Combined on-demand sildenafil citrate and tramadol hydrochloride is an effective and safe treatment for premature ejaculation: A randomized placebo-controlled double-blind clinical trial.

Background: Premature ejaculation (PE) is a common sexual dysfunction that harms both sex partners. Aim: To evaluate the safety, efficacy and impact on sexual satisfaction scores of the combined use of tramadol HCl and sildenafil citrate for the treatment of PE. Methods: One hundred and sixty otherwise healthy males complaining of PE (primary/secondary) were enrolled in this randomized, double-blind, placebo-controlled study. Only 155 patients (age range 22-48 years) completed the study. Of them, 81 patients had primary PE, and 74 had secondary PE. The comparative groups included the placebo group (n = 34), sildenafil citrate 50 mg group (n = 39), tramadol HCl 100 mg group (n = 40), and the combination therapy group (n = 42). The treatment duration for all groups was 10 weeks. Outcomes: This combination is safe and effective. Results: Five patients discontinued the study, all from the placebo group, due to a lack of improvement over the treatment course. No significant differences were reported between groups before treatment as regards Intravaginal ejaculatory Latency Time (p = 0.8), satisfaction score (p = 0.7), age (p = 0.9), or duration of marriage (p = 0.9). There was a significant improvement in IELT after treatment with a placebo (p = 0.0001), associated with an insignificant improvement in satisfaction score (p = 1.0). In the other three groups, there was a significant improvement in IELT after treatment (p = 0.0001 for all), which coincided with a significant improvement in satisfaction scores in all three groups (p = 0.0001 for all). Clinical Implications: We recommend this combination in the treatment of premature ejaculation. Strengths: It is a prospective randomized double-blind placebo-controlled clinical trial. Limitations: Limited number of participants. Conclusion: Combined therapy of PE, whether primary or secondary, with sildenafil citrate 50 mg and tramadol HCl 100 mg is safe and effective; and its therapeutic effect is superior to the utilization of either agent alone.

Endometrial Progesterone and Estrogen Receptors in Relation to Hormonal Levels in Women with Unexplained Recurrent Miscarriage.

OBJECTIVE: Recurrent miscarriage has been linked to hormonal disturbance due to dysregulation of its receptors rather than to the availability of the hormone. We aimed to investigate endometrial expression of progesterone and estrogen receptors in relation to serum and endometrial hormonal levels in unexplained recurrent miscarriage. METHODS: The present case control study included 20 cases with unexplained recurrent miscarriage and 20 parous women as controls. Ovulation was confirmed using an ovulation kit and 10 to 12 days after detecting the urinary luteinizing hormone surge, all women were subjected to a blood sample and to an endometrial biopsy. Progesterone and estrogen levels were measured in serum and in endometrial tissue and receptor concentrations were in the endometrial sample. RESULTS: Women with recurrent miscarriage showed significantly lower concentration of receptors in both the cytoplasm and the nucleus of endometrial tissue compared with controls. The nuclear/cytoplasm ratio of progesterone receptor was significantly higher in cases compared with controls, implicating that recurrent miscarriage is probably linked to nongenomic activity of the hormone; this was also significant for estrogen receptor. Serum progesterone and estrogen hormonal levels were comparable between groups while both hormones were significantly reduced in the endometrium of recurrent miscarriage cases. Receptors significantly correlated with endometrial hormonal level but not to serum level. CONCLUSION: Recurrent miscarriage might be linked to reduced endometrial progesterone and estrogen receptors and appears to be more related to nongenomic activity of progesterone. Endometrial receptors expression correlates to tissue hormonal level rather than to serum hormonal level.

Systems toxicology of complex wood combustion aerosol reveals gaseous carbonyl compounds as critical constituents.

