are not well understood. We performed in vivo imaging of the developing retinotectal system in the larval zebrafish to characterize the effects of immune system activation on refinement of an archetypal sensory processing circuit. Acute inflammatory insult induced hyper-dynamic remodeling of developing retinal axons in larval fish and increased axon arbor elaboration over days. Using calcium imaging in GCaMP6s transgenic fish we showed that these morphological changes were accompanied by a shift toward decreased visual acuity in tectal cells. This finding was supported by poorer performance in a visually guided behavioral task. We further found that the pro-inflammatory cytokine, interleukin-1ß (IL-1ß) is upregulated by the inflammatory insult, and that down-regulation of IL-1ß abrogated the effects of inflammation on axonal dynamics and growth. Moreover, baseline branching of the RGC arbors in IL-1ß morphant animals was significantly different from that in control larvae, and their performance in a predation assay was impaired, indicating a role for this cytokine in normal neuronal development. This work establishes a simple and powerful non-mammalian model of developmental immune activation and demonstrates a role for IL-1ß in mediating the pathological effects of inflammation on neuronal circuit development.SIGNIFICANCE STATEMENTMaternal immune activation (MIA) can increase the risk of neurodevelopmental disorders in offspring, however the mechanisms involved are not fully understood. Using a non-mammalian vertebrate model of developmental immune activation, we show that even brief activation of inflammatory pathways has immediate and long-term effects on the arborization of axons, and that these morphological changes have functional and behavioral consequences. Finally, we show that the pro-inflammatory cytokine IL-1ß plays an essential role in both the effects of inflammation on circuit formation and normal axonal development. Our data add to a growing body of evidence supporting epidemiological studies linking immune activation to neurodevelopmental disorders, and help shed light on the molecular and cellular processes that contribute to the etiology of these disorders.

Rabies in the Middle East, Eastern Europe, Central Asia and North Africa: Building evidence and delivering a regional approach to rabies elimination.

The Middle East, Eastern Europe, Central Asia and North Africa Rabies Control Network (MERACON), is built upon the achievements of the Middle East and Eastern Europe Rabies Expert Bureau (MEEREB). MERACON aims to foster collaboration among Member States (MS) and develop shared regional objectives, building momentum towards dog-mediated rabies control and elimination. Here we assess the epidemiology of rabies and preparedness in twelve participating MS, using case and rabies capacity data for 2017, and compare our findings with previous published reports and a predictive burden model. Across MS, the number of reported cases of dog rabies per 100,000 dog population and the number of reported human deaths per 100,000 population as a result of dog-mediated rabies appeared weakly associated. Compared to 2014 there has been a decrease in the number of reported human cases in five of the twelve MS, three MS reported an increase, two MS continued to report zero cases, and the remaining two MS were not listed in the 2014 study and therefore no comparison could be drawn. Vaccination coverage in dogs has increased since 2014 in half (4/8) of the MS where data are available. Most importantly, it is evident that there is a need for improved data collection, sharing and reporting at both the national and international levels. With the formation of the MERACON network, MS will be able to align with international best practices, while also fostering international support with other MS and international organisations.

Bioactive Compounds and Traditional Herbal Medicine: Promising Approaches for the Treatment of Dementia.

Dementia is a term that encompasses a group of clinical symptoms affecting memory, thinking and social abilities, characterized by progressive impairment of memory performance and cognitive functions. There are several factors involved in the pathogenesis and progression of dementia, such as old age, brain ischemia, toxin exposure, and oxidative stress. There are extensive similarities between dementia and Alzheimer's disease (AD) either in clinical manifestations or experimental animal models. AD is the most dominant form of dementia, characterized by the accumulation of beta-amyloid protein and cholinergic neurotransmission deficits in the brain. Currently available medications for the treatment of dementia, such as choline esterase inhibitors, N-methyl-D-aspartate (NMDA) antagonists (memantine), have short-term efficacy and only relieve symptoms rather than targeting the main underlying pathogenesis. Several animal studies and clinical trials are being conducted to provide a rational approach to these medicinal plants in the prevention or treatment of memory deficits. This review highlights the potential effects of medicinal plants and their derived lead molecules, and explains the related mechanisms and effects reviewed from published literature as major thrust aspects and hopeful strategies in the prevention or treatment of dementia.

