Synthesis,acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities,and molecular docking studies of a novel compound based on combination of flurbiprofen and isoniazide

Synthesis of a compound with balanced bioactivities against a specific target is always a challenging task. In this study, a novel compound (1) has been synthesized by combination of flurbiprofen and isoniazide and shows ∼2.5 times enhanced acetylcholinesterase (AChE) inhibition activity and ∼1.7 times improved butyrylcholinesterase (BuChE) inhibition activity compared to flurbiprofen and a standard drug (i.e. physostigmine). A comparative AutoDock study has been performed, based on the optimized structure, by the DFT/B3LYP method, which confirmed that compound (1) is more active against AChE and BuChE, with calculated binding energies of −12.9 kcal mol⁻¹ and −9.8 kcal mol⁻¹ respectively as compared to flurbiprofen and an eserine (physostigmine) standard for which the binding energy was calculated to be −10.1 kcal mol⁻¹ and −8.9 kcal mol⁻¹, respectively. A mixed mode of inhibition of AChE and BuChE with compound 1 was confirmed by Lineweaver–Burk plots. AChE and BuChE inhibition activity alongside docking results suggests that compound (1) could be used for treatment of Alzheimer''s disease. Moreover, compound (1) also exhibit better α-chymotrypsin activity compared to flurbiprofen. Furthermore, in vitro and in vivo analysis confirmed that compound (1) exhibit more activity and less toxicity than the parent compounds.

A novel compound (1) shows ∼2.5 and ∼1.7 times enhanced AChE inhibition activity and BuChE inhibition activity respectively compared to flurbiprofen and standard drug (i.e. physostigmine). It has also been confirmed by comparative AutoDock studies.     

Demographic,maternal, and infant health correlates of post‐partum depression in Jordan

This cross‐sectional correlational study examined post‐partum depression and its relationship with demographic, maternal, and infant health problems in urban Jordanian women. Participants (n = 315) were selected from five maternal child healthcare centers and one major hospital in Amman, Jordan. Patient Health Questionnaire‐9 was used to measure post‐partum depression within 12 weeks of birth. A number of socio‐demographic and health problems were examined for an association with post‐partum depression. Results showed that 25% of post‐partum women suffered moderate to severe depression and 50% of the sample had mild depression. None of the socio‐demographic variables (age, education, employment, income) were significantly related to post‐partum depression; however, two obstetric/infant variables (mode of birth and breastfeeding), were significantly associated with post‐partum depression. There was a significant association between post‐partum depression and 15 health problems of obstetric, gynecologic (i.e. episiotomy pain, infection), and general health conditions (i.e. fatigue, headache). Nurses and midwives need to emphasize post‐partum depression screening, follow‐up, and proper management of maternal and infant health factors predisposing to post‐partum depression rather than merely focusing on women's inherent demographic factors.     

Outcomes following cardiopulmonary resuscitation in an emergency department of a low- and middle-income country

Background

Cardiopulmonary resuscitation (CPR) is a key component of emergency care following cardiac arrest. A better understanding of factors that influence CPR outcomes and their prognostic implications would help guide care. A retrospective analysis of 800 adult patients that sustained an in- or out-of-hospital cardiac arrest and underwent CPR in the emergency department of a tertiary care facility in Karachi, Pakistan, between 2008 and 15 was conducted.

Methods

Patient demographics, clinical history, and CPR characteristics data were collected. Logistic regression model was applied to assess predictors of return of spontaneous circulation and survival to discharge. Analysis was conducted using SPSS v.21.0.

Results

Four hundred sixty-eight patients met the study’s inclusion criteria, and overall return of spontaneous circulation and survival to discharge were achieved in 128 (27.4%) and 35 (7.5%) patients respectively. Mean age of patients sustaining return of spontaneous circulation was 52 years and that of survival to discharge was 49 years. The independent predictors of return of spontaneous circulation included age ≤?49 years, witnessed arrest, ≤?30 min interval between collapse-to-start, and 1–4 shocks given during CPR (aOR (95% CI) 2.2 (1.3–3.6), 1.9 (1.0–3.7), 14.6 (4.9–43.4), and 3.0 (1.4–6.4) respectively), whereas, age ≤?52 years, bystander resuscitation, and initial rhythm documented (pulseless electrical activity and ventricular fibrillation) were independent predictors of survival to discharge (aOR (95% CI) 2.5 (0.9–6.5), 1.4 (0.5–3.8), 5.3 (1.5–18.4), and 3.1 (1.0–10.2) respectively).

Conclusion

Our study notes that while the majority of arrests occur out of the hospital, only a small proportion of those arrests receive on-site CPR, which is a key contributor to unfavorable outcomes in this group. It is recommended that effective pre-hospital emergency care systems be established in developing countries which could potentially improve post-arrest outcomes. Younger patients, CPR initiation soon after arrest, presenting rhythm of pulseless ventricular tachycardia and ventricular fibrillation, and those requiring up to four shocks to revive are more likely to achieve favorable outcomes.

