Effect of CYP3A4*22, CYP3A5*3 and POR*28 genetic polymorphisms on calcineurin inhibitors dose requirements in early phase renal transplant patients.

OBJECTIVE: This study aimed to investigate the combined effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on tacrolimus and cyclosporine dose requirements. METHODS: One hundred thirty renal transplant patients placed on either tacrolimus or cyclosporine were recruited, where the effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on their dose requirements were studied at days 14, 30, and 90 post-transplantations. RESULTS: The POR*28 allele frequency in the studied population was 29.61%. The tacrolimus dose-adjusted trough concentration ratio (C0/D) was significantly lower in the fast metabolizers group ( CYP3A5*1/POR*28(CT/TT ) carriers) than in the poor metabolizers group ( CYP3A5*3/*3/CYP3A4*22 carriers) throughout the study (14, 30, and 90 days) ( P = 0.001, <0.001, and 0.003, respectively). Meanwhile, there was no significant effect of this gene combination on cyclosporine C0/D. CONCLUSION: Combining the CYP3A5*3, POR*28 , and CYP3A4*22 genotypes can have a significant effect on early tacrolimus dose requirements determination and adjustments. However, it does not have such influence on cyclosporine dose requirements.

Inhibition of vascular endothelial growth factor-A downregulates angiogenesis in psoriasis: A pilot study.

Background: Vascular Endothelial Growth Factor (VEGF)-A-mediated angiogenesis participates in the pathogenesis of psoriasis, thus inviting the hypothesis that anti-VEGF-A therapy could be beneficial in psoriasis. While anti-angiogenic agents are used in oncology and ophthalmology, these therapeutic strategies remain unexplored for the management of psoriasis. Objective: Our objective was to investigate ex vivo how VEGF-A blockade impacts blood vessels, epidermis and immune cells in organ-cultured plaque and non-lesional skin from patients with psoriasis. Methods: Skin biopsies from patients with psoriasis (n = 6; plaque and non-lesional skin) and healthy controls (n = 6) were incubated with anti-VEGF-A monoclonal antibody (bevacizumab, Avastin®) or a human IgG1 isotype control for 72-h in serum-free organ culture. CD31/LYVE-1, Ki-67, and mast cell tryptase expression were assessed by quantitative immunohistomorphometry. VEGF-A levels in plasma, PBMCs and skin culture supernatants were measured. Results: Inhibition of VEGF-A blocked all free VEGF-A ex vivo, reduced blood vessel area and the number of blood vessel endothelial cells in plaques of psoriasis (*p < 0.05). The treatment effect correlated significantly with levels of VEGF-A in organ culture supernatants (r = 0.94; *p < 0.05) from plaque skin and with plasma levels of VEGF-A from patients with psoriasis (r = 0.943; *p = 0.017). Conclusions: These ex vivo data are the first studies to objectively investigate the potential of VEGF-A inhibition as a novel adjuvant treatment strategy for psoriasis. Taken together, our data encourage further investigation by clinical trial to explore whether downregulating pathological angiogenesis has clinical utility, especially in patients with severe psoriasis or those with elevated levels of VEGF-A in plasma and/or skin.

The Role of Lasers in Connective Tissue and Inflammatory Dermatoses: A 10-Year Retrospective Review of 60 Patients in a UK Tertiary Laser Clinic.

