Biophysical and Biochemical Characterization of Structurally Diverse Small Molecule Hits for KRAS Inhibition.

We describe six compounds as early hits for the development of direct inhibitors of KRAS, an important anticancer drug target. We show that these compounds bind to KRAS with affinities in the low micromolar range and exert different effects on its interactions with binding partners. Some of the compounds exhibit selective binding to the activated form of KRAS and inhibit signal transduction through both the MAPK or the phosphatidylinositide 3-kinase PI3K-protein kinase B (AKT) pathway in cells expressing mutant KRAS. Most inhibit intrinsic and/or SOS-mediated KRAS activation while others inhibit RAS-effector interaction. We propose these compounds as starting points for the development of non-covalent allosteric KRAS inhibitors.

The Resurgence of Lymphogranuloma Venereum: Changing Presentation of Lymphogranuloma Venereum in the Era of HIV Preexposure Prophylaxis, 2004 to 2022.

BACKGROUND: Before the early 2000s, the sexually transmitted infection lymphogranuloma venereum (LGV) was rare in high-income countries. Initially, most cases in these countries were among symptomatic men who have sex with men (MSM) living with HIV. In the context of widespread HIV preexposure prophylaxis (PrEP), LGV's epidemiology may be changing. We aimed to characterize the epidemiology and clinical presentation of LGV in the PrEP era. METHODS: A retrospective chart review was performed on all LGV cases occurring between November 2004 to October 2022 in British Columbia (BC), Canada. Cases were stratified by having occurred before (2004-2017) or after widespread PrEP availability in BC (2018-2022). Annual rates and test positivity percentages were calculated. Bivariate logistic regression was performed to identify drivers of asymptomatic infection in the PrEP era. RESULTS: Among 545 cases identified, 205 (37.6%) occurred pre-PrEP and 340 (62.4%) occurred during the PrEP era. Most cases were among MSM (97.2%). The estimated rate of LGV has doubled from 2018 to 2022, reaching 1535.2 cases per 100,000 PrEP users. Most PrEP-era cases were among HIV-negative individuals (65.3%), particularly those on PrEP (72.6%). Cases in the PrEP era were often asymptomatic compared with pre-PrEP (38.6% vs. 19.3%; P < 0.001). Users of PrEP were more likely to experience asymptomatic infection compared with HIV-negative PrEP nonusers (odds ratio, 2.07; 95% confidence interval, 1.07-3.99). CONCLUSIONS: In the context of increased asymptomatic testing, LGV may be increasing in BC. Most infections now occur among HIV-negative MSM. A high proportion of infections are asymptomatic.

Overexpression and repression of key rate-limiting enzymes (acetyl CoA carboxylase and HMG reductase) to enhance fatty acid production from Rhodotorula mucilaginosa.

Implementing two-way strategies to enhance the lipid production in Rhodotorula mucilaginosa with the help of metabolic engineering was focused on the overexpression of acetyl coenzyme A carboxylase (ACC1 carboxylase) gene and repression of 3-hydroxy 3-methylglutaryl reductase (HMG-CoA reductase). Using an inducer (sodium citrate) and inhibitor (rosuvastatin), the amounts of biomass, lipid, and carotenoid were estimated. In the presence of inhibitor (200 mM), 62% higher lipid concentration was observed, while 44% enhancement was recorded when inducer (3 mM) was used. A combination of both inhibitor and inducer resulted in a 57% increase in lipid concentration by the oleaginous yeast. These results were again confirmed by real-time polymerase chain reaction by targeting the expression of the genes coding for ACC1 carboxylase and 13-fold increase was recorded in the presence of inducer as compared with control. This combined strategy (inducer and inhibitor use) has been reported for the first time as far as the best of our knowledge. The metabolic engineering strategies reported here will be a powerful approach for the enhanced commercial production of lipids.

Evaluation of the Effects of Fluoride Prophylactic Agents on Mechanical Properties of Nickel Titanium Wires using Scanning Electron Microscope.