     

Systemic Delivery of Synthetic MicroRNA-16 Inhibits the Growth of Metastatic Prostate Tumors via Downregulation of Multiple Cell-cycle Genes

Recent reports have linked the expression of specific microRNAs (miRNAs) with tumorigenesis and metastasis. Here, we show that microRNA (miR)-16, which is expressed at lower levels in prostate cancer cells, affects the proliferation of human prostate cancer cell lines both in vitro and in vivo. Transient transfection with synthetic miR-16 significantly reduced cell proliferation of 22Rv1, Du145, PPC-1, and PC-3M-luc cells. A prostate cancer xenograft model revealed that atelocollagen could efficiently deliver synthetic miR-16 to tumor cells on bone tissues in mice when injected into tail veins. In the therapeutic bone metastasis model, injection of miR-16 with atelocollagen via tail vein significantly inhibited the growth of prostate tumors in bone. Cell model studies indicate that miR-16 likely suppresses prostate tumor growth by regulating the expression of genes such as CDK1 and CDK2 associated with cell-cycle control and cellular proliferation. There is a trend toward lower miR-16 expression in human prostate tumors versus normal prostate tissues. Thus, this study indicates the therapeutic potential of miRNA in an animal model of cancer metastasis with systemic miRNA injection and suggest that systemic delivery of miR-16 could be used to treat patients with advanced prostate cancer.     

Evidence that senescent human prostate epithelial cells enhance tumorigenicity: cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT

Normal human prostate (NHP) epithelial cells undergo senescence in vitro and in vivo but the potential role of senescent NHP cells in prostate tumorigenesis remain unclear. Here we show that senescent NHP cells enhance the in vivo tumorigenicity of low-tumorigenic LNCaP prostate cancer and low/non-tumorigenic subset of cells (called L cells) isolated from multiple bulk-cultured prostate (and other) cancer cell lines. Subsequent studies suggest cell-cell fusion as a potential mechanism for senescent NHP cell-enhanced tumor development. Using fluorescently tagged tumor cells and/or NHP cells, we find that NHP cells, like fibroblasts, can undergo fusion with unfractionated tumor cells or the L cells. Using 293T-L cells as the model cell system, we verify NHP and 293T-L cell fusion by using differential RT-PCR, karyotyping, and gene expression analyses. Further experiments demonstrate that senescent NHP cells that have lost progenitor markers, accumulated p16INK4a (p16) protein expression, and acquired the AR mRNA expression, appear to be the preferential fusion targets. Strikingly, the tumorigenicity of the NHP/293T-L hybrid cells was inhibited by exogenous p16 as well as hTERT. Chromosomal analyses revealed that hTERT probably inhibited the in vivo tumorigenicity by maintaining genomic stability. These results suggest that senescent NHP cells, like senescent fibroblasts, may promote tumor development and that one of the mechanisms underlying the senescent NHP cell-enhanced tumorigenicity could be through cell fusion.     

Management of platinum-based chemotherapy-induced acute nausea and vomiting: is there a superior serotonin receptor antagonist?

OBJECTIVE: The last decade has witnessed the great impact of 5-hydroxytryptamine-3 receptor (5-HT(3))antagonists in revolutionizing the management of platinum-based chemotherapy-induced acute nausea and vomiting (CINV). However, despite the availability of a variety of 5-HT(3) antagonists, little data is published to support superiority of one drug over another, leaving the choice of serotonin receptor antagonist largely empirical. The National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines for management of chemotherapy-associated nausea and vomiting cleary endorse the use of serotonin receptor antagonist; however, no single agent is preferred over the rest. METHODS: Data for patients (n=159) receiving platinum-based chemotherapy regimens were retrospectively collected . Patients getting 5-HT(3) antagonists without steriods or those with known history of brain metastasis, gastroparesis, and intestinal obstruction were not eligible for the study. Patient characteristics including age, gender, primary diagnosis, history of heavy alcohol intake, chemotherapy regimen administered , number of cycles, and Eastern Cooperative Group performance status at the start of therapy were noted. Primary outcome was the complete control of platinum-induced acute nausea and vomiting. Secondary outcome measures included control of > or = grade 1 nausea or vomiting, comparison of two doses of dexamethasone, and antiemetic eficacy among various platinum drugs. National Cancer Institute Common Toxicity Criteria version 2.0 was used to assess toxicity. RESULTS: A total of 126 patients received 369 cycles of platinum-based therapy. Dolasetron ( n=157), granisetron ( n=81), and ondansetron ( n=131) achieved complete control of vomiting in 89.8, 95.5, and 92.3% (p=0.67) of cycles, respectively. Respectively, complete nausea control was observed in 68.1, 75.3 and, 69.4% (p=0.50). Dexamethasone 20 mg was not superior to 10 mg in complete control of nausea and vomiting ( p= 0.15 and p=0.63, respectively). However, complete nausea control was signinficantly better in the subgroup of patients getting cisplatin-compared with carboplatin-based regimens (78.8% vs. 67.7%, p<0.05). CONCLUSION: No significant difference exists in the antiemetic efficacy of the three 5-HT(3) antagonists studied in controlling CINV when administered in combination with dexamethasone. Choicce of antiemetic regimen should therefore be based on drug cost.     