Introduction: The role of lasers in the treatment of standard therapy-resistant inflammatory dermatoses and connective tissue disorders has been controversial and evidence supporting the role of lasers in this setting is scarce. Objective: To assess the efficacy of lasers in the management of inflammatory dermatoses and connective tissue disorders (CTD). Materials and Methods: A retrospective case review of all inflammatory dermatoses/connective tissue diseases treated in a tertiary laser clinic between March 2010 and 2020 was undertaken. Results: A total of 60 cases (48 = female) were included and the average age was 51 years (range 21 to 74). The following conditions were treated: scleroderma n = 22 (37%), granuloma faciale n = 10 (17%), sarcoidosis n = 8 (13%), discoid lupus erythematosus n = 7 (12%), and systemic lupus erythematosus n = 2 (3%). Other diagnoses included necrobiosis lipoidica, pyoderma vegetans, hypertrophic lichen planus, and dermatomyositis. The most common type of laser used was pulsed dye laser (PDL) in n = 41 (68%) cases. Eight (13%) patients received treatment with the carbon dioxide (CO2) laser. The most common site treated was the face. A good response with a marked reduction of signs was seen in 62% of patients while 10% of the patients did not respond to laser treatment. Self-limiting complications included purpura and hyperpigmentation. Limitations: Lack of objective assessment and outcome measures. Conclusions: This is the largest cohort of patients to have undergone laser treatment for inflammatory dermatoses/connective tissue disease. Based on this retrospective review, we conclude that lasers can be a useful adjunct in the management of otherwise difficult-to-treat selected inflammatory and connective tissue diseases.

Correlates of Myopathy in Diabetic Patients Taking Statins.

Diabetes is one of the most common chronic ailments; its incidence has reached epidemic proportions in the 21st century. Diabetes significantly increases micro and macrovascular complications, which are effectively managed with statins. Therefore, statins' pharmacokinetics, pharmacodynamics, and pharmacogenetics have been extensively studied. Although statins act as a keystone in preventing cardiovascular complications, at the same time, they pose a threat to the quality of life of diabetics due to the resulting muscular side effects. This article summarizes the prevalence, clinical manifestations, pathophysiology, and risk factors of statin-induced myopathy in diabetic patients. Among the diverse predisposing risk factors, the primary variables identified for causing myopathy in diabetic patients include age, gender, ethnicity, duration and severity of illness, comorbid conditions, level of physical activity, alcohol use, cholecalciferol (vitamin D3) levels, type and dose of statins, and anti-diabetic drugs or other drugs used concomitantly. In addition, cardiovascular risk quotients also potentially impact diabetic patients making them more vulnerable to developing myopathy from statins. Therefore, this study highlights the importance of managing statin-associated myopathic side effects by providing consensus guidelines on diagnostic, monitoring, and treatment strategies. We also discussed statins' prognostic value in reducing cardiovascular events in diabetic individuals.

Chronic Obstructive Pulmonary Disease and Its Effect on Red Blood Cell Indices.

Chronic obstructive pulmonary disease (COPD) constitutes a set of heterogeneous symptoms affecting millions of people worldwide. The associated comorbidities developing in COPD involve dysregulation in physiological pathways resulting from systemic inflammation in respiratory airways. In addition to mentioning the pathophysiology, stages, and consequences of COPD, this paper also defines red blood cell (RBC) indices such as hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, red blood cell distribution width, and RBC count. It explains the role of RBC indices and RBC structural abnormalities with disease severity and exacerbations in COPD patients. Although many factors have been studied as a marker of morbidity and mortality for COPD patients, RBC indices have emerged as revolutionary evidence. Therefore, the effectiveness of evaluating RBC indices in COPD patients and their importance as a negative predictor of survival, mortality, and clinical outcomes have been debated through rigorous literature reviews. Furthermore, the prevalence, mechanisms of development, and prognosis of underlying anemia and polycythemia in COPD have also been evaluated, with anemia most significantly associated with COPD. Therefore, more studies should be conducted to address underlying anemia in COPD patients to lessen the severity and disease burden. Correcting the RBC indices in COPD patients remarkably impacts the quality of life and reduces in-patient admissions, healthcare resource utilization, and costs. Hence, it is noteworthy to understand the significance of considering RBC indices while dealing with COPD patients.

Investigation the effect of different ionic liquids based-aryl imidazole on the onset precipitation of asphaltene.

