Diagnostic Delays and Psychosocial Outcomes of Childhood-Onset Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that manifests in affected individuals with a variety of clinical features and involves multiple organs. Despite recent advances over the past decades, higher morbidity and mortality have been reported by studies in patients with childhood-onset systemic lupus erythematosus (cSLE) compared to patients with adult-onset. The interplay of several factors can cause diagnostic delays resulting in worse disease activity, multiple organ damage, increased risk of hospitalization, and management with aggressive treatment. Significant factors include demographic, clinical, and socioeconomic characteristics of patients with cSLE. Moreover, despite recent advances in lupus treatment, prolonged disease duration in these young patients can result in debilitating psychosocial outcomes and can significantly impact their health-related and general quality of life (QOL). Important domains affected include patient self-esteem, education, employment, healthcare utilization, and mental health. In this review, we examined the barriers that lead to a delay in diagnosing lupus in the pediatric population and addressed cSLE morbimortality and its long-term impact on patient health-related and general QOL.

The Association of Epstein-Barr Virus With Cancer.

Epstein-Barr virus (EBV) is classified as a herpesvirus and is known for being one of the few viruses that can lead to the development of cancer. This study has gathered several studies to provide evidence as to this association as well as some of the mechanisms specific to EBV that allow this to happen. The development of EBV into cancer as well as the proteins involved in this oncogenesis play a crucial role in understanding this problem as well as creating a solution for mitigating this disease process in the future. This study summarized three of the most common malignancies caused by EBV in order to consolidate information about each of them. Additional emphasis was placed on finding which EBV serum markers were seen to be most indicative of prognosis and likelihood of developing malignancy. Higher serum EBV viral DNA loads were seen to be a useful indicator in assessing the risk of various cancers and should be studied further in relation to cancers that were not mentioned in this review.

Cardiovascular Complications in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an auto-immune disease of a relapsing-remitting nature that can cause multiorgan damage depending on several factors, mainly the disease activity. Young age women are the most likely to be affected by the disease and the female-to-male prevalence ratio is approximately 1:10. As the number of SLE patients has been increasing in the last few decades, the annual number of deaths due to the disease and its complications has increased as well, and one of the most important systems to which high mortality is attributed is the cardiovascular system, leading to premature atherosclerosis and other events such as endocarditis and valve disease. In addition to the classical cardiovascular risk factors, studies have found a positive correlation between SLE and other cardio-harmful diseases such as metabolic syndrome and dyslipidemia. Moreover, some of the medications used in the treatment of SLE place a heavy burden on the heart. The article reviews the shared pathophysiology of SLE and cardiovascular disease along with the most common SLE- associated cardiac risks, events, and management.

The Effect of Sepsis on Myocardial Function: A Review of Pathophysiology, Diagnostic Criteria, and Treatment.

Sepsis remains a worldwide challenge for physicians with many patients admitted to ICUs with septic shock. Septic shock management involves targeted treatment to control infections, reduce end-organ damage, and reverse the injury. Sepsis-induced myocardial dysfunction or septic cardiomyopathy remains an avenue to be explored with regard to underlying pathophysiology and definite treatment guidelines. This article has compiled various studies to explain the possible mechanisms involved in the development of septic cardiomyopathy and the existing diagnostic criteria including radiological and laboratory tests to assess septic cardiomyopathy. Furthermore, the article highlights management options currently available for physicians dealing with myocardial dysfunction secondary to sepsis.

Maternal and Neonatal Outcomes of Adolescent Pregnancy: A Narrative Review.

Adolescent pregnancy is the pregnancy of girls aged 10-19 years, leading to many maternal and neonatal adverse effects. These pregnancies have been a global concern for many decades and yet are still prevailing. This article has reviewed the significant determinants of adolescent pregnancy and various maternal adverse effects, including preeclampsia, preterm premature rupture of the membrane (PPROM), maternal anemia, sexually transmitted diseases, postpartum depression, and maternal deaths, and adverse neonatal outcomes, including low birth weight (LBW), prematurity, stillbirths, early neonatal demise, and low Apgar score. Various pathophysiologic events that lead to such adverse consequences have been briefly discussed in the article and how such occurrences can be overcome. This article has also emphasized the need to implement various modalities such as sex education, availability of contraceptives, and bringing community-level awareness to lower the prevalence of adolescent pregnancy.

Digital technologies in management of chronic pain - a systematic review.

