Bilateral impairments of shoulder abduction in chronic hemiparesis: Electromyographic patterns and isokinetic muscle performance

ObjectiveTo analyze electromyographic (EMG) patterns and isokinetic muscle performance of shoulder abduction movement in individuals who sustained a cerebrovascular accident (CVA).DesignTwenty-two individuals who sustained a CVA and 22 healthy subjects volunteered for EMG activity and isokinetic shoulder abduction assessments. EMG onset time, root mean square (RMS) for upper trapezius and deltoid muscles, as well as the isokinetic variables of peak torque, total work, average power and acceleration time were compared between limbs and groups.ResultsThe paretic side showed a different onset activation pattern in shoulder abduction, along with a lower RMS for both muscles (21.8 ± 13.4% of the maximal voluntary isometric contraction (MVIC) for the deltoid and 25.9 ± 15.3% MVIC for the upper trapezius, about 50% lower than the control group). The non-paretic side showed a delay in both muscles activation and a lower RMS for the deltoid (32.2 ± 13.7% MVIC, about 25% lower than the control group). Both sides of the group of individuals who sustained a CVA presented a significantly lower isokinetic performance compared to the control group (paretic side ～60% lower; non-paretic side ～35% lower).ConclusionsShoulder abduction muscle performance is impaired in both paretic and non-paretic limbs of individuals who sustained a CVA.     

Exploring structural features of EGFR–HER2 dual inhibitors as anti-cancer agents using G-QSAR approach

Abstract

Simultaneous inhibition of EGFR and HER2 by dual-targeting inhibitors is an established anti-cancer strategy. Therefore, a recent trend in drug discovery involves understanding the features of such dual inhibitors. In this study, three different G-QSAR models were developed corresponding to individual EGFR, HER2 and the dual-model for both receptors. The dual-model provided site-specific information wherein (i) increasing electronegative character and higher index of saturated carbon at R4 position; (ii) presence of chlorine atom at R2 position; (iii) decreasing alpha modified shape index at R1 and R3 positions; and (iv) less electronegativity at R2 position; were found important for enhancing the dual activity. Also, comparison of dual-model with the EGFR/HER2 individual models revealed that it incorporates the properties of both models and, thus, represents a combination of EGFR/HER2. Further, fragment analysis revealed that R2 and R4 are important for imparting high potency while specificity is decided by R1/R3 fragment. We also checked the predictive ability of the dual-model by determining applicability domain using William’s plot. Also, analysis of active molecules showed they show favorable substitutions that agree with the constructed dual-model. Thus, we have been successful in developing a single dual-response QSAR model to get an insight into various structural features influencing EGFR/HER2 activity.     

In silico studies of urease inhibitors to explore ligand-enzyme interactions

In continuation of our previous study on the urease inhibition by a number of chalcones, 2,3-dihydro-1,5-benzothiazepines and 2,3,4,5-tetrahydro-1,5-benzothiazepines, FlexX docking has been exploited to get a deeper insight into the mechanism of their inhibitory action. A comparison of the IC₅₀ values of the active compounds reveals that, of the three classes of compounds studied, 2,3-dihydro-1,5-benzothiazepines were the most potent urease inhibitors. An in silico examination of these compounds showed that the activity is related to the interaction of ligand with the nickel metallocentre, its interaction with two amino acid residues, Asp224 and Cys322, in addition to the orientation of rings A and B in the catalytic core of the enzyme. The most active compound 2,3-dihydro-1,5-benzothiazepine (4) anchor tightly through a network of interactions with Ni701 and Ni702. This includes a number of hydrogen bonds and hydrophobic contacts with the amino acid residues in its vicinity. For their reduced analogs, the difference in the activity of different diastereomers has been observed to be configuration-dependent. This may be ascribed mainly to the difference in the orientation of ring B of the two stereoisomers and the extent of their interaction with Asp224 and Cys322 present in the catalytic core of the enzyme.     

NT Pro BNP Plasma Level and Atrial Volume Are Linked to the Severity of Liver Cirrhosis

Background and Aims

Plasma levels of NT-pro-BNP, a natriuretic peptide precursor, are raised in the presence of fluid retention of cardiac origin and can be used as markers of cardiac dysfunction. Recent studies showed high levels of NT pro BNP in patients with cirrhosis. We assessed NT pro-BNP and other parameters of cardiac dysfunction in patients with cirrhosis, with or without ascites, in order to determine whether the behaviour of NT pro BNP is linked to the stage of liver disease or to secondary cardiac dysfunction.