Precipitation and deposition of asphaltene are considered as catastrophic issues facing the petroleum industry. Asphaltene deposition mainly occurs at variety places such as formation pore spaces, pumps, pipelines, wellbore, wellhead, tubing, surface facilities and safety valves causing operational problems, production deficiencies and enormous economic losses. This work aims to study the effect of series of synthesized aryl ionic liquids (ILs) containing different alkyl chains, named as R8-IL, R10-IL, R12-IL, and R14-IL, on the onset precipitation point of asphaltene in crude oil. R8-IL, R10-IL, R12-IL, and R14-IL were synthesized with high yields (the yield varied between 82 and 88%) and characterized via different tools of analysis (FTIR, 1H NMR, and Elemental Analysis). Their Thermal Gravimetric Analysis (TGA) was investigated and showed a reasonable degree of stability. It was found that R8-IL (short alkyl chain) has the highest stability, while R14-IL (long alkyl chain) is the lowest one. Quantum chemical calculations were conducted to study the reactivity and geometry of their electronic structures. Moreover, surface and interfacial tension of them were studied. It was found that the efficiency of the surface active parameters increased by increasing the length of the alkyl chain. The ILs were evaluated to delay the onset precipitation point of asphaltene using to different methods; the kinematic viscosity and the refractive index. Results from the two methods showed delaying of onset precipitation after the addition of the prepared ILs. The asphaltene aggregates was dispersed due to the π-π* interactions and hydrogen bonds formation with the ILs.

Influence of CYP3A4*22 and CYP3A5*3 combined genotypes on tacrolimus dose requirements in Egyptian renal transplant patients.

BACKGROUND: Tacrolimus is a widely prescribed immunosuppressant agent for kidney transplantation. However, optimal dosing is challenging due to its narrow therapeutic index, potentially serious adverse effects, and wide inter-individual variability in pharmacokinetics. Cytochrome P450 3A (CPY3A) enzymes metabolize tacrolimus, so allelic variants such as CYP3A4*22 and CYP3A5*3 may contribute to individual differences in pharmacokinetics and therapeutic efficacy of tacrolimus. This study assessed the frequency and influences of CYP3A4*22 and CYP3A5*3 genotypes, alone and combined, on tacrolimus pharmacokinetics and dose requirements in Egyptian kidney transplant patients. METHODS: This is a prospective multicenter observational cohort study. Patients were genotyped for the CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746). Tacrolimus dose (mg), through blood level (ng/ml), and dose-adjusted trough concentration (C0/D) (ng/ml per mg/kg) were recorded during the first and third months post-transplantation and compared among genotype groups. RESULTS: The CYP3A4*22 allele was rare (3.2% of subjects) while the CYP3A5*3 allele was widespread (90.38%) in this cohort. At the third month post-transplantation, median C0/D was significantly higher among CYP3A4*22 carriers than CYP3A4*1/*1 (146.25 [100-380] versus 85.57 [27-370] ng/ml per mg/kg, p = 0.028). Patients harbouring the one copy of the CYP3A4*22 allele and the CYP3A5*3/*3 genotype (n = 5) were classified as poor tacrolimus metabolizers, the CYP3A5*3/*3 plus CYP3A4*1/*1 genotype as intermediate metabolizers (n = 60), and the CYP3A4*1/*1 plus CYP3A5*1/*1 genotype as normal metabolizers (n = 13). During the first month post-transplantation, C0/D was significantly greater in poor metabolizers (113.07 ng/ml per mg/kg) than intermediate and normal metabolizers (90.380 and 49.09 ng/ml per mg/kg) (p < 0.0005). This rank order was also observed during the third month. Acute rejection rate and renal function at discharge did not differ among genotypes. CONCLUSION: Pharmacogenetics testing for CYP3A4*22 and CYP3A5*3 before renal transplantation may help in the adjustment of tacrolimus starting dose and identify patients at risk of tacrolimus overexposure or underexposure.

Correlation of Coronary Artery Disease and Left Ventricular Hypertrophy.

