Evaluating Sex Differences in the Characteristics and Outcomes of Lupus Nephritis: A Systematic Review and Meta-Analysis.

Introduction: More frequent and severe lupus nephritis (LN) has been reported in men compared to women, but data are limited and inconsistent. We conducted a meta-analysis of the literature to compare the histopathologic findings and outcomes between men and women with biopsy-proven LN. Methods: A systematic search of MEDLINE, Embase, Cochrane, and Web of Science databases was conducted through February 2021. Clinical information was extracted and synthesized from 25 studies that met inclusion criteria (1,210 men and 6,635 women). Pooled odds ratios (OR) with corresponding 95% confidence intervals (CIs) were generated via meta-analysis, and meta-regression was performed to assess the impact of several covariates, both using random-effects models. Results: Twenty studies reported kidney histopathology, eleven reported kidney outcomes, and eight reported mortality rates. Men had greater odds of class IV ± V LN (OR 1.26, 95% CI: 1.01-1.56), and the composite of end-stage kidney disease, persistent eGFR <15 mL/min or doubling of serum creatinine (OR 2.20, 95% CI: 1.59-3.06), and lower odds of complete remission (OR 0.52, 95% CI: 0.39-0.68). Mortality was not statistically significantly different between sexes (OR 1.50, 95% CI: 0.92-2.46). Meta-regression did not reveal statistically significant study-level relationships between sex differences in any of the covariates that could account for the greater odds of worse kidney outcome in males. Conclusion: Our analysis confirms the association between male sex and increased severity of LN as well as worse kidney outcomes. Larger prospective studies are needed to validate this association and inform treatment strategies adapted to this population.

Fibronectin glomerulopathy in a kidney allograft biopsy.

BACKGROUND: Fibronectin glomerulopathy is a rare genetic nephropathy with only a few cases of post-transplant recurrence being reported previously. We highlight a case that was initially misdiagnosed and emphasize the importance of full immunofluorescence and electron microscopy evaluation in allograft biopsies. CASE PRESENTATION: A 36-year-old male with a history of end-stage kidney disease secondary to biopsy-proven type 1 membranoproliferative glomerulonephritis (MPGN) status-post living unrelated donor kidney transplant 12 years prior, presented with increasing creatinine and proteinuria. Biopsy was performed and was consistent with fibronectin glomerulopathy. Subsequent genetic testing revealed an FN1 mutation, the primary gene associated with this condition. CONCLUSIONS: Full histologic evaluation of the allograft biopsy corrected the diagnosis and additionally suggested that the patient's mother, who had expired in her 30s and had received a diagnosis of type 1 MPGN on autopsy, likely also had fibronectin glomerulopathy, enabling appropriate genetic counseling for the family.

Comparison of cytotoxic and apoptosis-inducing effects of MTA, propolis, and propolis-MTA on immature dental pulp stem cells.

BACKGROUND: Pulpotomy is a treatment option for the preservation of pulp vitality in primary teeth with extensive caries. Propolis is a natural resinous substance with optimal antimicrobial, anti-inflammatory, and immune-regulatory properties. Thus, this study aimed to compare the cytotoxic and apoptosis-inducing effects of mineral trioxide aggregate (MTA), propolis, and MTA-propolis on immature dental pulp stem cells (IDPSCs). METHODS: In this in vitro, experimental study, primary IDPSCs were exposed to propolis, MTA, and MTA-propolis for 24 and 72-h. The cytotoxicity and apoptosis-inducing effects were evaluated using the methyl thiazolyl tetrazolium (MTT) assay and flow cytometry, respectively. Data were analyzed using ANOVA and Tukey's test at 0.05 level of significance. RESULTS: The cytotoxicity of MTA and MTA-propolis was higher than that of propolis alone at both 24/48 h. In addition, all tested concentrations showed higher biocompatibility at 72-h compared with 24-h (P < 0.0001). In the assessment of apoptosis, propolis-MTA showed higher cell viability compared with other materials (P < 0.0001). CONCLUSION: Propolis-MTA showed higher biocompatibility than MTA. Addition of propolis to MTA improved cell proliferation in the first 24-h. Also, the cytotoxicity of propolis was lower than other materials in the first 24-h. Thus, propolis may serve as a promising pulp capping agent given that its other properties are approved.