Epidemiological studies identified air pollution as one of the prime causes for human morbidity and mortality, due to harmful effects mainly on the cardiovascular and respiratory systems. Damage to the lung leads to several severe diseases such as fibrosis, chronic obstructive pulmonary disease and cancer. Noxious environmental aerosols are comprised of a gas and particulate phase representing highly complex chemical mixtures composed of myriads of compounds. Although some critical pollutants, foremost particulate matter (PM), could be linked to adverse health effects, a comprehensive understanding of relevant biological mechanisms and detrimental aerosol constituents is still lacking. Here, we employed a systems toxicology approach focusing on wood combustion, an important source for air pollution, and demonstrate a key role of the gas phase, specifically carbonyls, in driving adverse effects. Transcriptional profiling and biochemical analysis of human lung cells exposed at the air-liquid-interface determined DNA damage and stress response, as well as perturbation of cellular metabolism, as major key events. Connectivity mapping revealed a high similarity of gene expression signatures induced by wood smoke and agents prompting DNA-protein crosslinks (DPCs). Indeed, various gaseous aldehydes were detected in wood smoke, which promote DPCs, initiate similar genomic responses and are responsible for DNA damage provoked by wood smoke. Hence, systems toxicology enables the discovery of critical constituents of complex mixtures i.e. aerosols and highlights the role of carbonyls on top of particulate matter as an important health hazard.

Reasons and effects of the decline of willing related potential living kidney donors.

BACKGROUND: Although the availability of related living donors (LDs) provides a better chance for receiving kidney transplantation (KT), the evaluation protocols for LD selection remain a safeguard for the LD's safety. These protocols are variable from one center to another, resulting in variable rates of decline of the potential LDs (PLDs). The decline of willing PLDs may occur at any stage of evaluation, starting from the initial contact and counseling to the day of operation. AIM: To identify the causes of the decline of PLDs, the predictors of PLD candidacy, and the effect on achieving LDKT. METHODS: A retrospective study was performed on the willing PLDs who attended our outpatient clinic for kidney donation to their related potential recipients between October 2015 and December 2022. The variables influencing their candidacy rate and the fate of their potential recipients were studied. Two groups of PLDs were compared: Candidate PLDs after a completed evaluation vs non-candidate PLDs with a complete or incomplete evaluation. A multivariate logistic regression was performed to assess the factors contributing to the achievement of PLD candidacy. RESULTS: Of 321 willing PLDs, 257 PLDs (80.1%) accessed the evaluation to variable extents for 212 potential recipients, with a mean age (range) of 40.5 ± 10.4 (18-65) years, including 169 females (65.8%). The remaining 64 PLDs (19.9%) did not access the evaluation. Only 58 PLDs (18.1%) succeeded in donating, but 199 PDLs (62.0%) were declined; exclusion occurred in 144 PLDs (56.0%) for immunological causes (37.5%), medical causes (54.9%), combined causes (9.7%), and financial causes (2.1%). Regression and release occurred in 55 PLDs (17.1%). The potential recipients with candidate PLDs were not significantly different from those with non-candidate PLDs, except in age (P = 0.041), rates of completed evaluation, and exclusion of PLDs (P < 0.001). There were no factors that independently influenced the rate of PLD candidacy. Most patients who failed to have KT after the decline of their PLDs remained on hemodialysis for 6 mo to 6 years. CONCLUSION: The rate of decline of willing related PLDs was high due to medical or immunological contraindications, release, or regression of PLDs. It reduced the chances of high percentages of potential recipients in LDKT.

Preemptive living donor kidney transplantation: Access, fate, and review of the status in Egypt.

BACKGROUND: Preemptive living donor kidney transplantation (PLDKT) is recommended as the optimal treatment for end-stage renal disease. AIM: To assess the rate of PLDKT among patients who accessed KT in our center and review the status of PLDKT in Egypt. METHODS: We performed a retrospective review of the patients who accessed KT in our center from November 2015 to November 2022. In addition, the PLDKT status in Egypt was reviewed relative to the literature. RESULTS: Of the 304 patients who accessed KT, 32 patients (10.5%) had preemptive access to KT (PAKT). The means of age and estimated glomerular filtration rate were 31.7 ± 13 years and 12.8 ± 3.5 mL/min/1.73 m2, respectively. Fifty-nine patients had KT, including 3 PLDKTs only (5.1% of total KTs and 9.4% of PAKT). Twenty-nine patients (90.6%) failed to receive PLDKT due to donor unavailability (25%), exclusion (28.6%), regression from donation (3.6%), and patient regression on starting dialysis (39.3%). In multivariate analysis, known primary kidney disease (P = 0.002), patient age (P = 0.031) and sex (P = 0.001) were independent predictors of achievement of KT in our center. However, PAKT was not significantly (P = 0.065) associated with the achievement of KT. Review of the literature revealed lower rates of PLDKT in Egypt than those in the literature. CONCLUSION: Patient age, sex, and primary kidney disease are independent predictors of achieving living donor KT. Despite its non-significant effect, PAKT may enhance the low rates of PLDKT. The main causes of non-achievement of PLDKT were patient regression on starting regular dialysis and donor unavailability or exclusion.