OBJECTIVE: To determine the effectiveness of digital health technologies in the management of chronic pain. METHODS: The systematic review comprised search for randomised controlled trials and controlled clinical trials involving patients with chronic pain published between 2010 and 2020. The search was conducted on PubMed, Google Scholar, MEDLINE, National Centre for Biotechnology Information, and National Library of Medicine databases. Risk bias tool was used to evaluate the biasness in the studies and Pedro scale was used to assess the quality of the included articles. RESULTS: Of the 33 articles fully assessed, 14(42.42%) were analysed. All the studies analysed were randomised controlled trials and scored 6-10 on the Pedro scale which showed high quality of methodology. The studies typically reported statistically significant benefits of digital health technologies in the management of chronic pain. One of the main benefits was enhanced pain coping skills of the patients. Additionally, majority of the studies included increased adherence to exercise as an essential advantage. CONCLUSIONS: All the studies analysed reported favourable conclusions regarding the use of digital intervention for chronic pain management.

Differences in symptoms and presentation delay times in myocardial infarction patients with and without diabetes: A cross-sectional study in Pakistan.

OBJECTIVE: A short pre-hospital delay, from the onset of symptoms to rapid initiation of reperfusion therapy, is a crucial factor in determining prognosis of myocardial infarction (MI). The purpose of this study was to evaluate symptoms and presentation delay times in MI patients with and without diabetes. METHODS: This cross-sectional study was conducted in 3 tertiary care hospitals of Pakistan over a period of 6 months. The study sample consisted of 280 consenting individuals diagnosed with ST-elevation MI (STEMI) or Non-ST elevation MI (NSTEMI), out of which 130 were diabetic and 150 were non-diabetic. Data was collected using a standardized questionnaire, investigating MI symptoms along with causes and duration of pre-hospital delay within 72hours of admission. RESULTS: No significant difference was found in the intensity of chest pain between diabetics and non-diabetics. Atypical symptoms of MI such as anxiety (p<0.001), cold sweats (p=0.034) and epigastric pain (p=0.017) were more frequently reported in diabetics. MI patients with diabetes had a significantly longer presentation delay time with 75% of the patients presenting after elapse of 3h. Only a few patients reported to the hospital within an hour of onset of symptoms (n=23, 8.2%), out of which majority were non-diabetics (n=18). A majority of patients (n=146, 52%) in both groups did not use emergency medical services. CONCLUSION: This study provides an incentive for further research, aiming to reduce pre hospital delay along with investigating the effectiveness of emergency medical services.

Ruptured Rudimentary Horn Pregnancy Revealed on Emergency Laparotomy: A Case of Primigravida Presenting in a Developing Country.

Developmental defects in the Mullerian ducts can result in several uterine anomalies including a unicornuate uterus with a rudimentary horn. Pregnancy in a rudimentary horn is extremely rare occurring in 1:76,000-1:160,000 pregnancies. We present a case of an 18-year-old primigravida with a ruptured rudimentary horn pregnancy (RHP) presenting as acute abdomen at 17 weeks of gestation. Hemodynamic instability led us to perform a life-saving emergency laparotomy. A 1.5 liters hemoperitoneum was encountered with a ruptured non-communicating rudimentary horn. Excision of the horn and unilateral salpingectomy was performed. In addition to ectopic pregnancy and appendicitis, rare uterine anomalies must also be considered in patients presenting with an acute abdomen especially after 10 weeks of gestation. Basic diagnostic facilities may not be available in developing countries. Therefore, clinicians must be aware of this rare entity in order to manage such patients efficiently.

Hospital-based study of epithelial malignancies of endometrial cancer frequency in lahore, pakistan, and common diagnostic pitfalls.

The current study was conducted to see the frequency of epithelial malignancies of endometrium with focus on the common diagnostic pitfalls and identify morphological and immunohistochemical markers helpful in the differential diagnosis between different subtypes. It is a retrospective descriptive study carried out on 52 specimens of endometrial tumors received in Fatima Memorial Hospital, Lahore, Pakistan, during three years (2010-2012). Patients were divided into 5 age groups: <40, 41-50, 51-60, 61-70, and >70 yrs. Tissues were fixed in 10% formalin and processed and stained with haematoxylin-eosin. Stained slides were examined to determine the histological types by WHO classification, and immunohistochemistry for WT1, p53, ER/PR, and MIB1 was done in cases where morphology alone was not helpful in making a confirmed diagnosis. 80% of specimens were of endometrioid adenocarcinomas, 11% of serous tumors, 4% of clear cell carcinoma, and 4% of squamous cell carcinomas involving both cervix and endometrium. Most of the patients (28.84%) with endometrial carcinomas fall in the age range of 51-60 yrs. Endometrioid adenocarcinoma is the most common type of epithelial endometrial malignancies. Morphology is the keystone in the evaluation of these tumors, but immunohistochemistry can also be helpful in establishing the correct diagnosis.

