Mucocutaneous Changes in End-Stage Renal Disease Under Regular Hemodialysis - A Cross-Sectional Study.

Introduction: Patients with end-stage renal disease (ESRD) suffer from mucocutaneous changes that could significantly impair the quality of life. We aimed this study to assess the mucocutaneous changes in hemodialysis patients and to correlate the serum creatinine to these changes. Methods: Data were collected from the Hemodialysis Center at Benha University. A cross-sectional study design on 130 chronic kidney disease (CKD) patients (30-60 years old, 84 males, 46 females) undergoing hemodialysis. Oral examinations were done for these patients as per the modified World Health Organization oral health survey 2013 criteria. All the mucocutaneous changes were recorded then types, distribution, and frequencies were calculated and correlated to serum creatinine. Results: Mucocutaneous abnormalities were present in 100% of the studied CKD sample. We observed that pallor (76.2%), xerostomia (70%), petechiae/purpura (49.2%), altered taste (49.2%), and lip pigmentation (40.8%) were the most prevalent mucocutaneous changes among the CKD patients undergoing hemodialysis. A strong association was detected between serum creatinine and the following: abnormal lip pigmentation and lichen planus. Discussion: There is an association between lip pigmentation and lichen planus in CKD patients and the level of serum creatinine as the higher level of serum creatinine was found in the patients with abnormal lip pigmentation and the atrophic lichen planus patients.

Sea urchin (Diadema savignyi) extract as a novel protective agent against cisplatin induced neurotoxicity in rats.

Neurotoxicity is a severe side effect of platinum compounds used for cancer chemotherapy such as Cisplatin. This neurotoxicity leads to severe cognitive and nervous dysfunction, therefore, limiting the dose of Cisplatin and compromising the treatment protocol.The present study investigates the neuroprotective effect of Sea Urchins which is a marine animal known for its rich bioactive compounds. Male Sprague Dawley rats received Cisplatin (2 mg/kg body weight) for 4 weeks, two times per week, followed by Sea Urchin extracts (50 and 100 mg/kg body weight) twice weekly for 4 weeks.Results show that rats treated with Urchin's extracts showed a significant improvement in the thermal (heat and cold) sensitivity compared to untreated rats. Liver enzymes Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) and Urea levels were also significantly decreased back to normal following treatment with sea urchin extracts. Brain tissue oxidative stress marker Nitric oxide (NO) and lipid peroxidation marker Malondialdehyde (MDA) increased significantly in the cisplatin-treated rats while the reduced glutathione levels (GSH) and catalase activity (CAT) showed a significant decrease. Treatment with sea Urchin extracts reversed these changes.Histological and immunohistochemical examination of the cerebral cortex reveled degenerative changes such as karyopyknosis and shrunken necrotic ghost like neurons in the cisplatin treated groups. There was also strong positive Glial fibrillary acidic protein (GFAP) reactivity and a negative B-cell leukemia/lymphoma 2 protein (Bcl2) reaction in most apparent neurons, indicating strong apoptotic changes. Treatment with Urchin extracts reversed these changes. Quantification of cerebral cortex neurons also revealed the strong effect of the extracts. Cisplatin treated groups showed 3708 cells/ mm3 compared to 8091 cells/mm3 in the normal rats. Extract treatment increased the neuronal numbers to almost normal levels. Quantification of the Immuno-histochemical expression of GFAP showed an increase by 10-folds after cisplatin administration. A remarkable decline from the cisplatin group was seen in the extract treated groups.In Conclusion, Sea Urchins extracts possess a strong neuroprotective activity and could provide a novel therapeutic method to prevent Cisplatin-induced neurotoxicity.

Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system xc-, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system xc- activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [18F]FSPG as predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

Wet Electrospun Nanofibers-Fortified Gelatin/Alginate-Based Nanocomposite as a Single-Dose Biomimicking Skin Substitute.