IVUS-guided versus OCT-guided PCI among patients presenting with acute coronary syndrome.

BACKGROUND: Intravascular imaging modalities such as intravascular ultrasound (IVUS) and, more recently, optical coherence tomography (OCT) improved the visualization of coronary anatomy and plaque pathology. We aimed to compare the procedural and short-term outcomes between IVUS-guided and OCT-guided percutaneous coronary interventions (PCIs) in patients with acute coronary syndrome (ACS). METHODS: In the present retrospective study, we reviewed the data of 50 patients who had IVUS-guided PCI and 50 patients who had OCT-guided PCI for ACS between January 2020 and June 2021. Intravascular imaging was done before and after stenting. Both groups were compared in terms of minimal luminal area (MLA), stent dimensions, final minimal stent area (MSA) and stent expansion as well as negative angiographic outcomes. Patients were followed for six months to record major adverse cardiac events (MACE). RESULTS: The patients' mean age was 57 ± 13 years with male predominance (78%). The radiation time and dose were significantly higher among IVUS group. Pre-stenting MLA was significantly higher in IVUS group (2.63 mm vs. 2.22 mm in OCT, P = 0.013). Stent expansion was significantly higher among OCT group (97% vs. 93% in IVUS group, P = 0.001) with no significant difference between both groups regarding MSA [mm2] (8.88 ± 2.87 in IVUS vs. 8.1 ± 2.76 in OCT, P = 0.169). No significant difference between both groups was noted regarding contrast volume, edge dissection, tissue prolapse, and no reflow. The rates of six-month MACE were significantly higher in the IVUS group. CONCLUSIONS: OCT-guided PCI in ACS is safe and is associated with similar MSA to that of IVUS-guided PCI. Future randomized trials are needed to confirm these findings.

Medium- and time-related effects on hypothermic storage of rat testicular cells.

OBJECTIVE: Testicular samples obtained for fertility preservation often need to be transported between clinics. This study aimed to mimic this short-term hypothermic storage (4-8 °C) and explore the impact of these conditions and the transport medium composition on prepubertal rat testicular tissue samples. METHODS: Testicular tissue samples obtained from seven days post-partum rats were transferred to six compositionally different basal culture media and a balanced salt solution, which had been kept at 4-8 °C prior to transfer. The samples were preserved for either 12 or 24 hours in these hypothermic conditions. The potential effects of the short-term storage were evaluated by assessing the morphology, measuring the testosterone levels by radioimmunoassay and analysing 96 genes with TaqMan Low-Density Arrays. Summarizing results: Levels of gene expression related to energy, apoptosis and angiogenesis pathways were altered after hypothermic storage for 12 and especially 24 hours. We observed only minor differences in gene expression profiles for germ and testicular somatic cells, and no differences in tissue morphology and testosterone production levels. CONCLUSIONS: Short-term hypothermic storage of testicular tissue with a maximum duration of 24 hours does not affect the overall expression profile of testicular cell-specific genes; however, in a minor way, it affects the expression of specific cellular genes.

Diosmin nanocrystal gel alleviates imiquimod-induced psoriasis in rats via modulating TLR7,8/NF-κB/micro RNA-31, AKT/mTOR/P70S6K milieu, and Tregs/Th17 balance.