Physical properties and pharmacological applications of Co3O4, CuO, NiO and ZnO nanoparticles.

Nano materials have found developing interest in biogenic approaches in the present times. In this study, metal oxide nanoparticles (NPs) such as cobalt oxide (Co3O4), copper oxide (CuO), nickel oxide (NiO) and zinc oxide (ZnO), were synthesized using a convenient and rapid method. The structural features of synthesized metal oxide NPs were studied using various microscopic and spectroscopic techniques like SEM, TEM, XRD, FTIR and EDX. The characterization results confirmed that the prepared NPs possess highly pure, unique and crystalline geometry with size ranging between 10 and 20 nm. The synthesized nanoparticles were successfully employed for pharmacological applications. Enzyme inhibition potential of NPs was evaluated against the urease and tyrosinase enzymes. The percent inhibition for the urease enzyme was observed as 80 to 90% by using Co3O4, CuO, NiO and ZnO NPs while ZnO NPs were found to have best anti-urease and anti-tyrosinase activities. Moreover, effective inhibition was observed in the case of ZnO NPs at IC50 values of 0.0833 and 0.1732 for urease and tyrosinase enzymes which were comparable to reference drugs thiourea and kojic acid. The lower the IC50 value, higher the free radical scavenging power. Antioxidant activity by DPPH free radical scavenging method was found moderately high for the synthesized metal oxide NPs while best results were obtained for Co3O4 and ZnO NPs as compared to the standard ascorbic acid. Antimicrobial potential was also evaluated via the disc diffusion and well diffusion methods. CuO NPs show a better zone of inhibition at 20 and 27 mm by using both methods. This study proves that the novel metal oxide NPs can compete with the standard materials used in the pharmacological studies nowadays.

Phytochemical analysis and nephroprotective potential of Ajwa date in doxorubicin-induced nephrotoxicity rats: Biochemical and molecular docking approaches.

The purpose of this study is to evaluate the likely defensive impact of Ajwa date aqueous extract (AJDAE) in alleviating the nephrotoxicity generated by doxorubicin (DOX) injection in rats. Sixty male Wister albino rats were randomly and equally separated into six groups (n = 10), and they were treated as follows: untreated control group, extract groups administered with 0.75 and 1.5 mg kg bw of AJDAE, toxicant control group administered with DOX, and prophylactic groups were treated with 0.75 and 1.5 mg/kg of AJDAE and 15 mg/kg DOX. Biochemical parameters, antioxidant enzymes, renal functions, DNA integrity, and histopathology were studied to evaluate the nephroprotective activity of AJDAE. Furthermore, bioactive compounds were utilized for in silico molecular docking. AJDAE treatment resulted in significant improvements in the amended renal biomarkers (urea, creatinine, calcium, phosphorous, and uric acid), antioxidative markers, and MDA. Noticeable histopathological improvements supported this result. Results of in silico studies revealed that d-Mannitol, 6TMS derivative, palmitic acid, and TMS derivative had a higher docking score with human soluble epoxide hydrolase (-10.9 kcal/mol) and NF-κB-DNA (-7 kcal/mol). The present findings indicated that AJDAE could decrease ROS generation and lipid peroxidation (LPO) and repair the DOX injection-related DNA damage.

Ketamine Infusion for Sedation and Analgesia during Mechanical Ventilation in the ICU: A Multicenter Evaluation.

