Comparing Complications and Patient Satisfaction Following Injectable Collagenase Versus Limited Fasciectomy for Dupuytren's Disease: A Systematic Review and Meta-Analysis.

Dupuytren's disease (DD) is a fibroproliferative disorder that manifests as an abnormal growth of myofibroblasts, causing nodule formation and contractures and affecting digit function. If left untreated, these contractures can lead to a loss of mobility and potentially impact hand function. This systematic review critically compares and evaluates the existing literature on the complications and patient satisfaction following injectable collagenase Clostridium histolyticum (CCH) versus limited fasciectomy (LF) for DD. We performed a comprehensive search of the PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), The Cochrane Library, and Excerpta Medica database (EMBASE) databases from 2006 to August 2023. This research targeted all clinical studies involving adults who underwent injectable collagenase and/or limited fasciectomy in the management of DD. Out of the 437 identified studies, only 53 were considered eligible for our analysis, and merely 14 met our inclusion criteria. These selected studies encompassed a total of 967 patients with 1,344 treated joints, with an average follow-up duration of 19.22 (ranging from one to 84.06) months. Within this cohort, 498 joints from 385 patients underwent LF, while 846 joints from 491 patients received CCH injections. Notably, among the 491 patients treated with CCH, 1,060 complications were reported, averaging 2.15 complications per patient, with the most common being contusion/bruising/hematoma/ecchymosis (22.54%), and edema/swelling (18.96%). In contrast, among the 385 patients treated with LF, only 97 complications were reported, translating to 0.25 complications per patient, with the most frequent being paraesthesia or numbness (23.7%), scar sequelae like skin laceration, tear, fissure, or hypertrophic scar (23.7%), and neuropraxia or nerve injury (22.6%). Our meta-analysis indicates that paraesthesia or numbness is more frequently observed in LF than CCH injections, although without statistical significance, with a risk ratio (RR) of 0.39 (95% confidence interval (CI) 0.13-1.18, p-value 0.1). However, scar sequelae (hypertrophic scar, skin laceration, tear, or fissure) show a contrasting pattern, being more commonly associated with CCH injections than LF, with an RR of 1.98 (95% CI 0.26-14.85, p-value 0.51), which, upon eliminating the source of heterogeneity, becomes statistically significant, with an RR of 4.98 (95% CI 1.40-17.72, p-value 0.01). Our data revealed a higher frequency of complications with CCH compared to LF, although more severe adverse effects were observed in the LF group, such as neuropraxia or nerve injury. Scar sequelae were more common with CCH injections. Despite both treatments showing increased patient satisfaction at the final follow-up, CCH injection resulted in earlier improvements in satisfaction.

Bioactivity and molecular docking of lactones isolated from Centaurea pseudosinaica Czerep.

Two cytotoxic sesquiterpene lactones, 17-epichlorohyssopifolin A (1) and chlorjanerin (2), and a monoterpene lactone, loliolide (3) were isolated from Centaurea pseudosinaica. The cytotoxicity of the total extract and terpenoids 1-3 were evaluated against three human cancer cells (HepG2, PC-3, and HT-29), along with the human normal primary epidermal keratinocytes (HEKa) cells. With IC50 values ranging between 0.6 ± 0.04 and 5.0 ± 0.61 µg/mL against HepG2; 0.2 ± 0.01 and 11.9 ± 1.31 µg/mL against PC-3, and 0.04 ± 0.013 and 8.9 ± 0.97 µg/mL against HT-29, the total extract, and lactones 1-3 demonstrated cytotoxic effects. Compound 1 displayed the strongest impact on all cancer cells and a slightly safe effect on the normal cells HEKa. Compound 1 caused accumulation of HepG2 and HT-29 cells in G1 phase as displayed cell cycle analysis. On the other hand, the cell distributions were increased in the S phase in PC-3 cells. Furthermore, 1 caused apoptosis in PC-3 and HePG2 cells with 91.50%, and 79.72 %, respectively. A higher fraction of necrotic cells was observed in HT-29 cells amounting to 23.60%. These results suggested that the promising cytotoxicity exhibited by 1 is brought by the apoptosis induction in the cancer cells, which were evaluated. As the compounds showed antiproliferative effect against the HT-29 cells, the docking simulation was performed aiming at determining how they would interact with the EGFR enzyme, whose PDB: 4I23 is considered one of the two distinct wild types of EGFR enzymes. The antibacterial activity results revealed that 3 showed the most remarkable antibacterial effects, especially against the examined Gram-positive bacteria. The total extract exhibited potent activity against all examined bacteria. The total extract showed a potent antifungal effect against two Candida and two Aspergillus pathogens. The antioxidant activity revealed the potency of the total extract and 3 as antioxidant candidates. The obtained results refer to the importance of Centaurea pseudosinaica as a source of potent antiproliferative agents and the whole plant as an antipathogenic and antioxidant agent.

