Enhanced Antidepressant Activity of Nanostructured Lipid Carriers Containing Levosulpiride in Behavioral Despair Tests in Mice.

The potential of levosulpiride-loaded nanostructured lipid carriers (LSP-NLCs) for enhanced antidepressant and anxiolytic effects was evaluated in the current study. A forced swim test (FST) and tail suspension test (TST) were carried out to determine the antidepressant effect whereas anxiolytic activity was investigated using light-dark box and open field tests. Behavioral changes were evaluated in lipopolysaccharide-induced depressed animals. The access of LSP to the brain to produce therapeutic effects was estimated qualitatively by using fluorescently labeled LSP-NLCs. The distribution of LSP-NLCs was analyzed using ex vivo imaging of major organs after oral and intraperitoneal administration. Acute toxicity studies were carried out to assess the safety of LSP-NLCs in vivo. An improved antidepressant effect of LSP-NLCs on LPS-induced depression showed an increase in swimming time (237 ± 51 s) and struggling time (226 ± 15 s) with a reduction in floating (123 ± 51 s) and immobility time (134 ± 15 s) in FST and TST. The anxiolytic activity in the light-dark box and open field tests exhibited superiority over LSP dispersion. Near-infrared images of fluorescently labeled LSP-NLCs demonstrated the presence of coumarin dye in the brain after 1 h of administration. An acute toxicity study revealed no significant changes in organ-to-body weight ratio, serum biochemistry or tissue histology of major organs. It can be concluded that nanostructured lipid carriers can efficiently deliver LSP to the brain for improved therapeutic efficacy.

Augmented Oral Bioavailability and Prokinetic Activity of Levosulpiride Delivered in Nanostructured Lipid Carriers.

The present study is aimed to develop and optimize levosulpiride-loaded nanostructured lipid carriers (LSP-NLCs) for improving oral bioavailability and prokinetic activity of LSP. LSP-NLCs were optimized with D-optimal mixture design using solid lipid, liquid lipid and surfactant concentrations as independent variables. The prepared LSP-NLCs were evaluated for physicochemical properties and solid-state characterization. The in vivo oral pharmacokinetics and prokinetic activity of LSP-NLCs were evaluated in rats. LSP-NLCs formulation was optimized at Precirol® ATO 5/Labrasol (80.55/19.45%, w/w) and Tween 80/Span 80 concentration of 5% (w/w) as a surfactant mixture. LSP-NLCs showed a spherical shape with a particle size of 152 nm, a polydispersity index of 0.230 and an entrapment efficiency of 88%. The DSC and PXRD analysis revealed conversion of crystalline LSP to amorphous state after loading into the lipid matrix. LSP-NLCs displayed a 3.42- and 4.38-flods increase in AUC and Cmax after oral administration compared to LSP dispersion. In addition, LSP-NLCs showed enhanced gastric emptying (61.4%), intestinal transit (63.0%), and fecal count (68.8) compared to LSP dispersion (39.7%, 38.0% and 51.0, respectively). Taken together, these results show improved oral bioavailability and prokinetic activity of LSP-NLCs and presents a promising strategy to improve therapeutic activity of LSP for efficient treatment of gastric diseases.

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability.

Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, Cmax, and lower Tmax than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.

Heat-related illnesses in a mass gathering event and the necessity for newer diagnostic criteria: a field study.

Heat-related illnesses (HRIs), mainly heat exhaustion (HE) and heat stroke (HS), are characterized by an elevation of core body temperature. In this study, we aimed to explore the HRIs' types and patient characteristics among a sample taken from various representative in-field points in the Hajj season. A cross-sectional study was conducted in 2018 at 80 data collection points distributed in the field. Data related to demographics, features and risk factors were collected and analyzed from all encountered cases with suspected HRIs. Moreover, we developed a diagnostic tree for HRIs by using the XGBoost model. Out of the 1200 persons encountered during the study period, 231 fulfilled the criteria of HRIs spectrum and were included in this study. Around 6% had HS and 20% had HE. All HS cases (100%) were from outside of Saudi Arabia as compared with 72.5% diagnosed with HE (27.5% were from Saudi Arabia). In addition, 16% were considered as heat-induced muscle spasms, and 7% had limb heat edema. Additionally, most of HRIs cases were reported between 11 am and 1 pm. The HRIs diagnostic tree model gave a diagnostic accuracy of 93.6%. This study highlights the magnitude of HRIs among pilgrims in Hajj and provides a diagnostic tree that can aid in the risk stratification and diagnosis of these patients. We advise the implementation of more educational campaigns to pilgrims regarding preventable measures especially for the vulnerable groups (e.g. from outside Saudi Arabia, those with comorbidities and light-skinned people).

