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.

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.

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 chest tube may not be needed after surgical repair of esophageal atresia and tracheoesophageal fistula.

BACKGROUND: After definitive repair of esophageal atresia (EA) and tracheoesophageal fistula (TEF), a chest tube (CT) may be left in place to diagnose and conservatively treat a postoperative anastomotic leak, although its necessity is controversial. The purpose of this study was to determine if the use of a CT decreases rates of early postoperative complications after EA and TEF repair. METHODS: A retrospective chart review was performed to identify all patients with EA and TEF who underwent repair between 1985 and 2012. Univariate analysis was performed to compare patients who did or did not have a CT in terms of preoperative characteristics and postoperative outcomes. RESULTS: One hundred twenty neonates were included; 69 had a CT inserted intraoperatively, while 51 did not. The two groups were similar in terms of patient characteristics. There was no statistically significant difference between the groups in terms of length of hospital stay (31 ± 12 vs. 36 ± 16 days, p = 0.5), or complication rates (13% vs. 12%, p = 0.9) for those with or without CT, respectively. CONCLUSIONS: The use of a CT does not alter early postoperative complications after EA/TEF repair.

Morphometric parameters and histological study of the filum terminale of adult human cadavers and magnetic resonance images.

BACKGROUND: Morphology and histology of filum terminale (FT) has a role in the pathophysiology of tethered cord syndrome (TCS). This research was implemented to investigate the morphometric parameters and histological structure of normal FT in adult human cadavers and magnetic resonance imaging (MRI) scans to correlate them with the pathophysiology of TCS. MATERIALS AND METHODS: Twenty five adult human cadavers (15 males, 10 females) and 100 MRI echo scans of lumbosacral region (50 males and 50 females), were used in this study. MRI patients were divided into 21-40 and 41-60 age groups. The cadavers were dissected at the prone position to explore their fila. The length of FT, filum terminale internum (FTI), filum terminale externum (FTE), vertebral level of beginning, dural piercing and termination of FT, and the initial, midpoint, and mid-FTE diameters were determined. Four segments were excised from lower conus, upper, middle, and lower thirds of FT. The specimens were processed for light microscopic examination. Statistical analysis was done for these parameters. RESULTS: MRI morphometrical parameters of FT, except FTI length, revealed no age effect or sex differences, where length of FTI, FTE, initial diameter, level of conus medullaris termination (CMT) and dural sac termination (DST) were 174.1 ± 16.8, 75.8 ± 9.5, 1.6 ± 0.21, L1-2 and S2U in males and 166.9 ± 18.9, 74.1 ± 9.3, 1.53 ± 0.25, L1-2 and S2M vertebrae in females, respectively. However, non-significant sex difference was observed in morphometric parameters of cadaveric FT, where length of FTI and FTE, initial diameter, CMT and DST levels were 164.2 ± 11.6, 76.7 ± 8.1, 1.7 ± 0.14, L1L and S2U vertebrae in males and 159.2 ± 10.1, 71.02 ± 7.3, 1.6 ± 0.29, L1L and S2U in females, respectively. Moreover, CMT below L2 vertebra was seen in 5% of MRI scans and 8% of cadavers. Also, the initial diameter of FT > 2 mm was recorded in 7% of MRI and 8% of cadaveric cases. Histologically, the structure of FT showed gradual reduction in nervous, glial, and vascular tissues with converse increase in collagen content in FTE compared with those of FTI. CONCLUSIONS: Knowledge of the morphometric parameters and the histological structure of FT are necessary for clinicians who dealing with diagnosis or treatment of tethered cord syndrome.

A comparative study of three extraction protocols of DNA from nails: Potential use in the diagnosis of onychomycoses.

Molecular techniques can be useful adjuncts to the diagnosis of onychomycoses. However, the nail presents difficulties in the extraction of its DNA. The comparison of three extraction protocols of DNA from nails and their ranking for possible use in the molecular diagnosis of onychomycoses are described. Extraction was performed on weighed nail clippings of equal size from positive (31) or negative (14) samples, according to the culture result. At Prot1, the extraction was performed according to Tahir and Watson, with an additional step implementing silica columns. At Prot2, the methodology proposed by the Statens Serum Institute of Copenhagen was used. At Prot3, DNA was extracted by the use of magnetic separation after homogenisation with glass beading. The evaluation parameters were DNA purity, DNA concentration, total DNA yield/g of tissue, cost and duration. The multiples of the means of medians of the first three parameters, for each protocol, were calculated. Prot3 showed the highest DNA purity. Prot2 presented the highest DNA concentration and DNA yield/g of tissue, while it was the cheapest and shortest. In total, the three protocols were graded as Prot2>Prot1>Prot3. The second method, although had a lower DNA purity, presented the higher DNA concentration and DNA yield, while its duration and cost were also favourable.