Development of UPLC method for simultaneous assay of some COVID-19 drugs utilizing novel instrumental standard addition and factorial design.

A green, rapid, and simple RP-UPLC method was developed and optimized by full factorial design for the simultaneous separation of oseltamivir phosphate, daclatasivir dihydrochloride, and remdesivir, with dexamethasone as a co-administered drug. The separation was established on a UPLC column BEH C18 1.7 µm (2.1 × 100.0 mm) connected with a UPLC pre-column BEH 1.7 µm (2.1 × 5.0 mm) at 25 °C with an injection volume of 10 µL. The detector (PDA) was set at 239 nm. The mobile phase consisted of methanol and ammonium acetate (8.1818 mM) in a ratio of 75.7: 24.3 (v/v). The flow rate was set at 0.048 mL min-1. The overall separation time was 9.5 min. The retention times of oseltamivir phosphate, dexamethasone, daclatasivir dihydrochloride, and remdesivir were 6.323 ± 0.145, 7.166 ± 0.036, 8.078 ± 0.124, and 8.572 ± 0.166 min (eight replicates), respectively. The proposed method demonstrated linearity in the ranges of 10.0-500.0 (ng mL-1) and 0.5-30.0 (µg mL-1) for oseltamivir phosphate, 50.0-5000.0 (ng mL-1) for dexamethasone, 25.0-1000.0 (ng mL-1) and 0.5-25.0 (µg mL-1) for daclatasvir dihydrochlorde, and 10.0-500.0 (ng mL-1) and 0.5-30.0 (µg mL-1) for remdesivir. The coefficients of determination (R2) were greater than 0.9999, with percentage recoveries greater than 99.5% for each drug. The limits of quantitation were 6.4, 1.8, 7.8, and 1.6 ng mL-1, and the limits of detection were 1.9, 0.5, 2.0, and 0.5 ng mL-1 for oseltamivir phosphate, dexamethasone, daclatasivir dihydrochloride, and remdesivir, respectively. The proposed method was highly precise, as indicated by the low percentage of relative standard deviation values of less than 1.2% for each drug. The average content and uniformity of dosage units in the studied drugs' dosage forms were determined. The average contents of oseltamivir phosphate, dexamethasone, daclatasivir dihydrochloride, and remdesivir were nearly 93%, 102%, 99%, and 95%, respectively, while the uniformity of dosage unit values were nearly 92%, 102%, 101%, and 97%. Two novel methods were established in this work. The first method was used to assess the stability of standard solutions. This novel method was based on the slope of regression equations. The second was to evaluate the excipient's interference using an innovative instrumental standard addition method. The novel instrumental standard addition method was performed using the UPLC instrument program. It was more accurate, sensitive, time-saving, economical, and eco-friendly than the classic standard addition method. The results showed that the proposed method can estimate the tested drugs' concentrations without interference from their dosage form excipients. According to the Eco-score (more than 75), the Green Analytical Procedure Index (GAPI), and the AGREE criteria (total score of 0.77), the suggested method was considered eco-friendly.

Growth, physiological, and molecular responses of three phaeophyte extracts on salt-stressed pea (Pisum sativum L.) seedlings.