Gßγ-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor α-induced cardiac ß-adrenergic receptor dysfunction.

BACKGROUND: Proinflammatory cytokine tumor necrosis factor-α (TNFα) induces ß-adrenergic receptor (ßAR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are not known. METHODS AND RESULTS: Two different proinflammatory transgenic mouse models with cardiac overexpression of myotrophin (a prohypertrophic molecule) or TNFα showed that TNFα alone is sufficient to mediate ßAR desensitization as measured by cardiac adenylyl cyclase activity. M-mode echocardiography in these mouse models showed cardiac dysfunction paralleling ßAR desensitization independent of sympathetic overdrive. TNFα-mediated ßAR desensitization that precedes cardiac dysfunction is associated with selective upregulation of G-protein coupled receptor kinase 2 (GRK2) in both mouse models. In vitro studies in ß2AR-overexpressing human embryonic kidney 293 cells showed significant ßAR desensitization, GRK2 upregulation, and recruitment to the ßAR complex following TNFα. Interestingly, inhibition of phosphoinositide 3-kinase abolished GRK2-mediated ßAR phosphorylation and GRK2 recruitment on TNFα. Furthermore, TNFα-mediated ßAR phosphorylation was not blocked with ßAR antagonist propranolol. Additionally, TNFα administration in transgenic mice with cardiac overexpression of Gßγ-sequestering peptide ßARK-ct could not prevent ßAR desensitization or cardiac dysfunction showing that GRK2 recruitment to the ßAR is Gßγ independent. Small interfering RNA knockdown of GRK2 resulted in the loss of TNFα-mediated ßAR phosphorylation. Consistently, cardiomyocytes from mice with cardiac-specific GRK2 ablation normalized the TNFα-mediated loss in contractility, showing that TNFα-induced ßAR desensitization is GRK2 dependent. CONCLUSIONS: TNFα-induced ßAR desensitization is mediated by GRK2 and is independent of Gßγ, uncovering a hitherto unknown cross-talk between TNFα and ßAR function, providing the underpinnings of inflammation-mediated cardiac dysfunction.

Inhibition of protein phosphatase 2A activity by PI3Kγ regulates ß-adrenergic receptor function.

Phosphoinositide 3-kinase γ (PI3Kγ) is activated by G protein-coupled receptors (GPCRs). We show here that PI3Kγ inhibits protein phosphatase 2A (PP2A) at the ß-adrenergic receptor (ßAR, a GPCR) complex altering G protein coupling. PI3Kγ inhibition results in significant increase of ßAR-associated phosphatase activity leading to receptor dephosphorylation and resensitization preserving cardiac function. Mechanistically, PI3Kγ inhibits PP2A activity at the ßAR complex by phosphorylating an intracellular inhibitor of PP2A (I2PP2A) on serine residues 9 and 93, resulting in enhanced binding to PP2A. Indeed, enhanced phosphorylation of ß2ARs is observed with a phosphomimetic I2PP2A mutant that was completely reversed with a mutant mimicking dephosphorylated state. siRNA depletion of endogenous I2PP2A augments PP2A activity despite active PI3K resulting in ß2AR dephosphorylation and sustained signaling. Our study provides the underpinnings of a PI3Kγ-mediated regulation of PP2A activity that has significant consequences on receptor function with broad implications in cellular signaling.

Synthesis of monofunctional curcumin derivatives, clicked curcumin dimer, and a PAMAM dendrimer curcumin conjugate for therapeutic applications.

Curcumin, the primary active ingredient in the spice turmeric, was converted to reactive monofunctional derivatives (carboxylic acid/azide/alkyne). The derivatives were employed to produce a 3 + 2 azide-alkyne "clicked" curcumin dimer and a poly(amidoamine) (PAMAM) dendrimer-curcumin conjugate. The monofunctional curcumin derivatives retain biological activity and are efficient for labeling and dissolving amyloid fibrils. The curcumin dimer selectively destroys human neurotumor cells. The synthetic methodology developed affords a general strategy for attaching curcumin to various macromolecular scaffolds.