Concurrence of monoenergetic electron beams and bright X-rays from an evolving laser-plasma bubble.

Desktop laser plasma acceleration has proven to be able to generate gigaelectronvolt-level quasi-monoenergetic electron beams. Moreover, such electron beams can oscillate transversely (wiggling motion) in the laser-produced plasma bubble/channel and emit collimated ultrashort X-ray flashes known as betatron radiation with photon energy ranging from kiloelectronvolts to megaelectronvolts. This implies that usually one cannot obtain bright betatron X-rays and high-quality electron beams with low emittance and small energy spread simultaneously in the same accelerating wave bucket. Here, we report the first (to our knowledge) experimental observation of two distinct electron bunches in a single laser shot, one featured with quasi-monoenergetic spectrum and another with continuous spectrum along with large emittance. The latter is able to generate high-flux betatron X-rays. Such is observed only when the laser self-guiding is extended over 4 mm at a fixed plasma density (4 × 10(18) cm(-3)). Numerical simulation reveals that two bunches of electrons are injected at different stages due to the bubble evolution. The first bunch is injected at the beginning to form a stable quasi-monoenergetic electron beam, whereas the second one is injected later due to the oscillation of the bubble size as a result of the change of the laser spot size during the propagation. Due to the inherent temporal synchronization, this unique electron-photon source can be ideal for pump-probe applications with femtosecond time resolution.

Percutaneous nephrolithotomy for staghorn stones: a randomised trial comparing high-power holmium laser versus ultrasonic lithotripsy.

OBJECTIVE: To compare high-power holmium laser lithotripsy (HP-HLL) and ultrasonic lithotripsy (US-L) for disintegration of staghorn stones during percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: A non-inferiority randomised controlled trial was conducted between August 2011 and September 2014. Inclusion criteria were patients' aged >18 years who had complete staghorn stones (branching to the three major calyces), without contraindications to PCNL. Eligible patients were randomised between two groups: HP-HLL and US- . A standard PCNL in the prone position was performed for all patients. The only difference between the treatment groups was the method of stone disintegration. In the first group (HP-HLL), a laser power of 40-60 W (2 J, 20-30 Hz) was used to pulverise the staghorn stone into very small fragments, which could pass through the Amplatz sheath with the irrigation fluid. US-L,with suction of the fragments, was used in the second group. The primary outcome (stone-free rate) was evaluated with non-contrast computed tomography after 3 months. Secondary outcomes of complications, blood transfusion, operative time, and haemoglobin deficit were compared. The outcome assessor was 'blinded' to the treatment arm. RESULTS: The study included 70 patients (35 in each group). The baseline characteristics (age, sex, body mass index, side, stone volume, and density) and operative technique (number, size of tracts, and need for second PCNL session) were comparable for both groups. Operative time was significantly shorter in US-L group, at a mean (SD) of 130 (34) vs 148.7 (35) min (P = 0.028). The haemoglobin deficit was significantly more with in the US-L group, at a mean (SD) of 1.7 (0.9) vs 1.3 (0.6) g/dL (P = 0.037). The differences in blood transfusion (17% for US-L vs 11% for HP-HLL) and the complication rates (34% for US-L vs 23% for HP-HLL) were not significant (P = 0.495 and P = 0.290, respectively). The stone-free rates at 3 months were comparable (60% for US-L and 66% for HPL-L; P = 0.621). CONCLUSIONS: Compared with US-L for intracorporeal lithotripsy of staghorn stones during PCNL, HP-HLL showed comparable safety and efficacy with a lower haemoglobin deficit but longer operative time.

Association between type 1, type 2 cytokines, diabetic autoantibodies and 25-hydroxyvitamin D in children with type 1 diabetes.

PURPOSE: Vitamin D may play a role in the pathogenesis of type 1 diabetes (T1D). The aim of the current study was to determine the possible association between 25-hydroxyvitamin D [25(OH)D] levels and circulating levels of type 1 and type 2 cytokines, as well as the pathophysiology of T1D in children. METHODS: A total of 250 T1D patients and 250 sex- and age-matched T1D-free controls were screened for 25(OH)D, hemoglobin A1c (HbA1c), type 1 and type 2 cytokines, C-reactive protein (CRP) and bone mineral metabolism, as well as antibodies against insulin, glutamic acid decarboxylase (anti-GAD 65) and islet cells. RESULTS: Our data showed that the plasma level of 25(OH)D was significantly lower in T1D patients and that there was a significant negative correlation between 25(OH)D levels and HbA1c values. There was a significant association between deficient levels of 25(OH)D and higher levels of cytokines (IFN-γ, TNF-α, IL-6, IL-1ß, IL-4 and IL-10) and CRP. Total blood hemoglobin, the hematocrit percentage, body mass index SDS values, phosphate and magnesium levels were significantly lower in T1D patients than in T1D-free subjects. The levels of parathyroid hormone and alkaline phosphatase were significantly higher in T1D patients. Higher levels of cytokines were significantly associated with deficient levels of 25(OH)D. Moreover, in T1D patients, higher levels of islet antibodies, anti-GAD antibodies and anti-insulin antibodies were significantly associated with deficient levels of 25(OH)D. CONCLUSIONS: In type 1 diabetic children, deficient levels of 25(OH)D are associated with high levels of HbA1c, circulatory cytokines and antibody markers.