BACKGROUND: Seaweeds are a viable bioresource for suffering plants against salt stress, as they abundant in nutrients, hormones, vitamins, secondary metabolites, and many other phytochemicals that sustain plants' growth under both typical and stressful situations. The alleviating capacity of extracts from three brown algae (Sargassum vulgare, Colpomenia sinuosa, and Pandia pavonica) in pea (Pisum sativum L.) was investigated in this study. METHODS: Pea seeds were primed for 2 h either with seaweed extracts (SWEs) or distilled water. Seeds were then subjected to salinity levels of 0.0, 50, 100, and 150 mM NaCl. On the 21st day, seedlings were harvested for growth, physiological and molecular investigations. RESULTS: SWEs helped reduce the adverse effects of salinity on pea, with S. vulgare extract being the most effective. Furthermore, SWEs diminished the effect of NaCl-salinity on germination, growth rate, and pigment content and raised the osmolytes proline and glycine betaine levels. On the molecular level, two low-molecular-weight proteins were newly synthesized by the NaCl treatments and three by priming pea seeds with SWEs. The number of inter-simple sequence repeats (ISSR) markers increased from 20 in the control to 36 in 150 mM NaCl-treated seedlings, including four unique markers. Priming with SWEs triggered more markers than the control, however about ten of the salinity-induced markers were not detected following seed priming before NaCl treatments. By priming with SWEs, seven unique markers were elicited. CONCLUSION: All in all, priming with SWEs alleviated salinity stress on pea seedlings. Salinity-responsive proteins and ISSR markers are produced in response to salt stress and priming with SWEs.

Is surgical intervention routinely required for congenital lobar overinflation? A case series from a tertiary hospital in Riyadh, Saudi Arabia.

Introduction: Congenital lobar overinflation (CLO) is a congenital overinflation of a pulmonary lobe. The treatment choice depends on the severity of its symptoms. Surgical intervention is indicated for patients with significant symptomatology, while a conservative approach is used to treat incidental and mildly symptomatic lesions. However, the conservative approach for children with mild symptoms is not very common among pulmonologist. Therefore, we evaluated this approach to treating mildly symptomatic children. Methods: This retrospective study examined mildly symptomatic patients (n = 14) with a radiological diagnosis of CLO between June 2005 and August 2018 who were treated conservatively at KFSHRC in Riyadh. The participants' ages ranged between two days and four years, with follow-up period ranged from four months to 10 years. Results: Fourteen patients with CLO-who were 2 days to four years old and comprised 10 boys (71.4%) and four girls (28.6%)-were treated conservatively. All patients were symptomatic upon presentation, and their main clinical findings were tachypnea (85.7%) and dyspnea (78.6%). A single lobe was affected for ten patients (71.4%). Congenital cardiac anomalies founded in six patients (42.9%). Radiological image showed overinflation of all patients' affected lobes. Significant mediastinal displacement was observed among two patients (14.3%). During their follow-up periods, nine patients (64.3%) became asymptomatic, three (21.4%) showed improvement, and two (14.3%) remained symptomatic and underwent lobectomy. Conclusions: The good outcomes for mildly symptomatic children with CLO in our series indicate that the conservative approach can be considered to treat these children at any age, along with close follow-up.

Chronic oestrogen deficiency induced by ovariectomy may cause lung fibrosis through activation of the renin-angiotensin system in rats.

CONTEXT: Oestrogen deficiency is linked with pulmonary fibrosis. Additionally, it may lead to over-activation of the renin-angiotensin system (RAS), which worsens lung fibrosis. OBJECTIVE: The present study aims to investigate the role of RAS on lung fibrosis associated with oestrogen deficiency in ovariectomised rats. MATERIALS AND METHODS: Serum 17ß-oestradiol (E2), arterial blood gases, plasma angiotensin II levels, lung tissue hydroxyproline content, and transforming growth factor beta 1 (TGF-ß1) concentration, the mRNA expression of angiotensin type 1 receptor (AT1R), and angiotensin-converting enzyme (ACE1) were evaluated. Moreover, lung tissues were examined by histopathology and immunohistochemistry. RESULTS: Hydroxyproline content, TGF-ß1 concentration, plasma angiotensin II, the relative mRNA expression of ACE1, and AT1R is found to increase in ovariectomised rats. The mentioned changes can be largely rescued by administration of RAS blockers. CONCLUSION: Oestrogen deficiency activates RAS, which consequently increases the expression of pro-fibrotic factors and stimulates the fibrotic cascade causing lung fibrosis.