We report the development and evaluation of a series of well-designed single-dose extracellular matrix (ECM)-mimicking nanofibers (NFs)-reinforced hydrogel (HG)-based skin substitute for wound healing. The HG matrix of the proposed skin substitute is composed of gelatin (GE) and sodium alginate (SA), and incorporates hyaluronic acid (HA) as a key component of the natural ECM, as well as the antimicrobial Punica granatum extract (PE). This HG nanocomposite was cross-linked by the biocompatible N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide hydrochloride (EDC) cross-linker, and was reinforced with fragmented trans-ferulic acid (FA)-loaded cellulose acetate/polycaprolactone (PCL/CA) NFs. The NFs were obtained via wet electrospinning into a poly(vinyl alcohol) (PVA) coagulating solution to closely resemble the porous structure of the ECM fibers, which facilitates cell migration, attachment, and proliferation. The proposed design of the skin substitute allows adjustable mechanical characteristics and outstanding physical properties (swelling and biodegradability), as well as an excellent porous microstructure. The developed skin substitutes were characterized using Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and electron microscopy. In addition, the biodegradability, biocompatibility, bioactivity, mechanical, and in vitro drug release characteristics were investigated. Moreover, an in vivo excisional full-thickness defect model was conducted to assess skin regeneration and healing effectiveness. The average diameters of the plain and FA-loaded NFs are 210 ± 12 nm and 452 ± 25 nm, respectively. The developed ECM-mimicking skin substitutes demonstrated good antibacterial activity, free-radical scavenging activity, cytocompatibility, porosity, water absorption ability, and good biodegradability. In vivo application of the ECM-mimicking skin substitutes revealed their excellent wound-healing activity and their suitability for single-dose treatment of deep wounds with reducing the wound diameter to 0.95 mm after 15 days of treatment. Moreover, the histological investigation of the wound area demonstrated that the applied skin substitutes have not only enhanced the wound healing progress, but also can participate in improving the quality of the regenerated skin in the treated area via facilitating collagen fibers regeneration and deposition.

Differential expression of FSHR and LHR genes and proteins during development of rabbit ovarian follicles.

The development of an ovarian follicle is a complex process at the cellular and molecular level that is mainly regulated by follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR). To elucidate the contribution of these receptors to ovarian follicle development, it is necessary to determine their expression profiles during this biological process. Therefore, this study aimed to investigate the relationship between ovarian development pattern and the differential ovarian expression pattern of FSHR and LHR genes as well as proteins at different developmental stages. Ovaries were collected from 30 New Zealand rabbits at day 0 (birth), week 2 (neonate), week 4 (cub), week 16 (maturity), and day 18 pregnancy. Ovarian histology, and gene as well as protein expression were determined using light microscopy, real-time PCR and western blotting, respectively. The results showed that the expression levels of FSHR mRNA and protein increased coincidently with age and the growth of ovarian follicles. The levels of LHR mRNA and protein remained low from the day of birth until week 4 and became significantly higher by week 16 coinciding with appearance of growing and antral follicles, which have a defined thecal layer. FSHR gene and protein expression decreased with pregnancy, whereas LHR increased, reaching a peak level during pregnancy. It can be concluded that changes in FSHR and LHR gene and protein expression could be related to the growth and development of follicles, indicating the regulatory role for these receptors in rabbit folliculogenesis.

Radiotracer stereochemistry affects substrate affinity and kinetics for improved imaging of system xC- in tumors.