Molecular Identification and Genetic Characterization of Macrophomina phaseolina Strains Causing Pathogenicity on Sunflower and Chickpea.

Macrophomina phaseolina is the most devastating pathogen which causes charcoal rot and root rot diseases in various economically important crops. Three strains M. phaseolina 1156, M. phaseolina 1160, and M. phaseolina PCMC/F1 were tested for their virulence on sunflower (Helianthus annuus L.) and chickpea (Cicer arietinum L.). The strains showed high virulence on both hosts with a disease score of 2 on chickpea and sunflower. The strains also increased the hydrogen per oxide (H2O2) content by 1.4- to 1.6-fold in root as well as shoot of chickpea and sunflower. A significant increase in antioxidant enzymes was observed in fungal infected plants which indicated prevalence of oxidative stress during pathogen propagation. The M. phaseolina strains also produced hydrolytic enzymes such as lipase, amylase, and protease with solubilization zone of 5-43 mm, 5-45 mm, and 12-35 mm, respectively. The M. phaseolina strains were identified by 18S rRNA and analyzed for genetic diversity by using random amplified polymorphic DNA (RAPD) markers. The findings based on RAPD markers and 18S rRNA sequence analysis clearly indicate genetic variation among the strains collected from different hosts. The genetically diverse strains were found to be pathogenic to sunflower and chickpea.

Demographic distribution of maxillofacial fractures in Ayub Teaching Hospital: 7-year review.

BACKGROUND: This retrospective study was carried out to determine the demographic distribution of Maxillofacial Fractures (MFF) in patients reported to Maxillofacial Surgical Unit, Ayub Teaching Hospital, Abbottabad from 2001 to 2007. METHODS: All the patients having a history of maxillofacial fractures were included according to age, gender distribution and risk factors. Isolated Nasal fractures, Naso-Orbito-Ethmiodal complex fractures and earthquake victims were excluded from this study. RESULTS: This study encompassed a total numbers of 952 patients. Males were 645 (67.8%) and females were 307 (32.2%) with male to female ratio 2.1:1. Most of the fractures occurred during third decade of life. The most common risk factor was Road Traffic Accident (RTA) n=70 (38.9%). Most of the fractures were occurred during the month of June, July and August. CONCLUSION: RTA is still the most common risk factor of maxillofacial fractures and is more common in male.

Distally based sural fasciocutaneous flap for soft tissue reconstruction of the distal leg, ankle and foot defects.

BACKGROUND: Soft tissue management around the lower third of the leg and foot presents a considerable challenge to the reconstructive plastic surgeon. The options in this region are limited. A durable flap is the preferred option for coverage of such defects. This descriptive study was conducted at Hayatabad Medical Complex and Said Anwar Medical Centre Peshawar over a period of 4 years to evaluate the efficacy of distally based Sural flap in coverage of the lower third of leg, ankle and foot defects, in 25 patients. METHODS: A descriptive study was conducted at the department of Plastic and Reconstructive Surgery at Hayatabad Medical Complex and Said Anwar Medical centre Peshawar. 25 patients with soft tissue defects over the distal leg and foot were included in this study. Distally based sural fasciocutaneous flap was used for coverage in all cases and its survival, successful coverage of the defect and donor site morbidity studied. RESULTS: Out of 25 flaps, 20 showed complete survival (80%). Partial flap loss was found in 2 patients (8%), marginal flap necrosis in 2 patients (8%) and complete loss in 1 patient (4%). CONCLUSIONS: The distally based sural flap is a versatile and reliable flap for the coverage of soft tissue defects of the distal lower extremity. The procedure is done as a single stage; the dissection is easy with short operating time and minimal morbidity.

Assessment of genetic variation within Indian mustard (Brassica juncea) germplasm using random amplified polymorphic DNA markers.