Diosmin is a flavonoid with promising anti-inflammatory and antioxidant properties. However, it has difficult physicochemical characteristics since its solubility demands a pH level of 12, which has an impact on the drug's bioavailability. The aim of this work is the development and characterization of diosmin nanocrystals using anti-solvent precipitation technique to be used for topical treatment of psoriasis. Results revealed that diosmin nanocrystals stabilized with hydroxypropyl methylcellulose (HPMC E15) in ratio (diosmin:polymer; 1:1) reached the desired particle size (276.9 ± 16.49 nm); provided promising colloidal properties and possessed high drug release profile. Additionally, in-vivo assessment was carried out to evaluate and compare the activities of diosmin nanocrystal gel using three different doses and diosmin powder gel in alleviating imiquimod-induced psoriasis in rats and investigating their possible anti-inflammatory mechanisms. Herein, 125 mg of 5% imiquimod cream (IMQ) was applied topically for 5 consecutive days on the shaved backs of rats to induce psoriasis. Diosmin nanocrystal gel especially in the highest dose used offered the best anti-inflammatory effect. This was confirmed by causing the most statistically significant reduction in the psoriasis area severity index (PASI) score and the serum inflammatory cytokines levels. Furthermore, it was capable of maintaining the balance between T helper (Th17) and T regulatory (Treg) cells. Moreover, it tackled TLR7/8/NF-κB, miRNA-31, AKT/mTOR/P70S6K and elevated the TNFAIP3/A20 (a negative regulator of NF-κB) expression in psoriatic skin tissues. This highlights the role of diosmin nanocrystal gel in tackling imiquimod-induced psoriasis in rats, and thus it could be a novel promising therapy for psoriasis.

Assessment of donor specific IgG Anti-HLA subclasses before and after kidney transplantation in Upper Egypt: A Single Center Study.

Donor specific antibodies (DSAs) are known as the leading cause of antibody mediated rejection (AMR), graft loss in kidney transplant (KT) recipients. DSAs characteristics, as immunoglobulin (Ig) classes, subclasses, and strength, are important to assess the immunological risk, early prediction of AMR, and therefor proper management. This longitudinal, case control study included 32 KT recipients at Assiut University Urology Hospital and 10 age and sex matched normal subjects as the control group. Total IgG, its subclasses and anti-human leukocyte antigen (anti-HLA) panel reactive antibody (PRA) were detected pre-transplantation (pre-TX), at 6-12- and 24-36-months post-TX. Rejection occurred in 4 recipients, 3 of them had high total IgG, IgG1 and/or IgG3. IgG2 and IgG4 were normal in all recipients. There were preformed anti-DSAs antibodies in 3/32 recipients (9.4%). Of these, two recipients became negative with no rejection occurred. The third recipient had high post-TX mean fluorescence intensity (MFI) and AMR occurred. The pre-TX PRA was negative in 29/32 recipients (90.6%). The PRA was negative in 8/29 recipients (27.6%) and the remaining 21/29 recipients (72.4%) developed de novo DSAs post-TX (MFI < 3000->10000). Rejection occurred with both low and high MFI. In 11 recipients, anti-HLA class I and II were not different between pre-TX, 3-6- and 24-36 months post-TX with no rejection occurred. The frequency and median levels of total IgG, IgG1 and IgG3 were increased in all recipients 24-36 months post-TX when compared with their levels pre-TX and 6-12 months post-TX in the 11 recipients and with the control group. The graft survival time significantly decreased in recipients with positive post-TX class I PRA. In conclusion, preformed DSAs may persist post-TX or turn negative. De novo DSAs developed post-TX even in non-sensitized recipients. Serum total IgG, IgG1 and IgG3 frequency increase 2-3 years post-TX.

Endometrial Progesterone and Estrogen Receptors in Relation to Hormonal Levels in Women with Unexplained Recurrent Miscarriage / Receptores endometriais de progesterona e estrogênio em relação aos níveis hormonais em mulheres com aborto recorrente inexplicável

Abstract Objective Recurrent miscarriage has been linked to hormonal disturbance due to dysregulation of its receptors rather than to the availability of the hormone. We aimed to investigate endometrial expression of progesterone and estrogen receptors in relation to serum and endometrial hormonal levels in unexplained recurrent miscarriage. Methods The present case control study included 20 cases with unexplained recurrent miscarriage and 20 parous women as controls. Ovulation was confirmed using an ovulation kit and 10 to 12 days after detecting the urinary luteinizing hormone surge, all women were subjected to a blood sample and to an endometrial biopsy. Progesterone and estrogen levels were measured in serum and in endometrial tissue and receptor concentrations were in the endometrial sample. Results Women with recurrent miscarriage showed significantly lower concentration of receptors in both the cytoplasm and the nucleus of endometrial tissue compared with controls. The nuclear/cytoplasm ratio of progesterone receptor was significantly higher in cases compared with controls, implicating that recurrent miscarriage is probably linked to nongenomic activity of the hormone; this was also significant for estrogen receptor. Serum progesterone and estrogen hormonal levels were comparable between groups while both hormones were significantly reduced in the endometrium of recurrent miscarriage cases. Receptors significantly correlated with endometrial hormonal level but not to serum level. Conclusion Recurrent miscarriage might be linked to reduced endometrial progesterone and estrogen receptors and appears to be more related to nongenomic activity of progesterone. Endometrial receptors expression correlates to tissue hormonal level rather than to serum hormonal level.