Epidemiology of superficial mycoses in Northern Greece: a 4-year study.

BACKGROUND: Superficial mycoses are defined as the fungal infections of skin, hair or nails that are caused by dermatophytes, yeasts and non-dermatophytic moulds. Dermatophytes are the most frequently isolated fungi from specimens of patients with superficial mycoses. OBJECTIVE: Studying the possible alteration of the epidemiology of superficial mycoses in Northern Greece during the last two to three decades. MATERIALS AND METHODS: Data concerning the superficial mycoses from patients coming mainly from the region of Macedonia, Northern Greece, between January 2010 and January 2014 were recorded and analysed. They included specimens from 438 patients (146 M/292 F), within an age range of 2-85 years old. 503 samples were collected from skin (81, 16.1%), hair (18, 3.6%) and nails (fingernails 84, 16.7%, toenails 320, 63.6%) lesions. RESULTS: Of a total of 222 positive cultures, 50 were considered as yielding clinically non-significant isolates (saprophytes). Among the rest (172), dermatophytes were the most prevalent isolates (102, 59.3%), followed by yeasts (51, 29.7%) and non-dermatophytic moulds (19, 11%). Trichophyton rubrum (55, 53.9%), Trichophyton mentagrophytes (18, 17.6%) and Microsporum canis (23, 22.5%) were the most common isolates among dermatophytes (total = 102). Candida parapsilosis (26, 51%), and Candida albicans (10, 19.6%) among yeasts (total = 51) whereas Fusarium (6, 31.6%) and Acremonium species (3, 15.8%) among the non-dermatophytic moulds (total=19). CONCLUSION: Compared to previous studies from Northern Greece, the epidemiology of superficial mycoses in the specific geographic region seems not to have been altered the last two to three decades.

Expression of Toll­like receptors 3 and 9 in Egyptian systemic lupus erythematosus patients.

BACKGROUND: Systemic lupus erythematosus (SLE) is a common complex disease characterized by chronic generalized inflammation which may involve several tissues and organs. OBJECTIVE: The aim of this work was to study the expression of Toll-like receptors (TLR) 3 and 9 in SLE patients, and to investigate their relationship to clinical features, disease activity, and damage. PATIENTS AND METHODS: The current study included 24 Egyptian female SLE patients and 15 matched controls. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI) and damage using the Systemic Lupus International Collaborating Clinics (SLICC) index. Expression of TLR3 and TLR9 in B- (CD19-positive) and T-lymphocytes (CD3-positive) was studied using flow cytometry. RESULTS: Patient age ranged between 17 and 42 years (mean 26.17 ± 5.78 years). There was a significant difference between patients and controls regarding TLR3/CD3, TLR3/CD19, TLR9/CD3, and TLR9/CD19 expression (p < 0.0001). There were significant correlations of TLR3/CD3, TLR3/CD19, and TLR9/CD19 with serum creatinine (r = 0.52, p = 0.009; r = 0.504, p = 0.012; and r = 0.58, p = 0.003; respectively) and negative correlations with ALT levels (r = -0.42, p = 0.04; r = -0.49, p = 0.016; and r = -0.472, p = 0.02; respectively). CONCLUSION: The results of the study suggest that TLR3 and TLR9 play a role in the pathogenesis of SLE, and have an impact on organ involvement in this disease. More studies concerning the biology and function of TLRs are required in larger patient cohorts, and may lead to development of a new class of drugs.

Vertebral level and measurements of conus medullaris and dural sac termination with special reference to the apex of the sacral hiatus: anatomical and magnetic resonance imaging radiologic study.