Ischemic heart disease (IHD) is the leading cause of death worldwide, and it is defined as an imbalance between myocardial oxygen supply and demand. Coronary artery disease (CAD) and left ventricular hypertrophy (LVH) are two common causes of IHD that independently result in myocardial ischemia. CAD decreases myocardial blood and oxygen supply whereas LVH increases myocardial oxygen demand. The coexistence of both CAD and LVH results in a significant increase in oxygen demand while simultaneously lowering oxygen supply. Since hypertension is a shared predisposing condition for both CAD and LVH, the left ventricular (LV) mass on noninvasive echocardiography can reflect on the severity of coronary artery stenosis. In clinical practice, it can help physicians decide whether to perform invasive cardiac catheterization to visualize the extent of the coronary block. Although, both CAD and LVH are directly proportional to mortality risk, the addition of eccentric LVH can further increase morbidity and mortality due to myocardial infarction. Therefore, the latest management of both the acute and chronic phases of CAD places an increased emphasis on controlling the predisposing factors to prevent or reverse LVH. For example, angiotensin-converting enzyme inhibitors and diuretics reduce LV mass by lowering the cardiac preload and afterload. This article aims to investigate the deleterious effects of the collaboration between CAD and LVH, establish a causal relationship, and explore the new prevention and management strategies.

Role of Kisspeptin on Hypothalamic-Pituitary-Gonadal Pathology and Its Effect on Reproduction.

Kisspeptin is a neuropeptide that plays a significant role in human reproduction by its action on the hypothalamic-pituitary-gonadal (HPG) axis and functions through a G-protein-coupled receptor called G-protein-coupled receptor 54/kisspeptin 1 receptor (GPR54/KISS1R). It is encoded by the kisspeptin 1 (KISS1) gene that is mainly expressed in the hypothalamus. Kisspeptins are also recognized as vital aspects of maturation and proper function of the reproductive system in both males and females. It also plays its role in the onset of puberty, sexual patterns, desires, ovum development in women, sperm quality in men, feedback mechanisms, pregnancy, and lactation. Studies proved the pathological role of kisspeptin dysregulation in disorders like polycystic ovarian syndrome (PCOS) and infertility. Mutations in the KISS1 gene also contribute to precocious puberty or hypogonadotropic hypogonadism, depending upon the nature of mutations. Levels of kisspeptin also aid in the identification of a few pregnancy-related complications like preeclampsia, intrauterine growth restriction, and act as a marker of miscarriage. Due to the wide range of effects that kisspeptin has on the reproductive axis, investigations are being carried out to develop it as a diagnostic marker, treat diseases like hypogonadism and PCOS, and solve infertility issues.

Paired-Box Gene 8 (PAX8) and Its Association With Epithelial Carcinomas.

Cancer is the second most common culprit of mortality in the United States and epithelial carcinomas are considered as one of the most predominant types of cancer. The association between epithelial cancers and paired-box gene 8 (PAX8) has been studied significantly before. PAX8 belongs to the paired-box gene family, which plays an important role in the organogenesis of different body organ systems, especially the thyroid gland, the renal system, and the Müllerian system. Immunohistochemical staining is being used to detect PAX8 expression in different epithelial cancers and differentiate them from PAX8-negative tumors. In follicular, papillary, and anaplastic thyroid carcinomas, targeting the PAX8/peroxisome proliferator-activated receptors (PPARs) fusion protein is being considered as a potential mechanism for therapy. Moreover, because of its high expression in primary ovarian cancers, PAX8 is being considered as a target for ovarian cancer treatment as well. More studies are needed to test the possibility of using PAX8 as a possible target for managing endometrial carcinomas. In this article, we review the functions of the PAX8 gene, how its mutations lead to the development of certain epithelial carcinomas, how it can be used as a diagnostic or a prognostic marker, and its potential as a therapeutic target for these cancers.

HIV and Messenger RNA (mRNA) Vaccine.