Holmium Laser En-bloc Resection Versus Conventional Transurethral Resection of Bladder Tumors for Treatment of Non-muscle-invasive Bladder Cancer: A Randomized Clinical Trial.

BACKGROUND: En-bloc resection of bladder tumors achieves complete tumor removal, improves the quality of resection, decreases perioperative complication, and potentially improves recurrence rates. OBJECTIVE: To assess the efficacy and safety of holmium laser en-bloc resection (HolERBT) versus conventional transurethral resection of bladder tumor (cTURBT). DESIGN, SETTING, AND PARTICIPANTS: Between September 2015 and September 2018, 100 patients with non-muscle-invasive bladder cancer were randomly allocated to cTURBT or HolERBT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was detection of residual tumor in reTURBT specimens at 4 wk after the primary resection. Operative parameters, specimen quality, perioperative complications, and recurrence-free survival (RFS) were compared. Independent sample t tests, χ2 tests, and Kaplan-Meier curves were used, as appropriate. RESULTS AND LIMITATIONS: The patient and tumor baseline characteristics were comparable between the groups. Residual tumors were detected in 7% and 27.7% of cases after HolERBT and cTURBT, respectively (p=0.01). Detrusor muscle was sampled in 98% of HolERBT and 62% of cTURBT cases (p<0.001). Lamina propria invasion substaging was feasible in only 68.2% of HolERBT and 18.4% of cTURBT cases (p<0.001). Following HolERBT, catheterization time (p<0.001) and hospital stay (p=0.001) were shorter when compared to cTURBT. Immediate postoperative instillation of chemotherapy in indicated cases was feasible for 100% of the HolERBT group and 91.5% of the cTURBT group (p=0.04). After follow-up of 20 ± 9.9 mo (13-36), RFS was 31.76 mo (95% confidence interval [CI] 28.67-34.86) in the HolERBT group and 28.25 mo (95% CI 24.87-31.64) in the cTURBT group (hazard ratio 0.43, 95% CI 0.17-1.1; p=0.07). However, this study was not powered to detect a difference in RFS. CONCLUSIONS: Compared to cTURBT, HolERBT is a safer procedure for bladder tumor resection. It fulfills the oncological criteria of optimized resection with less residual tumor and better specimen quality. PATIENT SUMMARY: En-bloc resection of bladder cancer tumors using a holmium laser is safer than the conventional technique. It has the advantages of less residual tumor and better specimen quality, with a similar tumor recurrence rate. This study is registered at ClinicalTrials.gov as NCT02555163.

Randomised trial of bipolar resection vs holmium laser enucleation vs Greenlight laser vapo-enucleation of the prostate for treatment of large benign prostate obstruction: 3-years outcomes.

OBJECTIVE: To compare transurethral resection in saline (TURIS), Greenlight laser vapo-enucleation of the prostate (GL.PVEP), and holmium laser enucleation of the prostate (HoLEP), for controlling lower urinary tract symptoms secondary to large benign prostatic hyperplasia (BPH) and to assess non-inferiority of 3-year re-treatment rates. PATIENTS AND METHODS: Eligible patients with BPH (prostate size 80-150 mL) were randomly assigned to one of the intervention groups. Non-inferiority of re-treatment rate was evaluated using a one-sided test at 5% level of significance. RESULTS: At the time of analysis, 60 GL.PVEP, 60 HoLEP and 62 TURIS procedures were included. Perioperative parameters were comparable between groups; however, the operative time was longer in GL.PVEP vs HoLEP and TURIS, at a mean (SD) of 92 (32) vs 73 (30) and 83 (28) min (P = 0.005); and was less effective with a mean (SD) removal of 1.2 (0.4) vs 1.7 (0.7) and 1.4 (0.6) g/min (P < 0.001), respectively. Perioperative complications and need for auxiliary procedures were similar in the three groups; however, there was a significantly higher rate of capsular perforation in TURIS group (five, 8%) compared to one (1.6%) in the GL.PVEP group and none in the HoLEP group (P = 0.01). There was a significantly longer hospital stay, catheter-time and higher rate of blood transfusion in the TURIS group. There was significant but comparable improvements in the International Prostate Symptom Score in three groups at different follow-up points. At 3 years, re-treatment for recurrent bladder outlet obstruction was required more after GL.PVEP and TURIS. More re-do surgeries for recurrent obstructing prostate adenoma was reported after GL.PVEP (four, 6.7%) and TURIS (six, 9.7%) than for HoLEP (none) (P = 0.04). CONCLUSION: The perioperative outcomes of GL.PVEP and HoLEP surpassed that of TURIS for the treatment of large prostates, but with a significantly prolonged operative time with GL.PVEP. The three techniques achieve good functional outcomes; however, 3-year re-treatment rates following TURIS and GL.PVEP were inferior to HoLEP.