BACKGROUND: Anatomical orientation of the caudal space and termination level of conus medullaris (CMT) and dural sac (DST) has great significance for anaesthetists and neurosurgeons. This study aimed to explore the anatomical landmarks important to perform save spinal anaesthesia, lumber puncture and caudal analgesia through the correlation between the vertebral level of CMT, DST and sacral hiatus apex (SHA) in human cadavers and by using magnetic resonance imaging (MRI). MATERIALS AND METHODS: Sixty adult cadavers (40 males, 20 females) and 200 (100 males, 100 females) MR lumbosacral images of 16-69-year-old persons were used in this study. Vertebral level of CMT, DST and SHA and their linear distances were determined in cadavers and MRI. Also, anteroposterior diameter at SHA, length and thickness of sacrococcygeal membrane were measured as well, and correlate these levels and their distances with age and sex. RESULTS: Mean and highest frequent number of MRI vertebral level of CMT was observed at lower third of L1 in men and L1-2 disc in women, that of DST at upper third of S2 in men and middle third of S2 in women, while SHA was seen at middle third of S4 in both men and women with no significant (p > 0.05) age or gender differences. In 5% of cases, CMT, DST and SHA were seen at vertebral level below L2, below S2-3 and above S3, respectively. However, mean vertebral level of CMT, DST, SHA was observed at L1L, S2M and S4U without sex differen-ce in cadaveric specimens, respectively. All linear distances of men MRI revealed significant difference (p < 0.05) compared with those of women except thickness of sacrococcygeal membrane and anterposterior diameter at SHA. CONCLUSIONS: Accurate knowledge of vertebral level of CMT, DST and SHA and the distances in-between might decrease the iatrogenic injury of dural sac, spinal cord and cauda equina.

Renoprotective Effects of Fenofibrate via Modulation of LKB1/AMPK mRNA Expression and Endothelial Dysfunction in a Rat Model of Diabetic Nephropathy.

This study was conducted to investigate whether the renoprotective effects of fenofibrate are mediated via attenuation of endothelial dysfunction and modulating the mRNA expression of adenosine monophosphate-activated protein kinase (AMPK) and its downstream kinase liver kinase B1 (LKB1) in rats with diabetic nephropathy (DN). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg kg(-1)). Fenofibrate (100 mg kg(-1), p.o.) was given to diabetic rats daily for 12 weeks. Treatment with fenofibrate significantly improved the renal function as revealed by the significant reductions in urinary albumin excretion and serum levels of creatinine and urea, in addition to the significant increase in creatinine clearance compared with the diabetic control group. Hyperglycemia-induced oxidative damage was ameliorated by treatment with fenofibrate as indicated by the significantly increased levels of glutathione and catalase together with the significant decrease in lipid peroxidation. Administration of fenofibrate caused significant increases in renal nitric oxide (NO) production and mRNA expression of endothelial NO synthase (eNOS), AMPK and LKB1, reflecting improvement of endothelial function. Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN via modulation of AMPK, LKB1 and eNOS mRNA expression.

Enhanced single-stage laser-driven electron acceleration by self-controlled ionization injection.

We report on overall enhancement of a single-stage laser wakefield acceleration (LWFA) using the ionization injection in a mixture of 0.3% nitrogen gas in 99.7% helium gas. Upon the interaction of 30-TW, 30-fs laser pulses with a gas jet of the above gas mixture, >300 MeV electron beams were generated at a helium plasma densities of 3.3-8.5 × 10(18) cm(-3). Compared with the uncontrolled electron self-injection in pure helium gas jet, the ionization injection process due to the presence of ultra-low nitrogen concentrations appears to be self-controlled; it has led to the generation of electron beams with higher energies, higher charge, lower density threshold for trapping, and a narrower energy spread without dark current (low energy electrons) or multiple bunches. It is foreseen that further optimization of such a scheme is expected to bring the electron beam energy-spread down to 1%, making them suitable for driving ultra-compact free-electron lasers.

Myocardial bridge and coronary arteries: morphological study and clinical significance.

Myocardial bridge (MB) is the myocardial bundles covering a segment of a coronary artery or one of its branches. This work aimed to study the morphological properties of MB and their effects on the structure of the dominant coronary artery. Sixty adult human hearts (40 male and 20 female) were obtained from the Anatomy Department, Faculty of Medicine, King Abdulaziz University. Dissection o fthe coronary arteries and their main branches was done. Number, site, length and thickness of MB were determined in correlation with coronary dominancy. External diameter of proximal and distal segments of bridged branches and histology of the different segments of the anterior interventricular artery were examined as well. Thirty-six MB were observed in 27 (45%) hearts (18 male and 9 female). MB were mostly observed on the middle segment of the anterior interventricular artery (52.8%) and to a lesser extent on its diagonal branch (13.8%), posterior interventricular artery (13.8%), median and left marginal branches (5.6%), and right coronary artery stem (2.8%). In 30% out of 56.7% of right, in 8.3% out of 26.7% of balanced and in 6.7% out of 16.7% of left dominant hearts revealed MB. The mean length of MB was 24.9 ± 1.98 mm and that of their thickness was 2.28 ± 0.13 mm. Morphological differences in external diameter and histological structure of the different parts of bridged branch were observed. Knowledge of morphological aspects and effects of MB provide better therapeutic and surgical interventions for clinicians dealing with patients having MB.

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.

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.

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.

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.

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.