Amino acid utilization is perturbed in cancer cells, which rewire their metabolism to support cell survival and proliferation. This metabolic reprogramming can be exploited for diagnostic purposes through positron emission tomography imaging of fluorine-18 labeled amino acids. Despite its promise, little is known regarding transporter-recognition of non-natural amino acid stereoisomers or their utility for cancer imaging. We report here the synthesis and in vivo characterization of a radiolabeled amino acid (R)-4-(3-18F-fluoropropyl)-ʟ-glutamate ([18F]FRPG) and compared its tumor imaging properties to the 4S-isomer, [18F]FSPG. Methods: [18F]FRPG and [18F]FSPG uptake was assessed in H460 lung cancer cells, with efflux measured 30 min after removal of exogenous activity. Specificity of [18F]FRPG for system xC- was further examined following transporter inhibition and blocking studies with system xC- substrates. [18F]FRPG and [18F]FSPG pharmacokinetics was next quantified in mice bearing subcutaneous A549, H460, VCAP and PC3 tumors, with mice bearing A549 tumors imaged by PET/CT. To better-understand differential tumor retention, radiometabolite analysis was performed on tissue and blood samples after imaging. Next, [18F]FRPG and [18F]FSPG retention in lipopolysaccharide-treated lungs were compared to an orthotopic H460 lung cancer model. Finally, the sensitivity of [18F]FRPG to manipulation of the redox environment was examined in cell and in vivo models. Results: [18F]FRPG was specifically transported across the plasma membrane by the cystine/glutamate antiporter system xC- and retained at high levels in multiple tumor models. Conversely, [18F]FRPG was rapidly extracted from the blood and cleared from tissues with low system xC- expression. Due to its favorable imaging properties, tumor-to-blood ratios ≥10 were achieved with [18F]FRPG, which were either equal to or greater than [18F]FSPG. In addition, [18F]FRPG retention in orthotopic lung tumors with high system xC- expression was 2.5-fold higher than inflamed tissue, allowing for clear tumor visualization. In vivo, [18F]FRPG and [18F]FSPG were metabolized to a single species, with [18F]FRPG showing a higher percentage of parent radiotracer in tumors compared to [18F]FSPG. [18F]FRPG was sensitive to redox manipulations and tumor retention was reduced following treatment with liposomal doxorubicin in mice bearing ovarian tumors. Conclusions: Given the fast clearance and low background retention of [18F]FRPG throughout the body, this radiotracer holds promise for the imaging of system xC- activity and treatment response monitoring in tumors of the thorax, abdomen, and head and neck. [18F]FRPG PET imaging provides a sensitive noninvasive measure of system xC- and excellent properties for cancer imaging.

Comparative efficacy of lidocaine-prilocaine cream and vaginal misoprostol in reducing pain during levonorgestrel intrauterine device insertion in women delivered only by cesarean delivery: A randomized controlled trial.

OBJECTIVE: To compare efficacy of lidocaine-prilocaine (LP) cream versus misoprostol versus placebo before levonorgestrel-releasing intrauterine device (LNG-IUD) insertion. METHODS: This randomized controlled trial (RCT) was conducted in a tertiary referral hospital from April 30, 2020 to March 1, 2021 on 210 parous women willing to receive LNG-IUD and delivered only by elective cesarean delivery (CD). Participants received 200 µg vaginal misoprostol or 5 ml of LP cream 5% or placebo 3 h before LNG-IUS insertion. Primary outcome was pain during LNG-IUD insertion, while secondary outcomes were pain 10 min post-procedure, ease of insertion, patient satisfaction, insertion time, and drug side effects. RESULTS: Pain during LNG-IUS insertion was reduced in LP group and misoprostol group compared to placebo group (2.1 ± 1.0 vs 3.7 ± 1.6; p <0.001) and (2.3 ± 1.3 vs 3.7 ± 1.6; p <0.001), respectively. Ease of procedure and patient satisfaction were significantly higher in LP and misoprostol groups than placebo (P <0.001). Need for additional analgesia was significantly higher in placebo group than in the other two groups (P = 0.009). Adverse events were not significantly different between the three groups except vomiting and abdominal cramps, which were higher with misoprostol. CONCLUSION: LP cream and 200 µg of vaginal misoprostol administration before LNG-IUD insertion in women delivered only by elective CD effectively reduced pain during insertion and 10 min post-procedure with easier insertions, high patient satisfaction, and tolerable side effects. Pain reduction with LP cream was clinically significant.