Methods

Fifty eight consecutive hospitalized patients mostly with viral or NAFLD-related cirrhosis were studied. All underwent abdominal ultrasound and upper GI endoscopy. Cardiac morpho-functional changes were evaluated by echocardiography and NT-pro-BNP plasma levels determined upon admission. Twenty-eight hypertensive patients, without evidence of liver disease served as controls.

Results

Fifty eight cirrhotic patients (72% men) with a median age of 62 years (11% with mild arterial hypertension and 31% with type 2 diabetes) had a normal renal function (mean creatinine 0.9 mg/dl, range 0.7–1.06). As compared to controls, cirrhotic patients had higher NT pro-BNP plasma levels (365.2±365.2 vs 70.8±70.6 pg/ml; p<0.001). Left atrial volume (LAV) (61.8±26.3 vs 43.5±14.1 ml; p = 0.001), and left ventricular ejection fraction (62.7±6.9 vs. 65.5±4%,; p = 0.05) were also altered in cirrhotic patients that in controls. Patients with F2-F3 oesophageal varices as compared to F0/F1, showed higher e'' velocity (0.91±0.23 vs 0.66±0.19 m/s, p<0.001), and accordingly a higher E/A ratio (1.21±0.46 vs 0.89±0.33 m/s., p = 0.006).

Conclusion

NT-pro-BNP plasma levels are increased proportionally to the stage of chronic liver disease. Advanced cirrhosis and high NT-pro-BNP levels are significantly associated to increased LAV and to signs of cardiac diastolic dysfunction. NT pro-BNP levels could hence be an useful prognostic indicators of early decompensation of cirrhosis.     

Mechanistic Phenotypes: An Aggregative Phenotyping Strategy to Identify Disease Mechanisms Using GWAS Data

A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with “mechanistic phenotypes”, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher''s p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10−5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10−6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.     

Metabonomics Analysis of Plasma Reveals the Lactate to Cholesterol Ratio as an Independent Prognostic Factor of Short-Term Mortality in Acute Heart Failure

Objective

Mortality in heart failure (AHF) remains high, especially during the first days of hospitalization. New prognostic biomarkers may help to optimize treatment. The aim of the study was to determine metabolites that have a high prognostic value.

Methods

We conducted a prospective study on a training cohort of AHF patients (n = 126) admitted in the cardiac intensive care unit and assessed survival at 30 days. Venous plasmas collected at admission were used for ¹H NMR – based metabonomics analysis. Differences between plasma metabolite profiles allow determination of discriminating metabolites. A cohort of AHF patients was subsequently constituted (n = 74) to validate the findings.

Results

Lactate and cholesterol were the major discriminating metabolites predicting 30-day mortality. Mortality was increased in patients with high lactate and low total cholesterol concentrations at admission. Accuracies of lactate, cholesterol concentration and lactate to cholesterol (Lact/Chol) ratio to predict 30-day mortality were evaluated using ROC analysis. The Lact/Chol ratio provided the best accuracy with an AUC of 0.82 (P < 0.0001). The acute physiology and chronic health evaluation (APACHE) II scoring system provided an AUC of 0.76 for predicting 30-day mortality. APACHE II score, Cardiogenic shock (CS) state and Lact/Chol ratio ≥ 0.4 (cutoff value with 82% sensitivity and 64% specificity) were significant independent predictors of 30-day mortality with hazard ratios (HR) of 1.11, 4.77 and 3.59, respectively. In CS patients, the HR of 30-day mortality risk for plasma Lact/Chol ratio ≥ 0.4 was 3.26 compared to a Lact/Chol ratio of < 0.4 (P  =  0.018). The predictive power of the Lact/Chol ratio for 30-day mortality outcome was confirmed with the independent validation cohort.

Conclusion

This study identifies the plasma Lact/Chol ratio as a useful objective and simple parameter to evaluate short term prognostic and could be integrated into quantitative guidance for decision making in heart failure care.     