INTRODUCTION: Orthodontic treatment these days is increasing in demand, and therefore, it is relatively imperative for the orthodontist to prescribe the use of fluoride-containing products, such as mouthwashes and gels, to help prevent dental caries and maintain healthy oral health. The aim of the study was to assess and evaluate the effects of fluoride prophylactic agents on mechanical properties of nickel titanium (NiTi) wires during orthodontic treatment using scanning electron microscope (SEM). MATERIALS AND METHODS: We used the commercially available round preformed NiTi orthodontic archwire (3M company) and three different mouthwash solutions, i.e., Phos-Flur gel (1.1% sodium acidulated phosphate fluoride, APF, 0.5% w/v fluoride, pH = 5.1; Colgate Oral Pharmaceuticals) and Prevident 5000 (1.1% sodium fluoride neutral agent, 0.5% w/v fluoride, pH = 7; Colgate Oral Pharmaceuticals). All the specimens were subjected to a three-point bending test on a universal testing machine. To observe the surface morphological changes, one wire from each group was randomly selected and observed under a SEM. RESULTS: It was observed that there was not much difference in the values of both modulus of elasticity and yield strength obtained after loading of stress on the wires in all the three experimental conditions. A significant difference in both modulus of elasticity and yield strength was observed during unloading of stress. Further, when the surface characteristics were observed for all the specimens using SEM images, it was observed that NiTi wires treated with Phos-Flur showed large surface defects which appeared as round, pitted areas depicting corrosion, numerous white inclusions, and overall damaged surface structure of the wire as compared with the control. CONCLUSION: Thus, fluoridated mouthwashes are essential to maintain good oral hygiene and decrease instance of caries in patients undergoing orthodontic treatment. The prophylactic usage of topical fluoride agents on NiTi wire seems to diminish the mechanical properties of the orthodontic wire that could significantly affect future treatment outcomes. CLINICAL SIGNIFICANCE: It has been proved that fluoride mouthwashes/gels do affect the structural surface qualities and strength of wires used during the orthodontic treatment irrespective of the composition of the wires. Therefore, it is the responsibility of the clinician to prescribe these prophylactic agents carefully while keeping in mind their pH so that the overall result of the treatment may not be hampered and delayed due to change in properties of the wires used.

Heart failure secondary to carfilzomib-induced heart block in multiple myeloma patients.

Carfilzomib is a proteasome inhibitor and immunomodulator used to treat patients with multiple myeloma who have disease progression refractory to bortezomib. The difference in agents is that carfilzomib is an irreversible inhibitor of 20 s proteasome. The most common side effects of carfilzomib are fatigue, nausea, diarrhea, anemia, thrombocytopenia, dyspnea, and pyrexia. Less frequent side effects include cardiac manifestations for which we will explore with more detail. In this case report, we describe a 70-year-old female with multiple myeloma presenting to the emergency department with complaint of dyspnea. Patient was discovered to be in heart failure with atrioventricular block necessitating placement of a pacemaker.

Design, Synthesis, and Biological Evaluation of Novel 1,2,4-Trioxanes as Potential Antimalarial Agents.

A series of substituted 1,2,4-trioxanes were synthesized and evaluated for their antimalarial potential, in silico ADME properties and cytotoxicity on neuronal cell lines. Among the 15 synthesized substituted 1,2,4-trioxanes, two compounds (compound 15, IC50 = 25.71 nM; compound 21, IC50 = 19.6 nM) exhibited promising in vitro antimalarial potential comparable to those of the existing drugs chloroquine and artemisinin. Both of these compounds were found to be nontoxic up to 20 µM concentration in neuronal PC-12 cells. Compound 21 may serve as an optimized lead compound because of its less in vitro toxicity and lower probability to cross the blood brain barrier.

Identification of novel amino acid derived CCK-2R antagonists as potential antiulcer agent: homology modeling, design, synthesis, and pharmacology.