The frequency of periodontitis in end-stage renal disease on hemodialysis in a sample of Egyptian population: multi-center clinical cross-sectional study.

BACKGROUND: There is a general assumption that periodontal disease is highly prevalent among patients with chronic renal failure undergoing hemodialysis. The aim of the study to estimate the frequency of periodontitis in patients on hemodialysis among a sample of the Egyptian population, as well as the correlation between different clinical parameters of periodontal status with serum creatinine and blood urea. This may rule out the bidirectional relationship between periodontitis and renal failure in patients on hemodialysis. METHODS: The study was conducted on 263 hemodialysis patients (165 males and 98 females) at three dialysis centers in Benha Governorate, Egypt (Benha Hospital, Tukh hospital, Qalyub hospital). Periodontal parameters including plaque index (PI), gingival index (GI), clinical attachment level (CAL), and probing pocket depth (PPD) had been recorded in these patients. Serum urea and creatinine levels had been measured, the data had been collected and undergone statistical analysis. RESULTS: Frequency of periodontitis was 85.6% with stage III is the most prevalent stage. There was a significant positive strong correlation between age and periodontitis stage (rs = 0.707, p < 0.001). There was a positive correlation between clinical parameters and serum creatinine level. CONCLUSION: In the present study, a high frequency of periodontitis had been found among ESRD patients on hemodialysis in the severe form (stage III) periodontitis. There was a significant direct correlation between the severity of periodontitis and CAL with a duration of hemodialysis. There was a weak insignificant association between periodontal indices (PD, BOP, and plaque score) and duration of hemodialysis.

Evaluation of novel coagulation and platelet function assays in patients with chronic kidney disease.

BACKGROUND: Hemostasis evaluation in chronic kidney disease (CKD) is critical for optimal management of thrombotic and bleeding events. Standard coagulation screens are inadequate for predicting coagulopathy in CKD. OBJECTIVE: To evaluate hemostasis parameters in patients with different stages of CKD using novel coagulation assays. PATIENTS/METHODS: Cross-sectional study of 30 healthy controls (HC) and 120 CKD patients (10 Stage 2, 20 Stage 3, 20 Stage 4, 20 Stage 5 not requiring renal replacement therapy, 20 transplant, 10 newly started on hemodialysis [HD], 20 established on HD). Standard laboratory tests were performed in addition to rotational thromboelastometry (ROTEM), multiple electrode aggregometry (MEA), thrombin generation assays, D-dimer, and markers of thrombogenesis (thrombin-antithrombin [TAT]), fibrinolysis, and endothelial activation (intercellular adhesion molecule-1 [ICAM-1]). RESULTS: D-dimer, TAT, and ICAM-1 concentrations were significantly higher in patients with CKD than HC (P < .01). ROTEM maximum clot firmness was significantly higher in patients than in HC (P < .01). In CKD Stage 5 patients (pre-HD and started HD) adenosine diphosphate and thrombin receptor activating peptide MEA tests were significantly lower than HC indicating platelet aggregation defect (P < .05). Multivariate analysis confirmed the direct effect of estimated glomerular filtration rate (eGFR) in the variance of ROTEM and MEA tests. Endogenous thrombin potential and peak thrombin were not statistically different between groups, but Stage 5 CKD patients had prolonged lag time (7.91 vs. 6.33, P < .001) and time to thrombin peak (10.8 vs. 9.5, P < .05) compared to HC. CONCLUSIONS: Patients with CKD exhibit features of concomitant hypercoagulability measured by ROTEM and platelet dysfunction measured with MEA. eGFR was an independent determinant of platelet dysfunction and hypercoagulability.

Microneedling-assisted topical tranexamic acid solution versus 4% hydroquinone for treating melasma: A split-face randomized study.