Artemisinins and immune system

Artemisinins in combination with other antimalarial drugs remain the mainstay of current antimalarial armamentarium. It is interesting to note that many traditional drugs with antiprotozoal background can wield immunomodulation on the recipient's immune system in a positive or negative direction. Artemisinins also attribute immunomodulatory distensions. For instance, they demonstrate predominant immunosuppressive traits toward different immune components by particularly regulating the cellular proliferation and cytokine release, which indicates that they possess some additional mechanisms and features demanding deliberate attentions. This article reviews the data-based immunomodulatory effects of artemisinins on different immune cells including neutrophils, macrophages, splenocytes, T and B cells in conjunction with their therapeutic prospective with regard to inflammation, autoimmunity and delayed-type hypersensitivity.     

Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival

Tumorigenesis can arise from inappropriate activation of developmental genes in mature tissues. Here, we show that the developmental regulator Six1 is overexpressed in ovarian carcinoma cell lines (OCC) compared with normal ovarian surface epithelium. As observed in other cancers, Six1 overexpression in OCC leads to increased A-type cyclin expression and increased proliferation. In addition, Six1 overexpression renders OCC resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis, and Six1 knockdown in the TRAIL-resistant SKOV3 ovarian carcinoma line dramatically sensitizes the cells to TRAIL. Because inactivation of the TRAIL response has been linked to metastasis, and because antibodies and recombinant ligand that activate the TRAIL pathway are currently in clinical trials against ovarian carcinoma, we screened normal ovarian and carcinoma specimens for Six1 mRNA. Six1 was overexpressed in 50% of the early-stage (stage I) and 63% of the late-stage (stages II, III, and IV) ovarian carcinomas examined, with late-stage carcinomas expressing approximately 3-fold higher Six1 mRNA levels on average compared with early-stage tumors. Importantly, in patients with late-stage disease, high Six1 expression was associated with significantly shortened survival (P = 0.0015). These data suggest that Six1 may contribute to ovarian epithelial carcinogenesis by simultaneously increasing proliferation and decreasing TRAIL-mediated apoptosis and imply that Six1 may be an important determinant of TRAIL therapy response that should be considered in patient selection for TRAIL-related clinical trials.     

Comparison of Office Hysteroscopy, Transvaginal Ultrasonography and Endometrial Biopsy in Evaluation of Abnormal Uterine Bleeding

Objective:

A comparison between office hysteroscopy, transvaginal ultrasonography and endometrial biopsy was performed, in terms of detection of intrauterine lesions. A secondary objective was assessment of evaluatory approach in the management of abnormal uterine bleeding in an outpatient setting.

Design:

Prospective observational study.

Material and Methods:

A total of 54 women were evaluated for abnormal uterine bleeding. Assessment included performance of an endometrial biopsy, a transvaginal ultra-sound scan followed by office hysteroscopy. Results of hysteroscopy were taken as the gold standard. Sensitivity and specificity of the investigations were assessed. The bleeding pattern was classified as heavy regular, irregular, postmenopausal and heavy or unscheduled bleeding on hormone replacement therapy.

Results:

The incidence of focal intrauterine lesions in patients presenting with abnormal bleeding was 52% for all ages and 31% for the postmenopausal group. Seventy-five percent of the patients with Hb < 11 gm% and 67% with an enlarged uterus harbored a focal pathology. The incidence of lesions in patients with heavy regular bleeding was 74%. The sensitivity and specificity of transvaginal ultrasound when compared with results of hysteroscopy was 0.60 and 0.88 respectively. A normal endometrial biopsy had a negative predictive value of 51%. The sensitivity and specificity of endometrial biopsy were 0.04 and 0.83, respectively.

Conclusion:

Both transvaginal ultrasound and endometrial biopsy exhibited poor sensitivity for detection of focal intrauterine lesions. Considering the significantly high incidence of intrauterine lesions in patients presenting with abnormal bleeding, the most cost-effective approach appears to be proceeding with hysteroscopy early in assessment.     

Sleep in women

The timing and continuity of sleep in healthy individuals is regulated by the synchronous function of the sleep homeostasis and the endogenous circadian rhythms. Multiple factors affect these two processes and the way they interact. Sleep disorders may manifest differently in men and women and these differences are particularly notable during pregnancy, lactation, and menopause. Insomnia may occur relatively commonly during pregnancy and in the postpartum, and may be the result of either a primary sleep disorder, such as obstructive sleep apnea (OSA), movement disorders such as restless legs syndrome (RLS), or sometimes depression, especially in the postpartum period. Obstructive sleep apnea may contribute to a higher risk of hypertension during pregnancy and doubles the risk for preeclampsia and preterm birth. Snoring, a frequent symptom of OSA, increases in frequency during pregnancy. Restless legs syndrome is more common in pregnant women, is more frequent in the third trimester of pregnancy, and tends to improve dramatically after delivery. Factors associated with increased RLS in pregnancy may be related to iron and folate metabolism. Risk for OSA increases after menopause and presentation with insomnia can delay the diagnosis of OSA. Various treatment options for sleep disorders in women are discussed.