Methods: We reviewed the electronic medical record of critically ill adults who received a continuous infusion of ketamine for ≥24 hours during invasive mechanical ventilation in three hospitals over a two-year period. We captured data including ketamine indication, dose, unintended effects, and adjustments to coadministered sedatives or opioids. We analyzed these data to determine the incidence of reported unintended effects of ketamine infusion (primary outcome) and changes in exposure to coadministered sedatives or opioids during ketamine use (secondary outcome). Results: 95 mechanically ventilated adults received a ketamine infusion for a median duration of 75 hours (interquartile range [IQR] 44-115) at a mean ± standard deviation (SD) infusion rate of 1.3 ± 0.5 mg/kg/hour for the first 24 hours. At least one unintended effect attributed to ketamine was documented in 24% of cases, most frequently tachycardia (6%) and sialorrhea (6%). Other sedative or opioid infusions were administered with ketamine in 76% and 92% of cases, respectively. Comparing the total amount of sedative or opioid administered in the 24 hours prior to ketamine infusion with the total amount administered during the first 24 hours on ketamine, there were no significant differences in propofol, midazolam, or dexmedetomidine exposure, but the average fentanyl exposure was higher after ketamine (2740 ± 1812 mcg) than before (1975 ± 1860 mcg) (absolute difference 766 mcg, 95% confidence interval [CI] 442 to 1089 mcg). Conclusions: In this multicenter cohort of critically ill, mechanically ventilated adults, ketamine infusion was primarily used as an adjunct to conventional sedative and opioid infusions, with noticeable but unintended effects potentially related to ketamine in nearly one-quarter of cases.

Bullous Pemphigoid Associated With Pembrolizumab Therapy for Non-Small-Cell Lung Cancer: A Case Report.

Pembrolizumab is an immune checkpoint inhibitor being increasingly used as immunotherapy for a multitude of cancers. With the increasing use of these agents, various immune-related adverse events are being recognized. Lichenoid reaction, pruritus, and eczema are well-established cutaneous side effects of pembrolizumab, but bullous pemphigoid (BP) is a rare side effect of the drug. It is difficult to establish this diagnosis because it needs a detailed history of the timeline of the evolution of symptoms and careful ruling out of other etiologies, especially other drugs. Here, we present the case of a 66-year-old male who developed BP after receiving pembrolizumab therapy for non-small-cell lung cancer. Discontinuation of pembrolizumab and the use of topical and systemic steroids led to the complete resolution of symptoms. Physicians should be aware of this potential complication and keep it on their differential diagnosis when treating patients on immune checkpoint inhibitors.

Isolated Unilateral Abducens Nerve Palsy Manifesting as a Rare Complication of Idiopathic Pituitary Apoplexy: A Case Report.

Pituitary apoplexy (PA) is an expansion of a pituitary adenoma due to infarction or hemorrhage of the gland. The term apoplexy usually describes larger bleeds leading to a sudden onset of symptoms. Although it is a rare condition, it can be a life-threatening emergency. PA usually presents with severe headache, nausea, vomiting, visual acuity, and field defects, frequently involving the cranial nerves directly adjacent to the pituitary gland, including third (oculomotor) cranial nerve, fourth (trochlear) cranial nerve, ophthalmic and maxillary branches of the fifth (trigeminal) cranial nerve, and, less commonly, the sixth (abducens) cranial nerve. Here, we present the case of a 36-year-old male who presented with a one-week history of worsening headache associated with double vision. On physical examination, the patient was noted to have left abducens nerve palsy. MRI brain showed anterior right T1 hyperintensity in the pituitary representing blood products. The patient was treated with analgesics and hormonal therapy with improvement in symptoms and eventual resolution of PA without the need for surgical intervention. PA is an unusual cause of acute isolated abducens nerve palsy which should be identified promptly as it is a life-threatening emergency that can be treated immediately with hormonal replacement followed by a decision to manage conservatively or surgically. The long-term follow-up includes endocrine assessment, visual assessment, and imaging surveillance.