The present study revisited the three-dimensional (3D) homology model of CCK-2R using human A(2a) adenosine receptor and the resolved NMR based structure of the third extracellular loop of the CCK-2R as templates. Further in order to identify novel antiulcer agents, rational designing have been performed utilizing the substructure of a well-known CCK-2R antagonist benzotript as a lead molecule and submitted to the combined docking and simulation studies. This led to the understanding of the essential structure requirement as well as variation of binding mode among conformational isomers of small molecule CCK-2R antagonists. In the next step, preparation of each configurational isomer of these molecules was carried out and submitted for their in vitro activity followed by in vivo screening into antiulcer rat model. The biological screening of these compounds has not only validated the developed homology model of CCK-2R but also led to the identification of highly potent CCK-2R antagonist 6a as an orally active and safe candidate molecule having better antiulcer properties than the well-known drug benzotript.

Small-Molecule Inhibition of KRAS through Conformational Selection.

Mutations in KRAS account for about 20% of human cancers. Despite the major progress in recent years toward the development of KRAS inhibitors, including the discovery of covalent inhibitors of the G12C KRAS variant for the treatment of non-small-cell lung cancer, much work remains to be done to discover broad-acting inhibitors to treat many other KRAS-driven cancers. In a previous report, we showed that a 308.4 Da small-molecule ligand [(2R)-2-(N'-(1H-indole-3-carbonyl)hydrazino)-2-phenyl-acetamide] binds to KRAS with low micro-molar affinity [Chem. Biol. Drug Des.2019; 94(2):1441-1456]. Binding of this ligand, which we call ACA22, to the p1 pocket of KRAS and its interactions with residues at beta-strand 1 and the switch loops have been supported by data from nuclear magnetic resonance spectroscopy and microscale thermophoresis experiments. However, the inhibitory potential of the compound was not demonstrated. Here, we show that ACA22 inhibits KRAS-mediated signal transduction in cells expressing wild type (WT) and G12D mutant KRAS and reduces levels of guanosine triphosphate-loaded WT KRAS more effectively than G12D KRAS. We ruled out the direct effect on nucleotide exchange or effector binding as possible mechanisms of inhibition using a variety of biophysical assays. Combining these observations with binding data that show comparable affinities of the compound for the active and inactive forms of the mutant but not the WT, we propose conformational selection as a possible mechanism of action of ACA22.

Pelvic Synovial Sarcoma Clinically Masquerading as an Ovarian Malignancy.

Background: Synovial sarcoma, a malignant mesenchymal tumor, commonly involves the extremities and is rarely found in the pelvis. Cytology with a biphasic pattern can suggest the diagnosis of synovial sarcoma. Case Report: A 32-year-old female presented with complaints of abdominal distension. She was initially evaluated in another hospital where she underwent ultrasound-guided fine needle aspiration cytology (FNAC) of the abdominal mass. The mass was diagnosed as ovarian adenocarcinoma, and the patient underwent 3 cycles of chemotherapy. After 3 months, she was referred to our institute for surgical excision of the mass. Contrast-enhanced computed tomography of the abdomen suggested a well-circumscribed, heterogeneous, solid-cystic mass in the left adnexal region measuring 13.9 × 10 × 9.1 cm and compressing the adjacent structures. No previous radiologic investigations were available. We reviewed the FNAC slide from the outside hospital and made a preliminary diagnosis of biphasic synovial sarcoma. The patient underwent debulking surgery consisting of panhysterectomy with excision of the pelvic mass. Microscopic examination of the pelvic mass showed a biphasic tumor composed of epithelial and mesenchymal components, suggestive of synovial sarcoma. The immunohistochemistry profile supported the morphologic diagnosis. Bilateral ovaries were unremarkable. The patient received 4 cycles of adjuvant chemotherapy and is presently asymptomatic. Conclusion: Although primary pelvic synovial sarcoma is a rare occurrence, this case illustrates that synovial sarcoma can be diagnosed or at least suspected on FNAC. Because of the importance of adjuvant chemotherapy, synovial sarcoma must be high on the list of differential diagnoses of high-grade intra-abdominal masses.

