Antihypertensive Effects of Sacubitril/Valsartan Versus Olmesartan: An Updated Systemic Review and Meta-Analysis of Randomized Controlled Trials.

Sacubitril/valsartan is a drug commonly prescribed for the management of hypertension. However, the complete understanding of its efficacy and safety as an antihypertensive agent remains a subject of ongoing investigation. To address this gap, a meta-analysis was conducted to assess and compare the efficacy and safety of sacubitril/valsartan in relation to olmesartan, an angiotensin receptor blocker (ARB). A thorough search of PubMed, Google Scholar, and Cochrane databases was performed to identify relevant randomized controlled trials (RCTs) and observational studies that could contribute to this meta-analysis. The selected studies were evaluated for their efficacy and safety parameters, including mean sitting and ambulatory blood pressure measurements, common side effects, adverse events, and drug discontinuation rates. A total of eight studies, involving 4488 hypertensive patients, were included in this analysis. Among the participants, 63.5% were administered sacubitril/valsartan, while 36.5% received olmesartan. The analysis revealed significant changes in mean sitting systolic blood pressure (MsSBP), mean sitting diastolic blood pressure (MsDBP), and mean sitting pulse pressure (MsPP) favoring sacubitril/valsartan, with p-values <0.00001, 0.07, and <0.00001, respectively. Additionally, sacubitril/valsartan demonstrated a significant reduction in mean ambulatory systolic blood pressure (MaSBP), mean ambulatory diastolic blood pressure (MaDBP), and mean ambulatory pulse pressure (MaPP) with p-values of 0.001, 0.001, and 0.02, respectively. However, it is important to note that safety outcomes indicated that sacubitril/valsartan was associated with slightly less favorable results compared to olmesartan. This meta-analysis highlights that sacubitril/valsartan exhibits superior efficacy in reducing blood pressure parameters compared to olmesartan in hypertensive patients. Nevertheless, its safety profile appears to be slightly less favorable. To reinforce these findings and provide more robust evidence, further studies with larger sample sizes should be conducted in the future. This comprehensive review serves as a valuable resource for healthcare professionals and researchers seeking to make informed decisions regarding antihypertensive treatment options.

High doses of clethodim-based herbicide GrassOut Max poses reproductive hazard by affecting male reproductive function and early embryogenesis in Swiss albino mice.

Clethodim is a widely used and approved class II herbicide, with little information about its impact on the reproductive system. Herein, we investigated the male reproductive toxicity of clethodim using a mouse model. GrassOut Max (26% clethodim-equivalent) or analytical grade clethodim (≥90%) were given orally to male mice for 10 d in varying doses. All parameters were assessed at 35 d post-treatment. Significant decrease in testicular weight, decreased germ cell population, elevated DNA damage in testicular cells and lower serum testosterone level was observed post clethodim based herbicide exposure. Epididymal spermatozoa were characterized with significant decrease in motility, elevated DNA damage, abnormal morphology, chromatin immaturity and, decreased acetylated-lysine of sperm proteins. In the testicular cells of clethodim-based herbicide treated mice, the expression of Erß and Gper was significantly higher. Proteomic analysis revealed lower metabolic activity, poor sperm-oocyte binding potential and defective mitochondrial electron transport in spermatozoa of clethodim-based herbicide treated mice. Further, fertilizing ability of spermatozoa was compromised and resulted in defective preimplantation embryo development. Together, our data suggest that clethodim exposure risks male reproductive function and early embryogenesis in Swiss albino mice via endocrine disrupting function.

A rare case of perforated jejunal diverticula of an uncommon origin.

Jejunal diverticula are often asymptomatic and rare, so they can go unnoticed until serious complications like obstruction, bleeding, perforation, volvulus, or diverticulitis occur. Elderly people over 60 are more likely to have this condition.

Haploid Parthenogenetic Embryos Exhibit Unique Stress Response to pH, Osmotic and Oxidative Stress.