Human immunodeficiency virus (HIV) is a part of the lentivirus genus of the retroviridae family that incorporates its genome into the host DNA via a series of complex steps. HIV can be classified into two types, HIV-type 1 (HIV-1) and HIV-type 2 (HIV-2), with HIV-1 being the most common type worldwide. Seventy-six million people have been infected since the start of the pandemic, with a mortality rate of 33 million. Even after 40 years, no cure has been developed for this pandemic. The development of the mRNA vaccine has led to further research for the utilization of mRNA vaccine in HIV, in attempts to create a prophylactic and therapeutic treatment. Although messenger RNA (mRNA) vaccine has been around for many years, it has recently drawn attention due to its role and response in the unforeseen coronavirus pandemic. mRNA vaccine has faced its fair-share of challenges, but it also offers many advantages compared to conventional vaccines such as safety, efficacy, rapid preparation, and versatility. mRNA vaccine has shown promising results and has great potential. In this review, we discuss the types of mRNA vaccine, along with development, delivery, advantages, challenges, and how we are working to overcome these challenges.

Gene Expression of the Circulating Long Noncoding RNA H19 and HOTAIR in Egyptian Colorectal Cancer Patients.

Background: HOX transcript antisense RNA (HOTAIR) and H19 are two long noncoding RNAs that play vital functions in the development of colorectal cancer (CRC). Subjects and Methods: The expression level of HOTAIR and H19 in the sera samples of Egyptian CRC patients along with normal controls was evaluated by quantitative real-time PCR. The possible correlations with the biochemical and clinicopathological characteristics were determined. Results: The expression of HOTAIR and H19 showed 7.55- and 11.38-fold increased levels, respectively, in CRC patients compared to the controls (p < 0.001). Furthermore, HOTAIR expression in CRC patients with regional lymph node metastasis was significantly higher when compared with CRC patients without regional lymph node metastasis (p = 0.034). HOTAIR and H19 expression showed no significant correlation with tumor site or carcinoembryonic antigen concentration. The sensitivity and specificity of HOTAIR and H19 in the detection of CRC cases were calculated as 92.9% and 100%, respectively. Conclusion: HOTAIR and H19 expression levels are upregulated in Egyptian CRC patients, and therefore can be considered noninvasive diagnostic biomarkers with high sensitivity and specificity.

Effect of isokinetic training on muscle strength and postural balance in children with Down's syndrome.

Children with Down's syndrome (DS) often have greater postural sway and delay in motor development. Muscle weakness and hypotonia, particularly of the lower extremities, are theorized to impair their overall physical health and ability to perform daily activities. Therefore, the aim of this study was to investigate the effects of isokinetic training on muscle strength and postural balance in children with DS. Thirty-one children with DS ranging in age from 9 to 12 years were assigned randomly into two groups. The control group received the conventional physical therapy, whereas the study group received the same therapy as the control group in addition to the isokinetic training 3 days a week for 12 weeks. Measurement of stability indices using the Biodex Stability System as well as peak torque of knee flexors and extensors of both sides using the isokinetic dynamometer was performed before and after 12 weeks of the treatment program. Each group showed significant improvements in postural balance and peak torque of knee flexors and extensors (P<0.05), with significantly greater improvements observed in the study group compared with the control group (P<0.05). These outcomes indicated that participation in the isokinetic training program induced greater improvements in muscle strength and postural balance in children with DS.

Focal Hyperhidrosis Associated with Recurrent Urinary Tract Infections.