Sleep testing during the pandemic.

BACKGROUND: The COVID-19 pandemic disrupted the U.S. healthcare system, reducing the capacity available for unrelated conditions, such as sleep disordered breathing, and increasing concerns about the safety of in-lab testing. This study characterizes how the pandemic impacted the assessment of sleep disordered breathing and use of associated services. METHODS: Sleep testing claims occurring between January 2019 and June 2021 were extracted from the database of a national healthcare organization. Utilization was trended. Logistic regressions were run to assess the association between quarter of initial testing, whether testing was followed by treatment, and whether testing was followed by a clinical visit with a diagnosis related to sleep apnea, after controlling for patient-related factors. A Cox proportional hazards model assessed factors influencing time to treatment. Finally, a logistic regression assessed factors influencing the finality of home-based testing. RESULTS: In Q2 2021, home-based testing utilization was 134% of its initial level, while in-lab and split night testing were both at 61% of initial levels. Patients receiving initial home-based testing did not significantly differ in their likelihood of treatment, but were significantly less likely to have a clinical visit for sleep apnea (P < 0.01). Patients initially tested in 2021 were treated significantly more quickly than those initially tested in Q1 2019. Home-based testing occurring in Q4 2019 or later was significantly more likely to be definitive than home-based testing occurring Q1 2019. CONCLUSIONS: Home-based sleep testing increased significantly and durably in 2020, and was associated with faster time to treatment than initial in-lab testing.

A Prospective Comparative Study of Laparoscopic Totally Extraperitoneal (TEP) and Laparoscopic Transabdominal Preperitoneal (TAPP) Inguinal Hernial Repair.

Introduction Inguinal hernia is a common surgical problem throughout the world. Currently, the management options available are open mesh hernioplasty and laparoscopic mesh repair. Laparoscopic mesh repair can be performed by either transabdominal preperitoneal (TAPP) repair or totally extraperitoneal (TEP) repair. Many studies comparing the two procedures have been unable to establish the superiority of one procedure over the other and have yielded conflicting results. Thus, we performed this study to compare TAPP and TEP. Aim The aim of this study is to compare the clinical outcomes and safety of laparoscopic TEP and laparoscopic TAPP for inguinal hernia repair. Materials and methods Patients were randomly divided into two groups on the basis of surgical procedures. The first group of patients underwent laparoscopic TAPP mesh repair, and the second group of patients underwent laparoscopic TEP mesh repair. Their intraoperative and postoperative findings were noted. Patients were followed up at regular intervals for up to six months. Results The mean age and mean weight distribution between the two groups were not significant. The duration of surgery needed (in minutes) for TAPP was found to be significantly less compared to TEP. In the TEP group, conversion to open occurred for three subjects (6.7%) while there was no conversion in the TAPP group. Postoperative pain at 24 hrs was found to be higher in TAPP subjects compared to that in TEP subjects, but the difference was statistically insignificant. Tolerance to a liquid diet started few hours after surgery was found to be the same in both groups. Association of the duration of hospital stays with the type of surgery was not significant. Six subjects (13.2%) showed hematoma in the TEP group while five subjects (11%) in the TAPP group showed hematoma after one week of surgery. Eight subjects (17.6%) showed seroma in the TEP group while three subjects (15.4%) in the TAPP group showed seroma after one week of surgery. Two subjects (4.4%) showed superficial wound infection in both the TEP group and TAPP group after one week of surgery. Four subjects each (8.9%) showed scrotal edema in the TEP group as well as the TAPP group after one week of surgery. No subject showed port site hernia without closure of the sheath at one-week, one-month, and six-month follow-up visits. Two subjects (4.4%) each showed groin pain in the TEP group as well as the TAPP group after one week of surgery. There were no instances of bowel obstruction or mesh infection. Conclusion TEP is a more skill-demanding procedure as compared to TAPP and thus takes more time to perform. However, it is superior on account of not breaching the peritoneum. TAPP is favorable for larger hernias. The choice of procedure should be individualized according to the patient's characteristics and surgeon's preference.