Ultrasound versus fluoroscopy-guided ureteroscopy for distal ureteric stones in adults.

Objective: To evaluate the safety and efficacy of ultrasound (US) as alternative to fluoroscopy for guidance of ureteroscopy (URS) during treatment of distal ureteric stones in adults. Materials and methods: This study enrolled 80 patients older than 18 years presented with a single distal ureteric radio-opaque stone of ≤15 mm in longest diameter. Patients were randomized and allocated into two groups: the fluoroscopy group and the ultrasound group (n = 40 patients in each group). Patients with bilateral ureteric stones, solitary kidney, ureteric congenital anomalies, history of failed ureteroscopy, history of ureteric surgery, patients with uremia and pregnant women were excluded. Patients' demographics, stone characteristics, operative data, stone-free status, hospital stay and complications were evaluated in both groups. Results: No statistically significant difference between both groups was found regarding patients' demographics and stone characteristics. Also there was no statistically significant difference in comparing fluoroscopy group versus ultrasound group regarding operative time (29.48 ± 15.3 versus 31.28 ± 18.24 min; P = 0.83), stone-free rate (97.5% versus 95%; P = 1.0), overall complications (15% versus 12.5%; P = 0.75), or hospital stay (1.17 ± 0.6 versus 1.02 ± 0.16 days; P = 0.12). Four patients (10%) in the ultrasound group required the addition of fluoroscopy beside ultrasound. Conclusion: Ultrasound is effective in guidance during ureteroscopy for distal ureteric stones. It was comparable to fluoroscopy in terms of stone free rate, operative time, overall complications, and hospital stay. However, fluoroscopy must be available to be used when needed.

Guidelines on Asset Management of Offshore Facilities for Monitoring, Sustainable Maintenance, and Safety Practices.

Recent activities in the oil and gas industry have shown an increasing need for monitoring engagements, such as in shipping, logistics, exploration, drilling, or production. Hence, there is a need to have asset management of these offshore assets (or facilities). Much of the offshore infrastructure is currently approaching or past its operational life expectancy. The study presents an overview on asset management of offshore facilities towards monitoring, safe practices, maintenance, and sustainability. This study outlines the major considerations and the steps to take when evaluating asset life extensions for an aging offshore structure (or asset). The design and construction of offshore structures require some materials that are used to make the structural units, such as offshore platform rigs, ships, and boats. Maintaining existing assets in the field and developing new platforms that are capable of extracting future oil and gas resources are the two key issues facing the offshore sector. This paper also discusses fault diagnosis using sensors in the offshore facilities. The ocean environment is constantly corrosive, and the production activities demand extremely high levels of safety and reliability. Due to the limited space and remote location of most offshore operations, producing cost-effective, efficient, and long-lasting equipment necessitates a high level of competence. This paper presents the guidelines on asset monitoring, sustainable maintenance, and safety practices for offshore structures. In this study, the management of offshore structures were also presented with some discussions on fault monitoring using sensors. It also proposes sustainable asset management approaches as guidelines that are advised, with policy implications.

Evaluation of Subepithelial Connective Tissue Graft Versus Acellular Dermal Matrix with Modified Coronally Advanced Tunnel Technique in Treatment of Multiple Gingival Recessions: A Randomized, Parallel-Design Clinical Trial.