A laser-plasma accelerator driven by two-color relativistic femtosecond laser pulses.

A typical laser-plasma accelerator (LPA) is driven by a single, ultrarelativistic laser pulse from terawatt- or petawatt-class lasers. Recently, there has been some theoretical work on the use of copropagating two-color laser pulses (CTLP) for LPA research. Here, we demonstrate the first LPA driven by CTLP where we observed substantial electron energy enhancements. Those results have been further confirmed in a practical application, where the electrons are used in a bremsstrahlung-based positron generation configuration, which led to a considerable boost in the positron energy as well. Numerical simulations suggest that the trailing second harmonic relativistic laser pulse is capable of sustaining the acceleration structure for much longer distances after the preceding fundamental pulse is depleted in the plasma. Therefore, our work confirms the merits of driving LPAs by two-color pulses and paves the way toward a downsizing of LPAs, making their potential applications in science and technology extremely attractive and affordable.

Delivery of intravesical botulinum toxin A using low-energy shockwaves in the treatment of overactive bladder: A preliminary clinical study.

Objective: To evaluate the efficacy and safety of botulinum toxin A (BoNT-A) instillation in the bladder under the effect of low-energy shockwaves (LESWs) for the treatment of refractory idiopathic overactive bladder (OAB). Patients and methods: A preliminary clinical study was conducted, including 15 patients with refractory OAB, between September 2016 and July 2017. Intravesical instillation of 100 IU of BoNT-A was done followed by LESWs (3000 shocks over 10 min) exposure to the supra-pubic area. Patients were followed-up by urine analysis, urine culture, post-void residual urine volume (PVR), and Overactive Bladder Symptom Score (OABSS) at 1, 2 and 3 months. Results: There were statistically significant improvements in all OABSS domains and the total score after 1 and 2 months of treatment (P < 0.05). Whereas, only the nocturia domain remained significantly improved after 3 months (P = 0.02). There was no significant increase in PVR throughout the study period (P > 0.05) and none of the patients required clean intermittent catheterisation. Two, two and three patients developed urinary tract infections after 1, 2 and 3 months, respectively. Conclusion: Intravesical instillation of BoNT-A and LESWs is safe and effective method for the treatment of refractory OAB with a durable response for 2 months. Abbreviations: BoNT-A: botulinum toxin A; CIC: clean intermittent catheterisation; DO: detrusor overactivity; LESWs: low-energy shockwaves; OAB: overactive bladder; OABSS: Overactive Bladder Symptom Score; Qmax: maximum urinary flow rate; QoL: quality of life; UUI: urgency urinary incontinence.

Sex-specific contribution of DHEA-cortisol ratio to prefrontal-hippocampal structural development, cognitive abilities and personality traits.