Preimplantation-stage embryos are susceptible to various types of stress when cultured in vitro. Parthenogenetic embryos that lack spermatozoa contribution exhibit aberrant developmental dynamics due to their uniparental origin. Herein, we assessed whether the absence of paternal genome affects the susceptibility of the embryos to pH, osmotic and oxidative stress. Haploid parthenogenetic embryos (HPE) (activated oocytes with 1 pronucleus and 2 polar bodies) were generated by incubating cumulus oocyte complexes of Swiss albino mice with 10 mM strontium chloride for 3 h. Normally fertilized embryos (NFE) (fertilized oocytes with 2 pronuclei and 2 polar bodies) were derived using in vitro fertilization. At 2-cell stage, both HPE and NFE were exposed to various stressors including pH (6.8 to 8.2), osmotic (isotonic, hypotonic, and hypertonic), and peroxidatic oxidative (H2O2, 25 µM) stress. Endoplasmic reticulum stress response, mitochondrial membrane potential, and the rate of blastocyst development were assessed. HPE were susceptible to alteration in the pH that was well tolerated by NFE. Similarly, HPE displayed remarkable difference in sensitivity to hypertonic stress and oxidative stress compared to NFE. The results clearly indicate that the oocytes that develop into embryos in the absence of paternal contribution are more vulnerable to environmental stressors, further highlighting the importance of spermatozoa contribution and/or the ploidy status in mitigating these stressors and towards healthy early embryo development.

Anti-tuberculosis drugs used in a directly observed treatment short course (DOTS) schedule alter endocrine patterns and reduce the ovarian reserve and oocyte quality in the mouse.

CONTEXT: Tuberculosis is one of the major infectious diseases, with people of reproductive age group having a high risk of infection. AIMS: The present study was designed to understand the consequences of anti-tuberculosis drugs (ATDs) used in DOTS (directly observed treatment short course) schedule on ovarian function. METHODS: Adult female Swiss albino mice were orally administered with combinations of ATDs used in the DOTS schedule every day for 4weeks. At 2weeks after the cessation of ATDs administration, the endocrine changes and ovarian function were assessed in mice. KEY RESULTS: Administration of ATDs to mice resulted in a prolonged estrous cycle, reduced ovarian follicle reserve, alteration in FSH, LH, and progesterone level, and decreased the number of ovulated oocytes. Further, the degree of fragmentation, degeneration, abnormal distribution of cytoplasmic organelles, abnormal spindle organisation, and chromosomal misalignment were higher in oocytes that were ovulated following superovulation. Blastocysts derived from ATDs treated mice had significantly lower total cell numbers and greater DNA damage. A marginal increase in the number of resorbed fetuses was observed in all the ATDs treated groups except in the multidrug resistance treatment group. Male progeny of ATDs treated mice had decreased sperm count and lower progressive motility, while female progeny exhibited a non-significant reduction in the number of oocytes ovulated. CONCLUSIONS: Theresults of this study suggest that ATDs can have significant adverse effects on the ovarian reserve, cytoplasmic organisation of oocytes, and can potentially cause transgenerational changes. IMPLICATIONS: The findings of the present study indicate ovarian toxicity of ATDs and warrant further research in the direction of identifying alternate drugs with minimal toxicity, and strategies to mitigate the ovarian toxicity induced by these drugs.

Concordance Between Indices of Malnutrition: Mid-Upper Arm Circumference V/S Weight for the Height Z Score in Different Age Groups in Karachi, Pakistan.

Objective To compare the WHO cut-off of the mid-upper arm circumference (MUAC) with the weight for height z-score (WHZ) in different age groups of children (6 months to 59 months of age) with acute malnutrition in Pakistan. Methodology A cross-sectional study was carried out in the pediatric unit of Ziauddin Medical University and Hospital on malnourished children from six to 59 months of age to compare two different indices of malnutrition, MUAC and WHZ. A total of 450 children with WHZ of <-2SD and <-3SD were included in the study after excluding children with failure to thrive due to chronic illness, congenital defects, and immune deficiencies/malabsorption. Results The study revealed a significant mean difference in weight, height, and MUAC among the participants (0.030, 0.053, and 0.02). The sensitivity of MUAC at <11.5 cm was highest in the 12-24-month age group with a decline at 24-48 months while specificity was highest at six to 12 months of age, which shows a mixed response. Conclusion The result revealed variation in the cut-off value of MUAC in different age groups; the best specificity of MUAC was found at six to 12 months of age and the best sensitivity at 12-24 months of age.