An Investigation of Fecal Volatile Organic Metabolites in Irritable Bowel Syndrome

Diagnosing irritable bowel syndrome (IBS) can be a challenge; many clinicians resort to invasive investigations in order to rule out other diseases and reassure their patients. Volatile organic metabolites (VOMs) are emitted from feces; understanding changes in the patterns of these VOMs could aid our understanding of the etiology of the disease and the development of biomarkers, which can assist in the diagnosis of IBS. We report the first comprehensive study of the fecal VOMs patterns in patients with diarrhea-predominant IBS (IBS-D), active Crohn''s disease (CD), ulcerative colitis (UC) and healthy controls. 30 patients with IBS-D, 62 with CD, 48 with UC and 109 healthy controls were studied. Diagnosis of IBS-D was made using the Manning criteria and all patients with CD and UC met endoscopic, histologic and/or radiologic criteria. Fecal VOMs were extracted by solid phase microextraction (SPME) and analyzed by gas chromatography-mass spectrometry (GC-MS). 240 VOMs were identified. Univariate analysis showed that esters of short chain fatty acids, cyclohexanecarboxylic acid and its ester derivatives were associated with IBS-D (p<0.05), while aldehydes were more abundant in IBD (p<0.05). A predictive model, developed by multivariate analysis, separated IBS-D from active CD, UC and healthy controls with a sensitivity of 94%, 96% and 90%; and a specificity of 82%, 80% and 80% respectively (p<0.05). The understanding of the derivation of these VOMs may cast light on the etiology of IBS-D and IBD. These data show that fecal VOMs analyses could contribute to the diagnosis of IBS-D, for which there is no laboratory test, as well as IBD.     

<i>Aspergillus tubingensis</i> Causes Leaf Spot of Cotton (<i>Gossypium hirsutum</i> L.) in Pakistan

Cotton (Gossypium hirsutum L.) is a key fiber crop of great commercial importance. Numerous phytopathogens decimate crop production by causing various diseases. During July-August 2018, leaf spot symptoms were recurrently observed on cotton leaves in Rahim Yar Khan, Pakistan and adjacent areas. Infected leaf samples were collected and plated on potato dextrose agar (PDA) media. Causal agent of cotton leaf spot was isolated, characterized and identified as Aspergillus tubingensis based on morphological and microscopic observations. Conclusive identification of pathogen was done on the comparative molecular analysis of CaM and β-tubulin gene sequences. BLAST analysis of both sequenced genes showed 99% similarity with A. tubingensis. Koch’s postulates were followed to confirm the pathogenicity of the isolated fungus. Healthy plants were inoculated with fungus and similar disease symptoms were observed. Fungus was re-isolated and identified to be identical to the inoculated fungus. To our knowledge, this is the first report describing the involvement of A. tubingensis in causing leaf spot disease of cotton in Pakistan and around the world.     

Aggressiveness spectrum and genetic variability of Fusarium spp. on rice and wheat varieties

Abstract

A total of 106 Fusarium spp. were isolated from infected roots and soil samples of wheat and rice. Of the 106 isolates, 32 from wheat, and 74 from rice, were isolated. Six Fusarium spp. (F. oxysporum, F. moniliforme, F. poae, F. graminearum, F. tricinctum and F. equiseti) were identified at specie level. In aggressiveness tests Fusarium spp. root rot causing fungi were screened out into different aggressiveness classes according to disease severity scales. The aggressiveness of Fusarium spp. was studied on wheat varieties (Inqalab-91 and chakwal-86) and on rice varieties (Basmati-385 and IRRI-6) under controlled conditions. The overall total number of aggressive isolates was higher in rice than in wheat. However, the percentage of severely aggressive isolates was high in wheat, whereas the percentage of moderately and slightly aggressiveness isolates was high in rice. In rice, five isolates were non-aggressive and on wheat 17 were non-aggressive. Random Amplified Polymorphism DNAs (RAPDs) were used to study the polymorphism and genetic variations within the population of Fusarium spp. that established to study correlation between taxonomical and genetical characters of fungi. Five random primers were used P1 (5′-AGGAGGACCC-3′), P2 (5′-ACGAGGGACT-3′), PE7 (5′-AGATGCAGCC-3′), P14 (5′-CCACAGCACG-3′) and PE20 (5′-AACGGTGACC-3′). Each of the 10-mer primers produced results based on the respective banding patterns they generated in present investigations. Primers distinguished the F. oxysporum, F. moniliforme, F. graminearum, F. tricinctum, F. poa and F. equiseti. All the tested primers yielded amplification products, and that were reproducible. Although there was some intraspecific variation with primers, some strains were similar and some were different in banding pattern. In F. oxysporum, F. moniliforme, F. graminearum, F. tricinctum, F. poa and F. equiseti were seen clustered close to one another but each primer separated them unambiguously. All primer (P1, P2, P14, PE7 and PE20) combination produced 62 bands. All primers have shown interspecific and intraspecific variations in banding patterns.