Although dehydroepiandrosterone (DHEA) may exert neuroprotective effects in the developing brain, prolonged or excessive elevations in cortisol may exert neurotoxic effects. The ratio between DHEA and cortisol (DC ratio) has been linked to internalising and externalising disorders, as well as cognitive performance, supporting the clinical relevance of this hormonal ratio during development. However, the brain mechanisms by which these effects may be mediated have not yet been identified. Furthermore, although there is evidence that the effects of cortisol in the central nervous system may be sexually dimorphic in humans, the opposite is true for DHEA, with human studies showing no sex-specific associations in cortical thickness, cortico-amygdalar or cortico-hippocampal structural covariance. Therefore, it remains unclear whether sex moderates the developmental associations between DC ratio, brain structure, cognition and behaviour. In the present study, we examined the associations between DC ratio, structural covariance of the hippocampus with whole-brain cortical thickness, and measures of personality, behaviour and cognition in a longitudinal sample of typically developing children, adolescents and young adults aged 6-22 years (N = 225 participants [F = 128]; 355 scans [F = 208]), using mixed effects models that accounted for both within- and between-subject variances. We found sex-specific interactions between DC ratio and anterior cingulate cortex-hippocampal structural covariance, with higher DC ratios being associated with a more negative covariance between these structures in girls, and a more positive covariance in boys. Furthermore, the negative prefrontal-hippocampal structural covariance found in girls was associated with higher verbal memory and mathematical ability, whereas the positive covariance found in boys was associated with lower cooperativeness and reward dependence personality traits. These findings support the notion that the ratio between DHEA and cortisol levels may contribute, at least in part, to the development of sex differences in cognitive abilities, as well as risk for internalising/externalising disorders, via an alteration in prefrontal-hippocampal structure during the transition from childhood to adulthood.

Association analysis between four vitamin D receptor gene polymorphisms and developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a congenital condition characterized by abnormality in acetabulum size and/or shape. The incidence rate of DDH differs between different populations with risk factors including positive family history, breech presentation, sex, firstborn status, side of the hip, mode of delivery and oligohydramnios. It is recognized that DDH has a genetic component that exhibit autosomal dominant patterns. Many candidate genes have been studied and found to be associated with the disease; most of them are normally involved in cartilage development and joint metabolism. In this study, the association of four single-nucleotide polymorphisms (SNPs) (rs731236, rs1544410, rs7975232 and rs2228570) in the vitamin D receptor (VDR) gene was studied by a case-control analysis. The study sample involves 50 cases with confirmed DDH presentation and 50 nonDDH controls. SNPs were genotyped using conventional polymerase chain reaction (PCR) and restriction fragment-length polymorphism (RFLP) techniques. Genotype and allele frequencies were analysed using SPSS software. No significant associations were found between the VDR polymorphisms analysed and DDH. Further work need to be performed using genomewide analysis to elucidate the genetic basis of DDH.

Role of DHEA and cortisol in prefrontal-amygdalar development and working memory.

There is accumulating evidence that both dehydroepiandrosterone (DHEA) and cortisol play an important role in regulating physical maturation and brain development. High DHEA levels tend to be associated with neuroprotective and indirect anabolic effects, while high cortisol levels tend to be associated with catabolic and neurotoxic properties. Previous literature has linked the ratio between DHEA and cortisol levels (DC ratio) to disorders of attention, emotional regulation and conduct, but little is known as to the relationship between this ratio and brain development. Due to the extensive links between the amygdala and the cortex as well as the known amygdalar involvement in emotional regulation, we examined associations between DC ratio, structural covariance of the amygdala with whole-brain cortical thickness, and validated report-based measures of attention, working memory, internalizing and externalizing symptoms, in a longitudinal sample of typically developing children and adolescents 6-22 years of age. We found that DC ratio predicted covariance between amygdalar volume and the medial anterior cingulate cortex, particularly in the right hemisphere. DC ratio had a significant indirect effect on working memory through its impact on prefrontal-amygdalar covariance, with higher DC ratios associated with a prefrontal-amygdalar covariance pattern predictive of higher scores on a measure of working memory. Taken together, these findings support the notion, as suggested by animal and in vitro studies, that there are opposing effects of DHEA and cortisol on brain development in humans, and that these effects may especially target prefrontal-amygdalar development and working memory, in a lateralized fashion.