Musca domestica (Diptera: Muscidae) as a biological model for the assessment of magnetite nanoparticles toxicity.

The use of nanoparticles (NPs) is rapidly expanding; there is a critical need for efficient assays to first determine the potential toxicity of NPs before their use in human applications. Magnetite nanoparticles (Fe3O4 NPs) have tremendous applications which include cell separation, arsenic removal from water and DNA separation. Spherically shaped Fe3O4 NPs with sizes ranging from 23 to 30 nm were used in this study. The housefly, Musca domestica is the most common fly species. It is present worldwide and considered to be an important medical insect which can carry and transmit over 100 human pathogens and zoonotic agents. It has been used in this study to assess Fe3O4NPs toxicity and give us an overview of their impact. The larvicidal activity of Fe3O4NPs was tested against the third instar larvae of M. domestica. We investigated the effects of six varying concentrations (15, 30, 45, 60, 75 and 90 µg/mL) used under laboratory conditions in two differential application assays: contact and feeding. The LC50 value for Fe3O4 NPs was 60 and 75 µg/mL by feeding and contact, respectively. To investigate the toxicity effects of Fe3O4 NPs on houseflies, morphological and histoarchitectural changes in larvae, pupae and adult flies were analyzed. NP exposure caused morphological abnormalities of larvae and pupae as well as larval pupal intermediates, and deformed adult with crumpled wings. Also, some adults couldn't emerge and remained in their puparia. The histological examinations showed that Fe3O4 NPs caused severe tissue damage especially in the cuticle and the digestive system. Thus, besides affecting the organ of first contact (digestive system), remote organs such as the integument are also targeted by Fe3O4 NPs suggesting a systemic impact on fly development and physiology.

Innovative derivative/zero ratio spectrophotometric method for simultaneous determination of sofosbuvir and ledipasvir: Application to average content and uniformity of dosage units.

An innovative simple, rapid and sensitive spectrophotometric method was developed for the simultaneous analysis of sofosbuvir (SOF) and ledipasvir (LED) in their combined dosage forms. Sofosbuvir with ledipasvir (SOF/LED) as a combined dosage form was tried at the pandemic COVID 19 crisis. This technique has the advantages of both zero order and first order spectrophotometry. The zero and first derivative amplitudes were measured at 274.2 nm for SOF (zero crossing point of LED in first derivative spectrum) and 314 nm for LED (zero crossing point of SOF in first derivative spectrum) over the concentration range of 2.0-50.0 µg mL-1 with coefficients of determination (R2) > 0.9999 for both drugs and mean percentage recoveries of 100.25 ± 1.61 and 99.85 ± 0.99 for SOF and LED; respectively. This original method was validated according to ICH requirements and statistically compared to published comparison methods. This method was applied to estimate the average content and the uniformity of dosage units of SOF/LED combined dosage form according to British Pharmacopeia requirements.

Molecular Phylogeny of Trifolium L. Section Trifolium with Reference to Chromosome Number and Subsections Delimitation.

The genus Trifolium is one of the largest genera of the legume family Fabaceae with ca. 255 species. The genus is divided into eight sections; the section Trifolium is a major section of the genus, comprising 73 species mainly distributed in the Mediterranean region. We used nuclear ribosomal DNA internal transcribed spacer (ITS) and morphological variation to reconsider the delimitation and phylogenetic relationships of species in the section Trifolium with reference to chromosomal variations. Bayesian analysis of ITS data delimited the species as three clades based on the analysis of ITS sequence and informative indels in combination with morphological variation. The phylogeny of the species by different analyses methods does not support their current delimitation in 17 subsections. The basic chromosome number x = 8 is the number for the genus Trifolium, from which x = 7, 6 and 5 were derived through successive aneuploidy events. With reference to the distribution of these numbers in the species of the section Trifolium, species in clade III and clade II are more evolved than species in clade I.

Antiproliferative Isoprenoid Derivatives from the Red Sea Alcyonacean Xenia umbellata.