BACKGROUND: Melasma, also known as chloasma or mask of pregnancy, is a common, acquired, hyperpigmentary disorder usually affecting females. Tranexamic acid (TA), a derivative of amino acid lysine, has shown promising results over the past few years when used along with other therapies and when used as a stand-alone therapy. AIM OF THE WORK: In this study, we aimed to evaluate and compare the effectiveness of topically applied tranexamic acid after microneedling versus topically applied hydroquinone (HQ) 4% alone in patients with melasma. PATIENTS AND METHODS: Fifty selected patients were divided randomly according to the random number allocation method into two groups (25 patients each) of A (topical 4% hydroquinone, nightly application) and B (microneedling + topical 4% TA, every other week). RESULTS: After eight weeks of treatment, the mean modified MASI score of the HQ treated side changed from 6.604 ± 4.02 to 3.032 ± 1.19 with a mean decrease percentage of 54.8% ± 19.4%. This reduction in modified MASI score was found to be statistically significant, (p < 0.001). MASI score of group B (TA +microneedling) changed from 6.348 ± 3.84 to 3.712 ± 1.19 with mean decrease percentage of 57.4% ± 23.4% which was also statistically significant, (p < 0.001). CONCLUSION: We demonstrated safety and efficacy of both used modalities and with minimal side effects. Topical HQ application achieved minimal non-significant higher satisfactory results among raters and subjects.

Effect of Systemic Calcitonin Delivery with and Without Adjunct Local Platelet-rich Fibrin Therapy on Osseointegration in Ovariectomized Osteoporotic Rabbits: A Scanning Electron Microscopy-based Study.

PURPOSE: It is hypothesised that systemic calcitonin delivery with adjunct local platelet-rich fibrin (PRF) therapy is more effective in augmenting osseointegration than calcitonin delivery alone under experimental osteoporosis conditions. The primary objective of the present experiment was to assess the effect of systemic calcitonin delivery with and without adjunct local PRF therapy on osseointegration in ovariectomised osteoporotic rabbits. MATERIALS AND METHODS: Thirty female bilaterally ovariectomized rabbits were used. The animals were fed a low-calcium diet to establish a model for osteoporosis. In each animal, 2 implants were bilaterally placed in tibia. The animals were randomly divided equally into 3 groups. In group 1, no treatment was offered (control group). In groups 2 and 3, the animals received intramuscular injections of calcitonin without and with local PRF delivery prior to implant placement, respectively. All animals were euthanised at 12 weeks, and osseointegration was assessed as the gap widths between the bone and implant surface in the cervical, middle and apical third using scanning electron microscopy and energy-dispersive x-ray spectroscopy. The bone-to-implant contact (BIC) was also measured. p < 0.05 was defined as statistically significant. RESULTS: Gap widths in the cervical (p < 0.001), middle (p < 0.001) and apical third (p < 0.001) were statistically significantly higher in group 1 than groups 2 and 3. Gap widths in the cervical (p < 0.001), middle (p < 0.001) and apical third (p < 0.001) were significantly higher in group 3 than group 2. The mean BIC was statistically significantly higher in the cervical (p < 0.001), middle (p < 0.001) and apical third (p < 0.001) in group 3 compared with groups 2 and 3. CONCLUSIONS: When used as an adjunct to calcitonin, PRF enhanced osseointegration in an experimental osteoporosis model. However, further well-designed studies with inclusion of additional groups (treatment with PRF alone) are needed.

Effect of Adipose-Derived Stem Cells and Their Exo as Adjunctive Therapy to Nonsurgical Periodontal Treatment: A Histologic and Histomorphometric Study in Rats.