An intraspecies Leishmania donovani hybrid from the Indian subcontinent is associated with an atypical phenotype of cutaneous disease.

Leishmaniasis is a neglected tropical disease endemic in over 90 countries. The disease has two main pathologies; cutaneous leishmaniasis (CL) that generally self-heals, and visceral leishmaniasis (VL) that is fatal if untreated. The majority of VL cases, concentrated on the Indian subcontinent (ISC) and East Africa, are caused by Leishmania donovani. However, recent foci of CL on the ISC have been attributed as an atypical phenotype of L. donovani including a recent outbreak in Himachal Pradesh, India. Whole genome sequencing and phylogenetic analysis was undertaken to investigate the origins and genetic factors leading to this pathology atypical of L. donovani. Here we demonstrate the isolate from Himachal Pradesh is derived from a genetic hybridization between two independent L. donovani parents from the 'Yeti' ISC1 divergent clade of parasites, identified in the Nepalese highlands. This reveals that intraspecies L. donovani hybrids can give rise to a novel strain associated with CL.

Current Insights and Latest Updates in Sperm Motility and Associated Applications in Assisted Reproduction.

Spermatozoon is a motile cell with a special ability to travel through the woman's reproductive tract and fertilize an oocyte. To reach and penetrate the oocyte, spermatozoa should possess progressive motility. Therefore, motility is an important parameter during both natural and assisted conception. The global trend of progressive reduction in the number and motility of healthy spermatozoa in the ejaculate is associated with increased risk of infertility. Therefore, developing approaches for maintaining or enhancing human sperm motility has been an important area of investigation. In this review we discuss the physiology of sperm, molecular pathways regulating sperm motility, risk factors affecting sperm motility, and the role of sperm motility in fertility outcomes. In addition, we discuss various pharmacological agents and biomolecules that can enhance sperm motility in vitro and in vivo conditions to improve assisted reproductive technology (ART) outcomes. This article opens dialogs to help toxicologists, clinicians, andrologists, and embryologists in understanding the mechanism of factors influencing sperm motility and various management strategies to improve treatment outcomes.

Simultaneous detection of aqueous aluminum(III) and chromium(III) using Persea americana reduced and capped silver nanoparticles.

There is a significant interest to develop sensing devices that detect water toxins, especially heavy metal ions. Although there have already been numerical reports on detecting toxic heavy metal ions, the use of adaptable devices could enable a broader range of sensing applications. Here, we used fresh peel extract (PeA) and dried peel extract (DPeA) of Persea americana (Avocado) as a reducing and capping agent to synthesize and stabilize AgNPs. The dimensions of NPs were controlled by tuning pH, temperature, and volume of the reducing agent. The sensitivity and selectivity of the AgNPs toward various metal ions viz. Ni(II), Cd(II), Al(III), Hg(II), Cr(III), Ba(II), Pb(II), Zn(II), Co(II), Mn(II), Cu(II), Ca(II), Mg(II), and K(I) were studied. The detection probe was found to be selective and sensitive toward Al(III) and Cr(III) ions with the detection limit of 0.04 ppm and 0.05 ppm, respectively. High-resolution transmission electron microscope (HRTEM), ultraviolet-visible (UV-Vis) spectroscopy, and dynamic light scattering (DLS) analysis results confirm an agglomeration-based mechanism for sensing both metal ions. This method can be exploited for the colorimetric detection of toxic heavy metals in real water samples.