A Case Report of COVID-Associated Catastrophic Antiphospholipid Syndrome Successfully Treated with Eculizumab.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by multiple episodes of venous and arterial thromboses or recurrent fetal losses in the presence of antiphospholipid antibodies against ß2GP1, frequently accompanied by moderate thrombocytopenia. Catastrophic APS (CAPS) is a severe manifestation of APS. COVID-19 may have an intense hypercoagulable state in critically ill patients. SARS-CoV2 may potentiate pathogenic APS effects, including the activation of endothelial cells, monocytes, platelets, and complement, resulting in a proinflammatory state and prothrombotic events. The endothelial tropism of SARS-CoV2 may also modify the clinical presentation of COVID-19 in susceptible individuals and trigger flares of underlying vascular diseases. We report a case of a 64-year-old woman with a history of triple-positive APS who had multiple thrombotic and bleeding episodes after being found to have a COVID-19 infection temporally associated with CAPS development that was successfully treated with eculizumab, preventing further macro- and microvascular thrombotic events at 1 month follow-up. Our case highlights the need for more research regarding the mechanism by which COVID-19 may potentiate APS and lead to the development of CAPS.

Efficacy of subcutaneous interferon-beta in COVID-19: a meta-analysis and systematic review.

Type 1 interferons, especially interferon-beta, has been reported to be effective in COVID-19 patients in multiple randomized controlled trials. The aim of our meta-analysis and systematic review is to assess efficacy of subcutaneous IFN-beta in regards to mortality and discharge rate. Prospective, retrospective and randomized controlled trials were included. Primary outcomes measured were 28-day mortality and discharge rate. Secondary outcomes measured were mean hospital stay and post-intervention intubation rate. A thorough literature search was conducted in Medline, PubMed, Ovid journals, Google Scholar, and Cochrane Central Register of Controlled Trials & Database of Systematic Reviews from 1 April 2020 to 28 February 2021. Relative risk was calculated using both the Mantel-Haenszel method (fixed-effects model) and DerSimonian Laird method (random effects model). The heterogeneity among studies was tested using Cochran's Q test, based upon inverse variance weights. 7 studies were included in the meta-analysis and systematic review. The IFN-beta group did not improve the 28-day mortality (RR = 1.276; 95% CI: 1.106-1.472, p = 0.001) or the discharge rate (RR = 0.906; 95% CI = 0.85-0.95, p = < 0.001). The mean hospital stay was 11.95± 2.5 days in the interferon-beta group and 11.43 ± 3.74 days in the traditional treatment group. Likewise, interferon-beta did not add any advantage to post-intervention intubation rate (RR = 0.92; 95% CI = 0.7841-1.0816, p = 0.3154). Our findings revealed that use of subcutaneous interferon-beta is futile in COVID-19.

Typhlitis: A Rare Appendicitis Mimic in a Young Healthy Female.

Typhlitis, also known as neutropenic enterocolitis, is a rare but serious condition characterized by inflammation of the cecum causing right lower quadrant (RLQ) pain and fever. It typically affects immunocompromised patients with neutropenia, hematologic malignancies, AIDS, or those on immunosuppressive therapy. This is an entity that should be considered in any differential for a patient with febrile RLQ pain, not just those with obvious immunosuppression.

Lisinopril-Induced Acute Necrotizing Pancreatitis.

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor that is used as one of the first-line antihypertensive medications. Necrotizing pancreatitis induced by the use of ACE inhibitors is an extremely rare occurrence. Although an uncommon risk factor, our aim is to further highlight that patients with chronic use of lisinopril can develop such complications and should be considered among the list of differential diagnoses for pancreatitis. A 53-year-old Caucasian male with a history of hypertension treated with lisinopril presented with a one-day history of nausea, vomiting, and severe epigastric pain. On physical examination, there was tenderness to palpation in the epigastric region and left lower quadrant without rebound tenderness or guarding. A complete blood count showed a slight increase in white blood cell count to 12,000 cells/mm3 and serum lipase level was elevated at 1028 U/L. A subsequent CT scan of the abdomen with contrast revealed findings supporting necrotizing pancreatitis. The patient was treated with conservative medical management with goal-directed intravenous fluid support, early enteral feeding, and pain control. His condition resolved, and he was found doing well on follow-up visits.

Global proteomic analysis of insulin receptor interactors in glomerular podocytes.