The addition of grafting material to the tunnel procedure has yielded more stable outcomes than the tunnel procedure alone, but currently there is no available evidence about the most effective grafting material. This study compared two grafting materials-subepithelial connective tissue graft (SCTG) and acellular dermal matrix (ADM)-with the modified coronally advanced tunnel technique (MCAT) in the management of multiple adjacent gingival recessions (MAGRs). Patients (n = 24) with recession type 1 MAGR sites were randomly allocated to treatment with ADM+MCAT (test group) or SCTG+MCAT (control group). The clinical parameters were recorded at baseline (before treatment) and 9 months postsurgery and included gingival recession depth (GRD), gingival recession width (GRW), gingival thickness (GT), keratinized tissue width (KTW), probing pocket depth (PPD), clinical attachment level (CAL), and percentage of root coverage. Patient esthetic satisfaction and postoperative pain were recorded using a visual analogue scale (VAS). After 9 months, significant reductions in GRD (2.10 ± 0.64 mm; 2.23 ± 0.68 mm) and GRW (2.41 ± 1.19 mm; 2.41 ± 1.94 mm), increases in GT (0.53 ± 0.41 mm; 0.94 ± 0.52 mm), and gains in CAL (2.46 ± 1.94 mm; 2.47 ± 1.28 mm) were recorded in the test and control groups, respectively. However, the control group showed more KTW gain (P = .0003) and increased GT (P = .002) than the test group. Patient satisfaction with esthetic outcome 9 months after treatment did not differ between test (VAS score: 8.24 ± 0.43) and control (VAS score: 8.24 ± 0.65) groups (P = 0.99). The use of ADM may represent an alternative to SCTG when used in conjunction with MCAT.

Effect of nanovesicular surface-functionalization via chitosan and/or PEGylation on cytotoxicity of tamoxifen in induced-breast cancer model.

AIMS: The effect of surface-modification of Tamoxifen (Tam)-loaded-niosomes on drug cytotoxicity and bio-distribution, via functionalization with chitosan and/or PEGylation, was investigated. MATERIALS AND METHODS: Tam-loaded hybrid-nanocarriers (Tam-loaded niosomes, chitosomes, PEGylated niosomes, and PEGylated chitosomes) were formulated and characterized. KEY FINDINGS: Chitosanization with/without PEGylation proved to selectively enhance Tam-release at the cancerous-acidic micromilieu. Cytotoxic activity study showed that Tam-loaded PEGylated niosomes had a lower IC50 value on MCF-7 cell line (0.39, 0.35, and 0.27 times) than Tam-loaded PEGylated chitosomes, Tam-loaded niosomes, and Tam-loaded chitosomes, respectively. Cell cycle analysis showed that PEGylation and/or Chitosanization significantly impact Tam efficiency in inducing apoptosis, with a preferential influence of PEGylation over chitosanization. The assay of Annexin-V/PI double staining revealed that chitosanized-nanocarriers had a significant role in increasing the incidence of apoptosis over necrosis. Besides, PEGylated-nanocarriers increased apoptosis, as well as total death and necrosis percentages more than what was shown from free Tam. Moreover, the average changes in both Bax/Bcl-2 ratio and Caspase 9 were best improved in cells treated by Tam-loaded PEGylated niosomes over all other formulations. The in-vivo study involving DMBA-induced-breast cancer rats revealed that PEGylation made the highest tumor-growth inhibition (84.9 %) and breast tumor selectivity, while chitosanization had a lower accumulation tendency in the blood (62.3 ng/ml) and liver tissues (103.67 ng/ml). The histopathological specimens from the group treated with Tam-loaded PEGylated niosomes showed the best improvement over other formulations. SIGNIFICANCE: All these results concluded the crucial effect of both PEGylation and chitosan-functionalization of Tam-loaded niosomes in enhancing effectiveness, targetability, and safety.

Anti-neoplastic action of Cimetidine/Vitamin C on histamine and the PI3K/AKT/mTOR pathway in Ehrlich breast cancer.

The main focus of our study is to assess the anti-cancer activity of cimetidine and vitamin C via combating the tumor supportive role of mast cell mediators (histamine, VEGF, and TNF-α) within the tumor microenvironment and their effect on the protein kinase A(PKA)/insulin receptor substrate-1(IRS-1)/phosphatidylinositol-3-kinase (PI3K)/serine/threonine kinase-1 (AKT)/mammalian target of rapamycin (mTOR) cue in Ehrlich induced breast cancer in mice. In vitro study was carried out to evaluate the anti-proliferative activity and combination index (CI) of the combined drugs. Moreover, the Ehrlich model was induced in mice via subcutaneous injection of Ehrlich ascites carcinoma cells (EAC) in the mammary fat pad, and then they were left for 9 days to develop obvious solid breast tumor. The combination therapy possessed the best anti-proliferative effect, and a CI < 1 in the MCF7 cell line indicates a synergistic type of drug interaction. Regarding the in vivo study, the combination abated the elevation in the tumor volume, and serum tumor marker carcinoembryonic antigen (CEA) level. The serum vascular endothelial growth factor (VEGF) level and immunohistochemical staining for CD34 as markers of angiogenesis were mitigated. Additionally, it reverted the state of oxidative stress and inflammation. Meanwhile, it caused an increment in apoptosis, which prevents tumor survival. Furthermore, it tackled the elevated histamine and cyclic adenosine monophosphate (cAMP) levels, preventing the activation of the (PKA/IRS-1/PI3K/AKT/mTOR) cue. Finally, we concluded that the synergistic combination provided a promising anti-neoplastic effect via reducing the angiogenesis, oxidative stress, increasing apoptosis,as well as inhibiting the activation of PI3K/AKT/mTOR cue, and suggesting its use as a treatment option for breast cancer.