Scaling and root planing (SRP) is of limited value in many cases, so adjunctive treatment was applied to augment its outcome. Adipose-derived stem/stromal cells (ADSCs) were investigated in periodontal regeneration with promising results. However, they have safety concerns. The exosomes (Exo.), which are extracellular vesicles mediating the action of stem/stromal cells, represent a new approach to overcome these concerns. Ligature-induced periodontitis was induced in 50 rats for 14 days, and they were divided into control (5 healthy rats for histologic comparison), SRP group, ADSCs group, and Exo. group, with evaluation intervals at 2 days, and 2 and 4 weeks, including 5 rats in each interval for each group. The specimens were evaluated for histologic description (H&E), histochemical study (Masson trichrome), and histomorphometric study, to evaluate the area % of newly formed tissues. The Exo. group revealed the best results in all intervals with significantly higher area % of newly formed tissues, followed by ADSCs and, finally, SRP. Both Exo. and ADSCs showed organized newly formed tissues with the Exo. group obtaining comparable histologic results to the normal, healthy tissues by 4 weeks. Adipose-derived stem/stromal cells and their Exo. represent a promising adjunctive treatment to SRP.

Effects of sleep disordered breathing on functional capacity and quality of life in chronic kidney disease Egyptian patients.

PURPOSE: We assessed the prevalence of sleep disordered breathing (SDB) and investigated its effects on the muscle functional capacity and quality of life (QoL) among chronic kidney disease (CKD) Egyptian patients, either maintained or not maintained on hemodialysis (HD). METHODS: The study population comprised 100 CKD patients who were divided into patients maintained on HD (n = 60; M/F = 28:32) and patients not maintained on HD (n = 40; M/F = 24:16). Patients were observed overnight using the pulse-oximetry technique and further subdivided into patients with SDB and patients without SDB, according to their calculated oxygen desaturation index (cutoff 5). All patients were subjected also to estimation of Kt/V ratio (which is a measure for the efficiency of HD), body-composition analysis, biochemical analysis, muscle functional capacity, and QoL measurements using standard methods and questionnaires, respectively. RESULTS: Primary outcomes were intergroup differences regarding physical capacity and muscle performance, QoL, and body-composition measurements. CKD patients in general, either maintained on HD or not, suffer from SDB, and the levels of urea and creatinine may increase the incidence of SDB in CKD patients not maintained on HD. CKD patients maintained on HD with SDB had poorer functional capacity, physical performance, and muscle composition, in comparison with those without SDB. CONCLUSIONS: Overall, SDB appears to partly contribute to the total diminished functional capacity of HD patients. Thus, CKD patients maintained on HD with SDB had significantly lower sleep quality and QoL as compared to those not maintained on HD with or without SDB.

Bone densitometric analysis in egyptian hemodialysis patients.

End-stage renal failure (ESRF) is the ultimate consequence of chronic renal failure, and in such cases dialysis is generally required. Almost all dialysed patients have abnormal bone histology and lower values of glomerular filtration rate have been associated with lower bone mineral density (BMD) at all sites. The objective of the present study was to investigate the effect of hemodialysis (HD) on body-composition (BC), specially segmental and total BMD in Egyptian ESRF patients. Forty ESRF patients (20 male/20 female; age range: 21.00-74.00 yr) undergoing regular HD 3 times/week (duration range: 0.08-20.00 yr) using bicarbonate dialysis and polysulphon membrane were matched with 40 healthy controls for age, height, and sex. Blood samples were obtained and serum levels of calcium (Ca), inorganic phosphate (P), osteocalcin (OC), and parathyroid hormone (PTH) were monitored for all participants. BC was evaluated by dual X-ray absorptiometry. HD patients manifested lower segmental and total BMD values in comparison with age-matched healthy controls (Z-score: -0.17 ± 1.12) due to significantly higher levels of P (4.04 ± 1.33 vs. 3.39 ± 0.51 mg/dl, p<0.001), PTH (538.17 ± 363.99 vs. 48.86 ± 19.64 ng/L, p<0.0001), and OC (50.39 ± 34.91 vs. 16.32 ± 5.37 µg/L, p<0.0001). Pelvis, lumbar spine, and total BMD (g/cm(2)) for HD patients were significantly correlated with HD duration (yr) (R=0.94, 80, and 92, respectively; p<0.0001). Thus, BC analysis is of utmost importance for efficiently providing tailored individual mineral supplementation to HD patients.