Background: Insulin signalling contributes to diverse cellular activities including protein synthesis, proliferation and cell survival. Insulin resistance describes the inability of cells to activate the insulin signalling pathway effectively; leading to pathological effects in multiple organ systems including the kidney. In diabetic kidney disease, there is progressive glomerular dysfunction and recent studies have demonstrated that the kidney podocyte is a direct target for insulin action. In this study we defined the literature-based insulin receptor (INSR) interactome and utilised an unbiased proteomic approach to examine INSR interactors in podocytes. Methods: Human podocytes expressing the INSR were characterised under basal and insulin resistant conditions. The INSR was isolated by whole cell immunoprecipitation following a time course stimulation of 2, 7, and 15 minutes with of 100nM insulin. The resulting INSR complexes were analysed by label-free mass spectrometry (MS) to detect protein interactors. Results: We identified 27 known, direct INSR interactors in addition to novel interactors including doublecortin domain-containing protein 2 (DCDC2). The interaction of DCDC2 with the INSR was confirmed by immunoprecipitation and immunofluorescence, and under insulin resistant conditions, DCDC2 had increased association with the INSR. siRNA knockdown of DCDC2 in podocytes resulted in cell morphological change and altered INSR localisation. Conclusion: This study provides insight into the complexity of INSR interactors in podocytes and highlights DCDC2 as a novel INSR binding protein. Involvement of this novel interactor in insulin signalling and podocyte biology may explain how insulin resistance alters morphology and integrity of the glomerular filtration barrier.

Ceramide-Rubusoside Nanomicelles, a Potential Therapeutic Approach to Target Cancers Carrying p53 Missense Mutations.

Ceramide (Cer) is an active cellular sphingolipid that can induce apoptosis or proliferation-arrest of cancer cells. Nanoparticle-based delivery offers an effective approach for overcoming bioavailability and biopharmaceutics issues attributable to the pronounced hydrophobicity of Cer. Missense mutations of the protein p53, which have been detected in approximately 42% of cancer cases, not only lose the tumor suppression activity of wild-type p53, but also gain oncogenic functions promoting tumor progression and drug resistance. Our previous works showed that cellular Cer can eradicate cancer cells that carry a p53 deletion-mutation by modulating alternative pre-mRNA splicing, restoring wild-type p53 protein expression. Here, we report that new ceramide-rubusoside (Cer-RUB) nanomicelles considerably enhance Cer in vivo bioavailability and restore p53-dependent tumor suppression in cancer cells carrying a p53 missense mutation. Natural RUB encapsulated short-chain C6-Cer so as to form Cer-RUB nanomicelles (∼32 nm in diameter) that substantially enhanced Cer solubility and its levels in tissues and tumors of mice dosed intraperitoneally. Intriguingly, Cer-RUB nanomicelle treatments restored p53-dependent tumor suppression and sensitivity to cisplatin in OVCAR-3 ovarian cancer cells and xenograft tumors carrying p53 R248Q mutation. Moreover, Cer-RUB nanomicelles showed no signs of significant nonspecific toxicity to noncancerous cells or normal tissues, including bone marrow. Furthermore, Cer-RUB nanomicelles restored p53 phosphorylated protein and downstream function to wild-type levels in p53 R172H/+ transgenic mice. Altogether, this study, for the first time, indicates that natural Cer-RUB nanomicelles offer a feasible approach for efficaciously and safely targeting cancers carrying p53 missense mutations.

An N6-methyladenosine at the transited codon 273 of p53 pre-mRNA promotes the expression of R273H mutant protein and drug resistance of cancer cells.