Galangin mitigates DOX-induced cognitive impairment in rats: Implication of NOX-1/Nrf-2/HMGB1/TLR4 and TNF-α/MAPKs/RIPK/MLKL/BDNF.

The cognitive and behavioral decline observed in cancer survivors who underwent doxorubicin (DOX)-based treatment raises the need for therapeutic interventions to counteract these complications. Galangin (GAL) is a flavonoid-based phytochemical with pronounced protective effects in various neurological disorders. However, its impact on DOX-provoked neurotoxicity has not been clarified. Hence, the current investigation aimed to explore the ability of GAL to ameliorate DOX-provoked chemo-brain in rats. DOX (2 mg/kg, once/week, i.p.) and GAL (50 mg/kg, 5 times/week., via gavage) were administered for four successive weeks. The MWM and EPM tests were used to evaluate memory disruption and anxiety-like behavior, respectively. Meanwhile, targeted biochemical markers and molecular signals were examined by the aid of ELISA, Western blotting, and immune-histochemistry. In contrast to DOX-impaired rats, GAL effectively preserved hippocampal neurons, improved cognitive/behavioral functions, and enhanced the expression of the cell repair/growth index, BDNF. The antioxidant feature of GAL was confirmed by the amelioration of MDA, NO and NOX-1, along with restoring the Nrf-2/HO-1/GSH cue. In addition, GAL displayed marked anti-inflammatory properties as verified by the suppression of the HMGB1/TLR4 nexus and p-NF-κB p65 to inhibit TNF-α, IL-6, IL-1ß, and iNOS. This inhibitory impact extended to entail astrocyte activation, as evidenced by the diminution of GFAP. These beneficial effects were associated with a notable reduction in p-p38MAPK, p-JNK1/2, and p-ERK1/2, as well as the necroptosis cascade p-RIPK1/p-RIPK3/p-MLKL. Together, these pleiotropic protective impacts advocate the concurrent use of GAL as an adjuvant agent for managing DOX-driven neurodegeneration and cognitive/behavioral deficits. DATA AVAILABILITY: The authors confirm that all relevant data are included in the supplementary materials.

Differentiation of Human-Induced Pluripotent Stem Cells (hiPSCs) into Human Primordial Germ Cell-like Cells (hPGCLCs) In Vitro.

In humans, germ cells are specified in the extraembryonic yolk sac, at proximity of allantois, around the second week of gestation. Derivation of human germ cell-like cells (hPGCLCs) from human pluripotent cells in vitro is of a great importance for research purposes, such as disease modeling, or studying the early human germ cell development and the effect of environmental factors on this development. As it is not possible to access human embryos at early developmental stages, a two-step protocol has been proposed by Sasaki and colleagues to differentiate hPGCLCs in vitro from human pluripotent stem cells. Here, we report a detailed protocol for in vitro hPGCLCs differentiation from induced pluripotent stem cells (iPSCs).

Urine-Derived Kidney Progenitor Cells in Cystinosis.