From the soft coral Xenia umbellata, seven isoprenoid derivatives were isolated, including a new xenicane diterpene, xeniolide O (5) and a new gorgostane derivative gorgst-3ß,5α,6ß,11α,20(S)-pentol-3-monoacetate (7), along with three known sesquiterpenes (1-3), a known diterpene (4), and a known steroid (6). The extensive analyses of the NMR, IR, and MS spectral data led to determination of their chemical structures. Compounds 1-7 displayed a cytotoxic effect against breast adenocarcinoma (MCF-7), hepatocellular carcinoma (HepG2), and cervix adenocarcinoma (HeLa), with IC50 values ranging between 1.5 ± 0.1-23.2 ± 1.5; 1.8 ± 0.1-30.6 ± 1.1 and 0.9 ± 0.05-12.8 ± 0.5 µg/mL, respectively. Compound 3 showed potent cytotoxic effects against MCF-7, HepG2, and HeLa with IC50 values = 2.4 ± 0.20, 3.1 ± 0.10 and 0.9 ± 0.05 µg/mL, respectively. Compounds 2, 5, and 7 displayed cytotoxic effect against Hela cells with IC50 values = 12.8 ± 0.50, 6.7 ± 1.00 and 11.5 ± 2.20 µg/mL, respectively. Two DNA binding dyes, acridine orange (AO) and ethidium bromide (EtBr) were used for the detection of viable, apoptotic, and necrotic cells. The early apoptotic cell death was observed in all types of treated cells. The late apoptotic cells were highly present in HepG2 cells. Compounds 5 and 7 induced a high percentage of necrosis towards HepG2 and HeLa cells. The late apoptosis was recorded as a high rate after treatment with 7 on all cancer cells.

Pain perception in chronic knee osteoarthritis with varying levels of pain inhibitory control: an exploratory study.

Background and aims Pain is a disabling symptom in knee osteoarthritis (KOA) and its underlying mechanism remains poorly understood. Dysfunction of descending pain modulatory pathways and reduced pain inhibition enhance pain facilitation in many chronic pain syndromes but do not fully explain pain levels in chronic musculoskeletal conditions. The objective of this study is to explore the association of clinical variables with pain intensity perception in KOA individuals with varying levels of Conditioned Pain Modulation (CPM) response. Methods This is a cross-sectional, exploratory analysis using baseline data of a randomized clinical trial investigating the effects of a non-invasive brain stimulation treatment on the perception of pain and functional limitations due to KOA. Sixty-three subjects with KOA were included in this study. Data on pain perception, mood perception, self-reported depression, physical function, quality of life, and quantitative sensory testing was collected. Multiple linear regression analysis was performed to explore the association between the clinical variables with pain perception for individuals with different levels of CPM response. Results For KOA patients with limited CPM response, perception of limitations at work/other activities due to emotional problems and stress scores were statistically significantly associated with pain scores, F(2, 37) = 7.02, p < 0.01. R-squared = 0.275. For KOA patients with normal CPM response, general health perception scores were statistically significantly associated with pain scores, F(1, 21) = 5.60, p < 0.05. R-squared = 0.2104. Limitations of this study include methodology details, small sample size and study design characteristics. Conclusions Pain intensity perception is associated differently with clinical variables according to the individual CPM response. Mechanistic models to explain pain perception in these two subgroups of KOA subjects are discussed.

Dental Materials Incorporated with Nanometals and Their Effect on the Bacterial Growth of Staphylococcus aureus.

PURPOSE: The purpose of this study was to investigate the effect of different commercially used dental materials (RelyX Luting Plus and Dyract Extra) mixed with either a metallic ionic solution or a colloidal suspension of metallic nanoparticles. Both the solution and the suspension contained a mixture of silver, copper, and lithium ions. METHODS: The metal/ion-incorporated dental materials were prepared into disk-shaped samples and tested against the growth of Staphylococcus aureus. The susceptibility of bacteria against the antibacterial dental disks was tested using two methods: counting the colony-forming units per milliliter and disk diffusion (Kirby-Bauer). The incorporated materials (Dyract and Rely cement) were tested for ion release using flame atomic absorption spectroscopy. RESULTS: Assessment showed efficient antibacterial activity of metal ion-incorporated Rely luting cement, exhibited by the formation of inhibition zones larger than those formed by the standard antibiotic, as well as a reduction in bacterial number of sevenfold after incubation for 24 hours. Dyract material incorporated with nanoparticles showed no significant clear zones and had no inhibiting effect on bacterial colony numbers after incubation for 24 hours. The release of silver, copper, and lithium metal ions depended on the type of both dental material and the incorporated nanoagents. The metal ion-incorporated Rely Plus cement released the highest levels of metal ions, which was attributed to its antibacterial efficiency. CONCLUSION: Rely Plus cement incorporated with the nanoparticle suspension demonstrated high antibacterial potency, due to the release of the highest concentrations of silver, copper, and lithium metal ions. This work is the first direct comparative study of dental materials with different forms of nanomixtures (metallic nanoparticles and soluble metallic ions) and their antibacterial effects after incubation with bacterial culture for 24 hours.