This is the first study to report the use of avocado peel extract to synthesize AgNPs in sensing aqueous Al(III) and Cr(III) at trace level concentration.

Curcumin nanocrystals attenuate cyclophosphamide-induced testicular toxicity in mice.

The cancer therapy using cyclophosphamide (CP) has been associated with adverse effects on the testicular function that raises concerns about the future fertility potential among cancer survivors. Curcumin, a polyphenol, has shown to possess a plethora of biological functions including tissue protective effects. In the present study, we investigated the protective effects of curcumin nanocrystals (NC) in mitigation of CP-induced testicular toxicity. Healthy adult (8-10 week) and prepubertal (2 week) male Swiss albino mice were injected with a single dose of CP (200 mg/kg) intraperitoneally (i.p). NC (4 mg/kg, i.p.) was administered every alternate day, for 35 days in adult mice while, a single dose of NC was injected intraperitoneally to prepubertal mice 1 h prior to CP. Administration of multiple doses of NC ameliorated CP-induced testicular toxicity in adult mice, which was evident from the improved sperm functional competence, sperm chromatin condensation, seminiferous tubule architecture and decreased apoptosis in testicular cells. Further, administration of NC 1 h prior to CP in prepubertal mice modulated the expression of genes pertaining to proliferation, pluripotency, DNA damage and DNA repair in spermatogonial cells at 24 h after the treatment. Overall, these results suggest that NC could be a promising chemoprotective agent, which can have potential application in male fertility preservation.

Sphingosine kinases negatively regulate the expression of matrix metalloproteases (MMP1 and MMP3) and their inhibitor TIMP3 genes via sphingosine 1-phosphate in extravillous trophoblasts.

PURPOSE: Extracellular matrix remodeling is essential for extravillous trophoblast (EVT) cell migration and invasion during placental development and regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteases (TIMPs). Sphingosine kinases (SPHK1 and SPHK2) synthesize sphingosine-1-phosphate (S1P), which works either intracellularly or extracellularly via its receptors S1PR1-5 in an autocrine or paracrine manner. The role of SPHKs/S1P in regulating the expression of MMPs and TIMPs in EVT is mostly unknown and forms the primary objective of the study. METHODS: HTR-8/SVneo cells were used as a model of EVT. To inhibit the expression of SPHKs, cells were treated with specific inhibitors, SK1-I and SKI-II, or gene-specific siRNAs. The expressions of MMPs and TIMPs were estimated by qPCR. RESULTS: We demonstrated that SPHK1, MMP1-3, and TIMP1-3 were highly expressed in HTR-8/SVneo cells. We found that treatment of cells with SK1-I, SKI-II, and knockdown of SPHK1 or SPHK2 increased the expression of MMP1, MMP3, and TIMP3. The addition of extracellular S1P inhibits the upregulation of MMPs and TIMPs in treated cells. CONCLUSIONS: SPHKs negatively regulate the expression of MMP1, MMP3, and TIMP3. The level of intracellular S1P acts as a negative feedback switch for MMP1, MMP3, and TIMP3 expression in EVT cells.

Typical and atypical cutaneous leishmaniasis in Himachal Pradesh (India).