As the World Struggles With the COVID-19 Pandemic, Another Emergency Threat Arrives on the Horizon, the Monkeypox: A Systematic Review.

The whole world got threatened by COVID-19, which made a significant loss in various sectors and pushed the world into a deep valley. Now a new threat, the emerging outbreak of monkeypox is rapidly spreading across the globe and is currently being observed in more than 110 countries with 79,473 confirmed cases and 50 deaths. Data were collected from PubMed, EMBASE, MEDLINE, Cochrane, Scopus database, African Journals OnLine, internet library sub-Saharan Africa, and Google Scholar. Most data were taken from the democratic Republic of Congo, the Central African Republic, Cameroon, the Republic of Congo, Liberia, Nigeria, the US, and the UK. Case reports, outbreak investigations, epidemiological studies, and surveillance studies were reviewed to find epidemiological details about the outbreak. A total of 50 peer-reviewed articles and 20 grey literature articles, including 9050 cases, were identified for data extraction. Our systematic review revealed that the group most affected is male (95.5%), with a median age of 33.8 years. A total of 55% of the transmission was sexually transmitted. The most commonly reported symptoms such as vesicular-pustular rashes (97.54%), fever (55.25%), inguinal lymphadenopathy (53.6%), exanthema (40.21%), fatigue, headache, asthenia (26.32%), myalgia (16.33%), vesicles and ulcers (30.61%) in the anogenital regions were some of the significant findings. The case fatality rate was observed to be up to 8.65%. The most affected country was the USA, which has the most fatalities in younger ages involved in homosexuality, suffering from HIV or sexually transmitted diseases (STDs).

Toward the identification of a reliable 3D QSAR pharmacophore model for the CCK2 receptor antagonism.

The present study describes application of computational approaches to identify a validated and reliable 3D QSAR pharmacophore model for the CCK-2R antagonism through integrated ligand and structure based studies using anthranilic sulfonamide and 1,3,4-benzotriazepine based CCK-2R antagonists. The best hypothesis consisted five features viz. two aliphatic hydrophobic, one aromatic hydrophobic, one H-bond acceptor, and one ring aromatic feature with an excellent correlation for 34 training set (r²(training) = 0.83) and 58 test set compounds (r²(test) = 0.74). This model was validated through F-test and docking studies at the active site of the plausible CCK-2R where the 99% significance and well corroboration with the pharmacophore model respectively describes the model's reliability. The model also predicts well to other known clinically effective CCK-2R antagonists. Therefore, the developed model may useful in finding new scaffolds that may aid in design and develop new chemical entities (NCEs) as potent CCK-2R antagonists before their synthesis.

Identification of novel S-adenosyl-L-homocysteine hydrolase inhibitors through homology-model-based virtual screening, synthesis, and biological evaluation.

The present study describes a successful application of computational approaches to identify novel Leishmania donovani (Ld) AdoHcyase inhibitors utilizing the differences for Ld AdoHcyase NAD(+) binding between human and Ld parasite. The development and validation of the three-dimensional (3D) structures of Ld AdoHcyase using the L. major AdoHcyase as template has been carried out. At the same time, cloning of the Ld AdoHcyase gene from clinical strains, its overexpression and purification have been performed. Further, the model was used in combined docking and molecular dynamics studies to validate the binding site of NAD in Ld. The hierarchical structure based virtual screening followed by the synthesis of five active hits and enzyme inhibition assay has resulted in the identification of novel Ld AdoHcyase inhibitors. The most potent inhibitor, compound 5, may serve as a "lead" for developing more potent Ld AdoHcy hydrolase inhibitors as potential antileishmanial agents.

Prescription Drug Insurance and Cost-Related Medication Nonadherence Among Lesbian, Gay, and Bisexual Individuals in Canada.