Marine-Derived Macrocyclic Alkaloids (MDMAs): Chemical and Biological Diversity.

The curiosity and attention that researchers have devoted to alkaloids are due to their bioactivities, structural diversity, and intriguing chemistry. Marine-derived macrocyclic alkaloids (MDMAs) are considered to be a potential source of drugs. Trabectedin, a tetrahydroisoquinoline derivative, has been approved for the treatment of metastatic soft tissue sarcoma and ovarian cancers. MDMAs displayed potent activities that enabled them to be used as anticancer, anti-invasion, antimalarial, antiplasmodial, and antimicrobial. This review presents the reported chemical structures, biological activities, and structure-activity relationships of macrocyclic alkaloids from marine organisms that have been published since their discovery until May 2020. This includes 204 compounds that are categorized under eight subclasses: pyrroles, quinolines, bis-quinolizidines, bis-1-oxaquinolizidines, 3-alkylpiperidines, manzamines, 3-alkyl pyridinium salts, and motuporamines.

Influence of allicin administration on reproductive efficiency, immunity and lipid peroxidation of rabbit does under high ambient temperature.

This study investigated the effect of daily oral administration with allicin levels (0, 5 and 10 mg/kg of female body weight), 30 days pre-insemination, on reproductive performance in vivo and in vitro, immunity, and oxidative stress of rabbit does under high ambient temperature. Niliparous NZW does (n = 105) were randomly divided into three groups (35 in each) treated with 0, 5 and 10 mg allicin dissolved in 2 ml distilled water, respectively, for 30 days pre-insemination. At the end of treatment (30 days), does were artificially inseminated with fresh diluted semen of 20 fertile NZW bucks. Reproductive performance and ovulatory response parameters were determined. Serum biochemicals, enzyme activity, immunoglobulins (IgG and IgM) and antioxidant status were determined on day 30 of treatment. Serum progesterone and prolactin were determined pre-insemination (30 days of treatment), on 15 days of pregnancy and 7 days post-partum. Results showed that both allicin levels increased live litter size, and bunny viability rat and litter size at birth and weaning. Allicin levels increased ovulation rate and improved embryo quality. Number of total follicles decreased only with 10 mg allicin. Progesterone increased pre-insemination, 15 days of pregnancy and 7 days post-partum progesterone by allicin levels. Prolactin pre-insemination and on day 7 post-partum increased with 10 mg allicin. Serum total proteins, albumin, globulin, IgG and IgM increased, while glucose, aspartate and alanine aminotransaminases, and thiobarbituric acid reaction decreased by both allicin levels. In conclusion, the mechanism by which allicin administration 30 days pre-insemination to improve the reproductive performance of rabbit does is based on that allicin can play an important role, as a natural exogenous antioxidant, increasing immune response and reducing lipid peroxidation.

Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly.

BACKGROUND: Protein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways. METHODS: Eight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis. RESULTS: An identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72 repeat expansion toxicity, patients showed no evidence of C9ORF72 repeat expansions. CONCLUSION: The TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72 expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

Earth-friendly spectrophotometric methods for simultaneous determination of ledipasvir and sofosbuvir: Application to average content and uniformity of dosage unit testing.