Genetic diversity among 45 Indian mustard (Brassica juncea L.) genotypes comprising 37 germplasm collections, five advance breeding lines and three improved cultivars was investigated at the DNA level using the random amplified polymorphic DNA (RAPD) technique. Fifteen primers used generated a total of 92 RAPD fragments, of which 81 (88%) were polymorphic. Of these, 13 were unique to accession 'Pak85559'. Each primer produced four to nine amplified products with an average of 6.13 bands per primer. Based on pairwise comparisons of RAPD amplification products, Nei and Li's similarity coefficients were calculated to evaluate the relationships among the accessions. Pairwise similarity indices were higher among the oilseed accessions and cultivars showing narrow ranges of 0.77-0.99. An unweighted pair-group method with arithmetic averages cluster analysis based on these genetic similarities placed most of the collections and oilseed cultivars close to each other, showing a low level of polymorphism between the accessions used. However, the clusters formed by oilseed collections and cultivars were comparatively distinct from that of advanced breeding lines. Genetically, all of the accessions were classified into a few major groups and a number of individual accessions. Advanced breeding lines were relatively divergent from the rest of the accessions and formed independent clusters. Clustering of the accessions did not show any pattern of association between the RAPD markers and the collection sites. A low level of genetic variability of oilseed mustard was attributed to the selection for similar traits and horticultural uses. Perhaps close parentage of these accessions further contributed towards their little diversity. The study demonstrated that RAPD is a simple and fast technique to compare the genetic relationship and pattern of variation among the gene pool of this crop.

Management protocol of mandibular fractures at Pakistan Institute of Medical Sciences, Islamabad, Pakistan.

BACKGROUND: Maxillofacial trauma is very frequent and associated with a high incidence of mandibular fractures. Although there is universal agreement as to the treatment goals and basic therapeutic principles of reduction and stabilization, a variety of currently accepted treatment modalities indicate a lack of consensus. The authors evaluate the incidence, etiology, management and complications of 344 mandibular fractures in 228 patients treated in the Department of Plastic and Reconstructive Surgery at Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan, during a three year period. Indications and techniques for closed and open treatment of mandibular fractures are reviewed along with any complications of these fractures or their management. METHODS: A total of 344 mandibular fractures in 228 patients were included in this study. The sex, age, etiology, presentation, fracture characteristics, associated injuries, various methods of management and any pre or postoperative complications were evaluated. RESULTS: Although various devices and techniques have been used to treat these fractures, modern plate and screw fixation systems have proved to provide the best rigid stabilization, early mobility and associated with least complications. There was a satisfactory bone healing in all the patients and a minimal complication rate associated with open reduction and internal fixation (ORIF). CONCLUSION: Mandibular fractures occur with high frequency in road traffic accidents and interpersonal violence. They are among the most common types of facial fractures treated by the plastic surgeons. They must be managed carefully to maintain the function of the mandible, reestablish proper occlusion, and minimize secondary complications. Open reduction and internal fixation has proven to be the most effective method for treatment of mandibular fractures.

Down-modulation of the CXCR4 co-receptor by intracellular expression of a single chain variable fragment (SFv) inhibits HIV-1 entry into primary human brain microvascular endothelial cells and post-mitotic neurons.

Our laboratories previously demonstrated that expression of a single chain variable antibody fragment (SFv), anti-CXCR4 SFv, in human lymphoid cells suppresses surface display of the chemokine co-receptor CXCR4 and inhibits infectious entry of human immunodeficiency virus type I (HIV-1). We now sought to extend these results to two types of central nervous system (CNS) cells, primary isolated human brain microvascular endothelial cells (MVECs), and post-mitotic differentiated human neurons, both of which normally express significant levels of CXCR4. The anti-CXCR4 SFv expression construct was delivered using an HIV-1-based vector, and control cells received LacZ-expressing viral particles. Upon intracellular expression of the anti-CXCR4 SFv, immunostaining revealed a marked reduction in surface display of CXCR4 on both cell types. Consequently, post-mitotic neurons expressing the anti-CXCR4 SFv were significantly protected from HIV-1 infection, as measured by HIV-1 p24 antigen production, and partial protection was observed in human brain MVECs. The ability to selectively down-modulate the surface expression of CXCR4 in CNS cells may allow for the development of clinical molecular therapy strategies against HIV-1-related neurodegenerative disorders and neuroinvasion.