Hyperhidrosis affects almost 3% of the population and is characterized by sweating that occurs in excess of that needed for normal thermoregulation. It can occur as a primary disease or secondary to underlying clinical conditions. Hyperhidrosis can stem from neurogenic sympathetic over activity involving normal eccrine glands. We report the interesting case of a 75-year-old male patient with a 6-month history of new onset secondary focal hyperhidrosis of buttocks, pelvis, and upper thighs. Each time his symptoms worsened he was found to have culture positive urine samples for Escherichia coli (E. coli). He underwent urological investigation and was found to have urethral strictures and cystitis. The hyperhidrosis improved each time his urinary tract infection (UTI) was treated with antibiotics and continued to remain stable with a course of prophylactic trimethoprim. We hypothesize that the patient's urethral strictures led to inhibition in voiding which in turn increased the susceptibility to UTIs. Accumulation of urine and increased bladder pressure in turn raised sympathetic nerve discharge leading to excessive sweating. We recommend that a urine dip form part of the routine assessment of patients presenting with new onset focal hyperhidrosis of pelvis, buttocks, and upper thighs. Timely urological referral should be made for all male patients with recurrent UTI. To the authors' knowledge, there have been no other reports of UTI-associated focal hyperhidrosis.

Neocortical and thalamic spread of amygdala kindled seizures.

PURPOSE: Amygdala kindling is an epilepsy model involving long-term network plasticity in the nervous system. In this model, repeated weak stimulation of the amygdala eventually leads to severe motor seizures. The mechanisms for worsening behavioral seizures, and the possible role of enhanced connectivity between the amygdala and other structures have not been thoroughly investigated. METHODS: We performed simultaneous field potential recordings from the amygdala, frontal cortex, and medial thalamus during kindling in rats. Seizures were analyzed for signal power compared with baseline and for correlation between recording sites. Interictal signals were analyzed for changes in coherence between electrode contacts in kindled animals compared with sham kindled controls. RESULTS: We found that increased behavioral severity of seizures was related to increased seizure duration and to increased signal power in the frontal cortex and medial thalamus. Kindling was associated with increased connectivity between the amygdala and frontal cortex, based on increased amygdala-frontal signal correlation during seizures. In addition, during the interictal period, increased coherence was noted between amygdala and frontal contacts in kindled animals compared with controls. CONCLUSIONS: We found evidence for increased connectivity between the amygdala and frontal cortex both during seizures and in the interictal period, as a result of kindling. Enhanced connections between limbic and neocortical circuits may be important for the development of epilepsy, as well as for normal long-range network plasticity in the nervous system.

Role of germanium L-cysteine alpha-tocopherol complex as stimulator of some antioxidant defense systems in gamma-irradiated rats.

This study was conducted to evaluate the potency of the newly prepared germanium L-cysteine-alpha-tocopherol complex [germanium dichloro tetrakis (L-cysteinyl-alpha-tocopherol amide) dichloride] as a protective agent against gamma-irradiation-induced free radicals production and liver toxicity. Male Swiss albino rats were injected intraperitoneally with the germanium complex in a concentration of 75 mg kg(-1) body mass per dose, for 6 successive doses, last dose administered twenty minutes pre-exposure to a single dose of whole body y-irradiation of 6.5 Gy. Lipid peroxidation (LPx), nitric oxide (NO), glutathione (GSH) levels, and activity of the antioxidant enzymes glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were estimated in blood and liver. Blood total protein, cholesterol, triglyceride and alpha-tocopherol content were estimated as well. The results revealed that administration of germanium complex pre-irradiation resulted in significant (p < 0.001) improvement compared to the irradiated group in the level of hepatic and blood LPx. Hepatic GSH revealed a significant increase (p < 0.001), while its level showed no significant variation in blood. Also, the level of NO in blood and liver increased significantly (p < 0.001). On the other hand, pretreatment with the germanium complex normalized the activities of SOD, GPx and CAT in blood and liver when compared to the irradiated group. The study also documents a marked decrease in a blood triglyceride and cholesterol (p < 0.001) and a significant increase (p < 0.001) of alpha-tocopherol and total protein contents in blood. These biochemical changes were associated with marked improvement of histological status. Therefore, the germanium L-cysteine alpha-tocopherol complex may be a good candidate for ameliorating the changes induced by irradiation, which indicates the beneficial radio-protective role of this antioxidant agent.