Simple, rapid, sensitive, accurate, precise and earth-friendly spectrophotometric methods were developed for the simultaneous analysis of ledipasvir (LED) and sofosbuvir (SOF) without interference of both sunset yellow dye and copovidone excipients (the most probable interferents) in their combined dosage form. These proposed methods were based on measurement of LED in synthetic mixtures and combined dosage form by first derivative (1D) spectrophotometry at 314 nm over the concentration range of 2-50 µg mL-1 with coefficient of determination (R2) > 0.9999, mean percentage recovery of 99.98 ±â€¯0.62. On the other hand, SOF in synthetic mixtures and combined dosage form was determined by five methods. Method I is based on the use of 1D spectrophotometry at 274.2 nm (zero crossing point of LED). Method II involves the application of conventional dual wavelength method (DW) at the absolute difference between SOF zero order amplitudes at 261 nm (λmax of SOF) and 364.7 nm. At these wavelengths, the absolute difference between LED zero order amplitudes was observed to equal zero. Method III depends on isosbestic point method (ISP) in which the total concentration of both drugs was measured at isosbestic point at 262.7 nm. Concentration of SOF could be obtained by subtraction of LED concentration. While, method IV depends on absorbance correction method (absorption factor method), which is based on determination of SOF concentration at 262.7 nm (λISP) and LED at 333 nm (λmax of LED). Finally, method V depends on absorbance ratio method (Q-analysis) in which 262.7 nm (λISP) and 261 nm (λmax of SOF) were selected to determine SOF concentration. The linearity range for all methods for SOF determination was 2-50 µg mL-1 with coefficient of determination (R2) > 0.9999. Methods I, II & III were also applied for determination of SOF concentration in single dosage form. Their mean percentage recoveries were 100.35 ±â€¯1.85, 99.97 ±â€¯0.54 and 100.03 ±â€¯0.49, for the three methods respectively. The proposed methods were validated according to international conference of harmonization (ICH) requirements and statistically compared to published reference methods. The ANOVA test confirmed that there is no significant differences between the proposed methods, and can be used for routine analysis of LED and SOF in commercial tablets. These developed methods were applied to estimate the average content and uniformity of dosage unit for LED/SOF combined dosage form and SOF single dosage form according to British pharmacopeia (BP) requirements.

The glucagon-like peptide-1 receptor agonist Exendin-4, ameliorates contrast-induced nephropathy through suppression of oxidative stress, vascular dysfunction and apoptosis independent of glycaemia.

Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury, particularly in diabetic patients. Previous studies have shown renoprotective effects of glucagon-like peptide-1 (GLP-1) signalling; however, its role in CIN remains unexplored. This study investigates the prophylactic effect of exendin-4, a GLP-1R agonist, against CIN in a rat model mimicking both healthy and diabetic conditions. Animals were randomly divided into 7 groups: a control sham group (n = 8), and 2 identical sets of 3 disease groups, one received exendin-4 before exposure to contrast medium (CM), while the other served as untreated control. The 3 disease groups represented diabetes (n = 8), CIN (n = 8), or diabetes and CIN combined (n = 8). Untreated groups showed deteriorating renal function as indicated by significantly higher levels of serum creatinine and blood urea nitrogen, malondialdehyde, and endothelin-1 and caspase-3 expression compared to the sham control group. This was accompanied by a significant decrease in tissue reserves of reduced glutathione, superoxide dismutase, nitrate and endothelin nitric oxide synthase as well as deteriorating renal histology. The CM-induced changes in diabetic rats indicate impaired renal function, oxidative stress, vascular dysfunction, and apoptosis, and were significance higher in intensity compared to non-diabetic rats. Pretreatment with exendin-4 ameliorated all the aforementioned CM-induced nephropathic effects independent of the glycemic state. To our knowledge, this is the first study describing the prophylactic renoprotective effects of exendin-4 against CIN. With the current pharmaceutical use of exendin-4 as a hypoglycaemic agent, the GLP-1R agonist becomes an interesting candidate for human clinical trials on CIN prevention.

Role of Bone Marrow Derived Mesenchymal Stem Cells and the Protective Effect of Silymarin in Cisplatin-Induced Acute Renal Failure in Rats.