BACKGROUND: Visceral leishmaniasis (VL) is in elimination phase in India while cutaneous leishmaniasis (CL) is being reported from new foci. In Himachal Pradesh (HP), a foci of CL had been reported along Satluj River, but the causative agent poses a dilemma, hence the present study was undertaken in Shimla, Kullu and Kinnaur districts. METHODS: A total of 28 CL patients from Indira Gandhi Medical College and Hospital Shimla (IGMC) in 2018, were tested by rK39., Twelve fresh cases were subjected to microscopic detection of Leishmania parasite, PCR and sequencing. Skin biopsies of 3-4 mm diameter were cultured, as well as imprints were prepared for the detection of Leishmania amastigotes. Biopsy samples were inoculated into different culture media (M199, RPMI 1640, NNN) and were incubated at 22-24 °C. Polymerase chain reaction (PCR) was performed to characterize Leishmania parasite species. RESULTS: Of 28 patients, one was positive by rK39 dipstick test and one imprint was found positive for Leishmania amstigotes. Twelve biopsy DNA samples subjected to PCR for Leishmania kDNA, were found Lesihmania positive. Identification of Leishmania species was confirmed by PCR-RFLP and sequencing method. Of 12 Leishmania positive samples, six were identified as L. donovani, three L. tropica, two L.major and one remained unidentified. CONCLUSIONS: This study revealed the existence of three species of parasites i.e., L. donovani, L. tropica and L. major indicating the existence of typical and atypical leishmaniasis in Himachal Pradesh. The occurrence of CL cases in HP, Kerala or elsewhere should not be ignored considering them just cases of CL alone. Further studies are warranted to confirm the existence of L.donovani zymodeme MON37 from cases of CL in HP or L.donovani zymodeme MON2 strain causing VL in Bihar. Elimination of CL should also be considered along with goal of Kala -Azar elimination.

Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies.

Phosphodiesterase (PDE) inhibitors, such as pentoxifylline (PTX), are used as pharmacological agents to enhance sperm motility in assisted reproductive technology (ART), mainly to aid the selection of viable sperm in asthenozoospermic ejaculates and testicular spermatozoa, prior to intracytoplasmic sperm injection (ICSI). However, PTX is reported to induce premature acrosome reaction (AR) and, exert toxic effects on oocyte function and early embryo development. Additionally, in vitro binding studies as well as computational binding free energy (ΔGbind) suggest that PTX exhibits weak binding to sperm PDEs, indicating room for improvement. Aiming to reduce the adverse effects and to enhance the sperm motility, we designed and studied PTX analogues. Using structure-guided in silico approach and by considering the physico-chemical properties of the binding pocket of the PDEs, designed analogues of PTX. In silico assessments indicated that PTX analogues bind more tightly to PDEs and form stable complexes. Particularly, ex vivo evaluation of sperm treated with one of the PTX analogues (PTXm-1), showed comparable beneficial effect at much lower concentration-slower AR, higher DNA integrity and extended longevity of  spermatozoa and  superior embryo quality. PTXm-1 is proposed to be a better pharmacological agent for ART than PTX for sperm function enhancement.

Organophosphorus pesticide quinalphos (Ekalux 25 E.C.) reduces sperm functional competence and decreases the fertilisation potential in Swiss albino mice.

Quinalphos (QP) is one of the most commonly used organophosphate pesticide for agriculture. In this study, adult Swiss albino male mice were orally administered with 0.25, 0.5 and 1.0 mg/kg of QP (Ekalux 25 E.C.) for ten consecutive days and the reproductive function was assessed at 35 and 70 days after QP treatment. At highest dose (1.0 mg/kg), QP exposure resulted in significant decrease in motility and increase in sperm head defects and DNA damage. Pharmacokinetic data showed a threefold increase in concentration of QP in the testis as compared to serum. QP was detectable in testes even after 24 hr of administration indicating slow clearance from tissue. In addition, high oestradiol, low testosterone level with a parallel increase in aromatase and cytochrome P450 transcript levels was observed. Significant decrease in fertilisation, lower blastocyst rate and poor blastocyst quality was observed when spermatozoa collected from QP exposed mice were subjected to in vitro fertilisation. In conclusion, exposure of QP to male mice decreases the sperm functional competence and fertilising ability, which appears to be mediated through elevated oxidative stress and altered steroidogenesis in testes.

Quinoline Derivative Enhances Human Sperm Motility and Improves the Functional Competence.