Nephropathic cystinosis is an inherited lysosomal storage disorder caused by pathogenic variants in the cystinosin (CTNS) gene and is characterized by the excessive shedding of proximal tubular epithelial cells (PTECs) and podocytes into urine, development of the renal Fanconi syndrome and end-stage kidney disease (ESKD). We hypothesized that in compensation for epithelial cell losses, cystinosis kidneys undertake a regenerative effort, and searched for the presence of kidney progenitor cells (KPCs) in the urine of cystinosis patients. Urine was cultured in a specific progenitor medium to isolate undifferentiated cells. Of these, clones were characterized by qPCR, subjected to a differentiation protocol to PTECs and podocytes and assessed by qPCR, Western blot, immunostainings and functional assays. Cystinosis patients voided high numbers of undifferentiated cells in urine, of which various clonal cell lines showed a high capacity for self-renewal and expressed kidney progenitor markers, which therefore were assigned as cystinosis urine-derived KPCs (Cys-uKPCs). Cys-uKPC clones showed the capacity to differentiate between functional PTECs and/or podocytes. Gene addition with wild-type CTNS using lentiviral vector technology resulted in significant reductions in cystine levels. We conclude that KPCs present in the urine of cystinosis patients can be isolated, differentiated and complemented with CTNS in vitro, serving as a novel tool for disease modeling.

Investigation of the effect of the calcium channel blocker, verapamil, on the parasite burden, inflammatory response and angiogenesis in experimental Trichinella spiralis infection in mice.

Trichinella spiralis larvae have very special characters that make them able to completely transform the function of the affected muscle cells towards a self-serving environment, offering them nourishment and protection via what is known as "nurse cells". This setting may be affected by drugs that are used for the treatment of co-morbidities and co-infections as calcium channel blockers, which are widely used in clinical practice. In the present study, the effects of verapamil, ivermectin (IVM), and their combined administration on the parasitic burden, immuno-pathology and angiogenesis were investigated during experimental trichinellosis. Estimation of intestinal adult parasitic stages and muscle larvae was done. VEGF gene expression and CD31 immunohistochemical local expression were measured to investigate angiogenesis, in addition to histopathological examination to explore the extent of inflammation. Although verapamil did not have an effect on the adult worm count during the intestinal phase, it induced an anti-inflammatory effect on intestinal pathology. During the muscle phase, it was very effective in reducing the larval count by 93.78%. IVM effectively reduced the worm count by 85.34%, and the muscle larval count by 97.84%, while combined verapamil and IVM administration resulted in a significant reduction in both adult parasites by 69.5% and larval stages by 99%. Both verapamil and IVM and their combination induced a potent decrease in local CD31 protein expression and VEGF gene expression. The important role of calcium and calcium channels during the pathology of trichinellosis, in addition to the pivotal role of calcium on biological processes such as immunity and angiogenesis, make calcium-channel blockers promising candidates for drug repurposing in the management of helminthic infection.

Short-term impact of COVID-19 infection on right ventricular functions: single center observational study.

BACKGROUND: COVID-19 pandemic is associated with high morbidity and mortality. Cardiovascular insult is a leading cause of in-hospital mortality in COVID-19 patients, especially right ventricular (RV) dysfunction and massive pulmonary embolism. This study aims to assess short-term impact of COVID 19 infection on (RV) functions among hospitalized patients with moderate or severe illness using bed side trans-thoracic echocardiogram. This study was conducted in 3 isolation hospitals in Cairo, spanning over 3 months during the expected pandemic peak in Egypt in 2020. The study recruited 100 consecutive patients with moderate or severe COVID-19 infection. Four patients refused to participate in the study. Patients with pre-existing structural heart diseases were excluded. All patients underwent full history taking and clinical examination. Bed side echocardiography was done emphasizing on (RV), and (RA) dimensions, (LV) functions and pulmonary artery systolic pressure (PSAS). Cardiac biomarkers were withdrawn and CT angiography was ordered when clinically warranted. RESULTS: The mean age of the studied cohort was 59.5 ± 8.6 years with males comprising 71.9% of the studied group. (RV) and (RA) dilatation was noted in 8 cases (8.3%). (LV) dysfunction was noted in 11 cases (11.4%). (PASP) showed a statistically significant negative correlation with (LV) function. However, (PSAP) was positively correlated to (RA) and (RV) dimensions, tricuspid regurgitation (TR) jet severity, previous COVID infection and elevated cardiac biomarkers. Mortality was noted in 3 cases (3.1%), all had LV dysfunction with elevated troponin level. Six patients (6.2%) had combined (LV) and (RV) dysfunction. CONCLUSIONS: COVID-19 illness had a negative impact on (RV) and (LV) functions, that could be assessed accurately by trans-thoracic 2 D echocardiogram. The degree of ventricular dysfunction correlated with the rise in cardiac biomarkers as well as the degree of (PASP).