BACKGROUND: Cisplatin is a highly effective antitumor agent whose clinical application is limited by its nephrotoxicity, which is associated with high mortality and morbidity rates. We aimed to study the protective role of silymarin and mesenchymal stem cells as a therapeutic tool of cisplatin nephrotoxicity. MATERIALS AND METHODS: We injected rats with cisplatin in a dose of 5mg/kg body weight for 5 days to induce acute renal failure (ARF). Silymarin was administrated 6 hours before cisplatin injection and mesenchymal stem cells were injected 24 hours after cisplatin-induced ARF. RESULTS: We assessed the ARF biochemically by elevation of kidney function tests and histopathologically by an alteration of the histological architecture of the renal cortex in the form of shrinkage of glomeruli, lobulated tufts and glomerular hypertrophy with narrowing capsular space. The tubules showed extensive tubular degeneration with cellular hyaline materials and debris in the lumen of the renal tubules. The renal blood vessels appeared sclerotic with marked thickened walls. When silymarin was given in different doses before cisplatin, it decreased the toxic effect of cisplatin in the kidney but sclerotic blood vessels remained. Injection of mesenchymal stem cells in rats with cisplatin-induced ARF improved the histopathological effects of cisplatin in renal tissues and kidney function tests were significantly improved. CONCLUSIONS: There was a significant improvement in kidney function tests and renal histopathology by using silymarin as protective mechanism in cisplatin-induced ARF. Administration of mesenchymal stem cells denoted a more remarkable therapeutic effect in ARF.

Protective effect of rimonabant, a canabinoid receptor 1 antagonist, on nonalcoholic fatty liver disease in a rat model through modulation of the hepatic expression of activin A and follistatin.

Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver morbidity and mortality, and there is still no proven effective therapy. The endocannabinoid system plays an important role in various liver diseases. Activin A is a member of the transforming growth factor beta (TGF-ß) superfamily and inhibits hepatocyte growth. Follistatin antagonizes the biological actions of activin A. This study was designed to investigate the effect of rimonabant (a potent cannabinoid receptor1 (CB1) antagonist) on NAFLD induced with a choline-deficient (CD) diet in rats, as well as to detect whether it can alter the hepatic expression of activin A and follistatin. Forty rats were distributed among 4 groups: the control group, the rimonabant treatment group (normal rats that received rimonabant); the CD diet group (NAFLD induced with a CD diet); and the CD diet + rimonabant group (NAFLD treated with rimonabant). It was found that the CD diet caused significant increase in liver index, serum levels of liver enzymes, malondialdehyde (MDA), TGF-ß1, activin A, and CB1 expression in liver tissue, with a significant decrease in glutathione peroxidase (GSH-Px) and follistatin mRNA expression in liver tissues. The administration of rimonabant significantly improved all of the studied parameters compared with the group fed the CD diet alone. Histopathological examination supported these results. We concluded that rimonabant significantly counteracted NAFLD induced with the CD diet by decreasing oxidative stress and hepatic expression of TGF-ß1, and modulating the hepatic expression of activin A and follistatin.

Magnetic nanoparticle-enhanced PCR for the detection and identification of Staphylococcus aureus and Salmonella enteritidis.

This paper evaluated magnetic nanoparticle-enhanced PCR for the detection and identification of Staphylococcus aureus and Salmonella enteritidis. Two different types of magnetic nanoparticles designated MPIO (iron concentration 2.5 mg/ml, size 1 µm) and NP (iron concentration 8.7 mg/ml, size 60 nm), both conjugated with S. aureus or S. enteritidis antibodies were evaluated as an enrichment procedure for PCR-detection of the pathogens in Trypticase Soy Broth, milk, blood and meat broth. Bacterial suspensions (1.5x108 cfu/ml) were prepared and serial diluted 10-1. The MPIO and NP nanoparticles were added, followed by incubation for 1 hour at room temperature, magnetic separation of the pellet, DNA extraction and PCR, targeting the femA and invA sequences. The nanoparticle-free and the NP-supplemented dilutions were positive down to the 1.5x102 cfu/ml concentration for both bacteria. The MPIO-supplemented dilutions were positive down to approx. 2x100 cfu/ml concentration, respectively. Bacteria-free TSB was negative by PCR. MPIO nanoparticles (size 1 µm) enhanced the detection of S. aureus and S. enteritidis by PCR, whilst NP nanoparticles (size 60 nm) did not, thus indicating that the size of the magnetic nanoparticles play a significant role in the enrichment procedure.