Purpose: This study estimates the frequency of uninsurance for prescription drugs and cost-related medication nonadherence (CRNA) among lesbian, gay, and bisexual (LGB) persons in Canada, compared with the heterosexual population. Methods: Logistic regression was used to quantify associations between sexual orientation, insurance status, and CRNA within the national probability-based Canadian Community Health Survey, 2015-2016. This sample included 98,413 individuals aged 15-80 years, including 2803 LGB individuals. Results: From our sample of Canadians, 22.2% of LGB respondents reported being uninsured for prescription drugs, compared with 20.0% of heterosexual persons (unadjusted odds ratio [UOR] 1.14, 95% confidence interval [CI] 0.97-1.35). LGB individuals had more than twice the odds of reporting CRNA compared with heterosexual individuals (UOR 2.48, 95% CI 1.99-3.10). This disparity was most pronounced among bisexual respondents, who had over three times the odds of reporting CRNA in comparison to heterosexual respondents (UOR 3.45, 95% CI 2.65-4.51). The odds ratio (OR) for CRNA comparing bisexual with heterosexual individuals remained statistically significant after adjustment for race/ethnicity, gender/sex, and age (OR 2.67, 95% CI 1.97-3.61) and was further attenuated with adjustment for partnership status, employment status, income, educational attainment, prescription drug insurance status, general health status, and immigration status (OR 2.09, 95% CI 1.51-2.89). Conclusion: LGB Canadians reported more CRNA but comparable prescription drug insurance frequencies to heterosexual persons. Factors pertaining to medication access (e.g., income, partnership status) and health needs appear to be the most important contributors to disparities.

Utility of Antibodies in the Diagnoses of Thyroid Diseases: A Review Article.

Thyroid problems are among the most widespread endocrine illnesses, affecting individuals in India and the global population. A thyroid function test is used to diagnose, screen, and monitor patients. Hyperthyroidism is a clinical condition due to excessive circulation of thyroid hormone; in contrast, hypothyroidism is due to a deficiency of thyroid hormone. Graves' disease (GD) is a form of hyperthyroidism due to thyroid-stimulating hormone receptor autoantibodies (TRAb), and anti-thyroid peroxidase antibodies (anti-TPO antibodies). The most common reason for hypothyroidism is Hashimoto's thyroiditis (HT), in which patients have thyroid receptor antibodies (TRAb), antibodies to thyroid peroxidase (TPO), and thyroglobulin antibodies. Many essential genes, including the thyroid-specific genes thyroglobulin (TSGT), TSH-receptor gene, human leukocyte antigen (HLA) genes, cytotoxic T lymphocyte-associated antigen (CTLA) genes, thyroglobulin gene, vitamin D receptor gene, and many immune-regulatory genes were associated with autoimmune thyroid diseases' (AITDs') etiology. This review paper aims to determine if antibodies are beneficial in detecting autoimmune thyroid disease or not. We have also discussed the etiology of autoimmune thyroid illness, serum antibodies in autoimmune thyroid disease, pathophysiology, and TSH receptor features.

KRAS Inhibitor that Simultaneously Inhibits Nucleotide Exchange Activity and Effector Engagement.

We describe a small molecule ligand ACA-14 (2-hydroxy-5-{[(2-phenylcyclopropyl) carbonyl] amino} benzoic acid) as an initial lead for the development of direct inhibitors of KRAS, a notoriously difficult anticancer drug target. We show that the compound binds to KRAS near the switch regions with affinities in the low micromolar range and exerts different effects on KRAS interactions with binding partners. Specifically, ACA-14 impedes the interaction of KRAS with its effector Raf and reduces both intrinsic and SOS-mediated nucleotide exchange rates. Likely as a result of these effects, ACA-14 inhibits signal transduction through the MAPK pathway in cells expressing mutant KRAS and inhibits the growth of pancreatic and colon cancer cells harboring mutant KRAS. We thus propose compound ACA-14 as a useful initial lead for the development of broad-acting inhibitors that target multiple KRAS mutants and simultaneously deplete the fraction of GTP-loaded KRAS while abrogating the effector-binding ability of the already GTP-loaded fraction.