In this study, we aimed to explore the beneficial properties of novel quinoline derivatives on human sperm motility and its functional competence. Nine novel quinoline derivatives were screened for their effect on motility in human spermatozoa from normozoospermic ejaculates. Compounds with impressive sperm motility enhancement properties were further assessed for their effect on functional competence of human spermatozoa. To determine the effect on the fertilizing ability of spermatozoa processed with quinoline derivatives and to assess developmental competence of embryos derived, in vitro fertilization (IVF) was performed using mouse model. Among the nine quinoline derivatives, 2 compounds (6MQT and 2,6DQT) exhibited significant enhancement in sperm progressive motility and survival at 24 h. Further, non-significant increase in curvilinear velocity (VCL), straight line velocity (VSL), and amplitude of lateral head displacement (ALH) was observed. Capacitation, intracellular cAMP level and tyrosine phosphorylated sperm proteins were significantly higher in 6MQT (P < 0.05) and 2,6DQT (P < 0.001) compared to control. In vitro fertilization (IVF) experiments using Swiss albino mice revealed that spermatozoa processed with 6MQT had non-significantly higher blastocyst rate and a superior blastocyst quality, while, 2,6DQT resulted in significantly lower blastocyst rate (P < 0.05) compared to control. Quinoline derivative 6MQT has significant motility enhancement property under in vitro conditions. Graphical abstract.

High-fat diet leads to elevated lipid accumulation and endoplasmic reticulum stress in oocytes, causing poor embryo development.

The present study was designed to investigate the effect of diet-induced obesity on endoplasmic reticulum (ER) stress in oocytes. Swiss albino mice (3 weeks old) were fed with a high-fat diet (HFD) for 8 weeks. Oocytes were assessed for lipid droplet accumulation, oxidative stress, ER stress and their developmental potential invitro. High lipid accumulation (P<0.01) and elevated intracellular levels of reactive oxygen species were observed in both germinal vesicle and MII oocytes of HFD-fed mice (P<0.05 and P<0.01 respectively compared with control). Further, expression of the ER stress markers X-box binding protein 1 (XBP1), glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4) and activating transcription factor 6 (ATF6) was significantly (P<0.001) higher in oocytes of the HFD than control group. Oocytes from HFD-fed mice exhibited poor fertilisation and blastocyst rates, a decrease in total cell number and high levels of DNA damage (P<0.01) compared with controls. In conclusion, diet-induced obesity resulted in elevated lipid levels and higher oxidative and ER stress in oocytes, which contributed to the compromised developmental potential of embryos.

Leishmania donovani Infection with Atypical Cutaneous Manifestations, Himachal Pradesh, India, 2014-2018.

We conducted a molecular study of parasite sequences from a cohort of cutaneous leishmaniasis patients in Himachal Pradesh, India. Results revealed atypical cutaneous disease caused by Leishmania donovani parasites. L. donovani variants causing cutaneous manifestations in this region are different from those causing visceral leishmaniasis in northeastern India.

Antidiabetic drug metformin affects the developmental competence of cleavage-stage embryos.

PURPOSE: Metformin is the most commonly prescribed drug in the management of metabolic disorders such as polycystic ovarian syndrome (PCOS) and gestational diabetes in women of reproductive age. Insulin-sensitizing effect of metformin helps in improving from PCOS features such as hyperandrogenism, anovulation, and infertility. However, its ability to cross placental barrier raises concern about safety of the drug on early embryonic development. In this study, we evaluated the effect of metformin on the ovarian function and embryo development. METHODS: Adult Swiss albino female mice were administered with metformin (0, 50, 100, and 200 mg/kg body weight) for 4 weeks and assessed for reproductive function and preimplantation embryo development. Further, effect of metformin (0, 10, 25, 50, 100, 250, and 500 µg/mL) exposure to 2-cell-stage embryos was tested under in vitro conditions. RESULTS: Metformin did not alter the body weight, blood glucose, ovarian weight, and follicular reserve. However, the early embryo development was significantly affected in mice treated with metformin in vivo at highest dose. Moreover, embryos which were exposed to metformin in vitro showed dose-dependent decline in blastocyst rate and hatching rate. Furthermore, at highest concentration of metformin (500 µg/mL), all the embryos were arrested at compaction stage. CONCLUSION: The study revealed that metformin affects the early embryonic development and raises concern about its use during conception.