Mutant p53 proteins that promote cancer cell invasive growth, metastasis and drug resistance emerge as therapeutic targets. Previously, we reported that suppression of ceramide glycosylation restored wild-type p53 protein and tumor suppressing function in cancer cells heterozygously carrying p53 R273H, a hot-spot missense mutation; however, the mechanisms underlying the control of mutant protein expression remain elusive. Herein, we report that an N6-methyladenosine (m6A) at the point-mutated codon 273 (G > A) of p53 pre-mRNA determines the mutant protein expression. Methylation of the transited adenosine was catalyzed by methyltransferase like 3 (METTL3), and this m6A-RNA promoted a preferential pre-mRNA splicing; consequently, the produced p53 R273H mutant protein resulted in acquired multidrug resistance in colon cancer cells. Furthermore, glycosphingolipids (particularly globotriaosylceramide) generated from serial ceramide glycosylation were seen to activate cSrc and ß-catenin signaling so as to upregulate METTL3 expression, in turn promoting expression of p53 R273H mutant protein, with consequent drug resistance. Conversely, either silencing METTL3 expression by using small interfering RNA (siRNA) or inhibiting RNA methylation with neplanocin A suppressed m6A formation in p53 pre-mRNA, and substantially increased the level of phosphorylated p53 protein (Ser15) and its function in cells heterozygously carrying the R273H mutation, thereby re-sensitizing these cells to anticancer drugs. Concordantly, suppression of ceramide glycosylation repressed METTL3 expression and m6A formation in p53 pre-mRNA, thus sensitizing cells carrying R273H to anticancer drugs. This study uncovers a novel function of pre-mRNA m6A as a determinant of mutant protein expression in cancer cells heterozygously carrying the TP53 R273H mutation. Suppressing both RNA methylation and ceramide glycosylation might constitute an efficacious and specific approach for targeting TP53 missense mutations coding for a G > A transition, thereby improving cancer treatments.

Constrictive Pericarditis Presenting as Bilateral Pleural Effusion: A Report of Two Cases.

Constrictive pericarditis is a rare presentation. We need a very high index of clinical suspicion to diagnose the disease. It most commonly presents secondary to tuberculosis (TB) in the developing world and post-radiation therapy in the developed world. Classically, it presents with symptoms of heart failure and as pericardial thickening or calcification on imaging studies. In hospital settings, constrictive pericarditis is not usually considered as a differential in patients presenting with pleural effusion. According to the literature, associated pleural effusions in cases of constrictive pericarditis could be left-sided. Herein, we present two unusual presentations of cases with bilateral pleural effusions. One of our cases developed constrictive pericarditis with concurrent active tuberculosis. This is a rare presentation because, normally, constrictive pericarditis is a late complication of tuberculosis. We suggest that when dealing with cases of bilateral pleural effusion, the etiology of constrictive pericarditis should be considered.

Proposed information outreach programme in primary and secondary health care of Punjab, Pakistan.

The study reported is part of Dr. Naeem's doctoral research, supervised by Professor Bhatti, with the objective to propose an information outreach programme for health care professionals working in rural areas of the Punjab province, Pakistan. A cross-sectional survey was conducted involving 517 practitioners from across different health care facilities in the area. The goals of the outreach programme are identified on the basis of the findings regarding practitioners' current usage and awareness of, as well as attitude and self-efficacy towards using health information resources. The identification of these goals and their related activities, including logistical, promotional and educational, results in a model of the required inputs and investments to achieve both the short term, intermediate and long term results of the programme. F.J.

Calcium l-Lactate Frameworks as Naturally Degradable Carriers for Pesticides.

Two porous, chiral metal-organic frameworks (MOFs), Ca14(l-lactate)20(acetate)8(C2H5OH)(H2O) (MOF-1201) and Ca6(l-lactate)3(acetate)9(H2O) (MOF-1203), are constructed from Ca2+ ions and l-lactate [CH3CH(OH)COO-], where Ca2+ ions are bridged by the carboxylate and hydroxyl groups of lactate and the carboxylate group of acetate to give a three-dimensional arrangement of Ca(-COO, -OH) polyhedra supporting one-dimensional pores with apertures and internal diameters of 7.8 and 9.6 Å (MOF-1201) and 4.6 and 5.6 Å (MOF-1203), respectively. These MOFs represent the first examples of extended porous structures based on Ca2+ and lactate. They show permanent porosity of 430 and 160 m2 g-1, respectively, and can encapsulate an agriculturally important fumigant, cis-1,3-dichloropropene. MOF-1201 shows a 100 times lower release rate compared with liquid cis-1,3-dichloropropene under the same test conditions (25 °C, air flow rate of 1 cm3 min-1). The hydrolysis of MOF-1201 in water makes it the first example of a degradable porous solid carrier for such fumigants.