Design and development of a portable resistive sensor based on α-MnO2 /GQD nanocomposites for trace quantification of Pb(II) in water.

The occurrence of heavy metal ions in food chain is appearing to be a major problem for mankind. The traces of heavy metals, especially Pb(II) ions present in water bodies remains undetected, untreated, and it remains in the food cycle causing serious health hazards for human and livestock. The consumption of Pb(II) ions may lead to serious medical complications including multiple organ failure which can be fatal. The conventional methods of heavy metal detection are costly, time-consuming and require laboratory space. There is an immediate need to develop a cost-effective and portable sensing system which can easily be used by the common man without any technical knowhow. A portable resistive device with miniaturized electronics is developed with microfluidic well and α-MnO2 /GQD nanocomposites as a sensing material for the sensitive detection of Pb(II). α-MnO2 /GQD nanocomposites which can be easily integrated with the miniaturized electronics for real-time on-field applications. The proposed sensor exhibited a tremendous potential to be integrated with conventional water purification appliances (household and commercial) to give an indication of safety index for the drinking water. The developed portable sensor required low sample volume (200 µL) and was assessed within the Pb(II) concentration range of 0.001 nM to 1 uM. The Limit of Detection (LoD) and sensitivity was calculated to be 0.81 nM and 1.05 kΩ/nM/mm2 , and was validated with the commercial impedance analyser. The shelf-life of the portable sensor was found to be ∼45 days.

Arterial pulsatile hemodynamic load induced by isometric exercise strongly predicts left ventricular mass in hypertension.

Although resting hemodynamic load has been extensively investigated as a determinant of left ventricular (LV) hypertrophy, little is known about the relationship between provoked hemodynamic load and the risk of LV hypertrophy. We studied central pressure-flow relations among 40 hypertensive and 19 normotensive adults using carotid applanation tonometry and Doppler echocardiography at rest and during a 40% maximal voluntary forearm contraction (handgrip) maneuver. Carotid-femoral pulse wave velocity (CF-PWV) was measured at rest. Hypertensive subjects demonstrated various abnormalities in resting and induced pulsatile load. Isometric exercise significantly increased systemic vascular resistance, aortic characteristic impedance (Zc), induced earlier wave reflections, increased augmentation index, and decreased total arterial compliance (TAC; all P < or = 0.01). In hypertensive subjects, CF-PWV was the strongest resting predictor of LV mass index (LVMI) and remained an independent predictor after adjustment for age, gender, systemic vascular resistance, reflection magnitude, aortic Zc, and TAC (beta = 2.52 m/s; P < 0.0001). Age, sex, CF-PWV, and resting hemodynamic indexes explained 48% of the interindividual variability in LVMI. In stepwise regression, TAC (beta = -17.85; P < 0.0001) during handgrip, Zc during handgrip (beta = -150; P < 0.0001), and the change in the timing of wave reflections during handgrip (beta = -0.63; P = 0.03) were independent predictors of LVMI. A model that included indexes of provoked hemodynamic load explained 68% of the interindividual variability in LVMI. Hemodynamic load provoked by isometric exercise strongly predicts LVMI in hypertension. The magnitude of this association is far greater than for resting hemodynamic load, suggesting that provoked testing captures important arterial properties that are not apparent at rest and is advantageous to assess dynamic arterial load in hypertension.

Integrated ligand and structure based studies of flavonoids as fatty acid biosynthesis inhibitors of Plasmodium falciparum.

A common feature pharmacophore with two hydrogen-bond acceptor and one aromatic hydrophobic feature has been generated using seven active flavonoids. Docking studies of these compounds well corroborates with the pharmacophore model. Therefore models could be useful for identification of potential novel FAS-II inhibitors.