Effect of acute intermittent hypoxia treatment on ventilatory load compensation and magnitude estimation of inspiratory resistive loads in an individual with chronic incomplete cervical spinal cord injury

Context

Spinal cord injury (SCI) causes disruption of the efferent input to and afferent input from respiratory muscles, which impairs respiratory motor and sensory functions, respectively. This disturbs the injured individual''s ability to respond to ventilatory loads and may alter the respiratory perceptual sensitivity of applied loads. Acute intermittent hypoxia with elevated CO₂ (AIH treatment) has been shown to induce ventilatory long-term facilitation in individuals with chronic SCI. This study evaluated the effect of ten days of AIH treatment on ventilatory load compensation and respiratory perceptual sensitivity to inspiratory resistive loads (IRL), in an individual with chronic, incomplete cervical SCI.

Methods

Case report and literature review.

Findings

We report a case of a 55-year-old female with a C4 chronic, incomplete SCI (American Spinal Injury Association Impairment Scale D). The subject underwent evaluation at four time-points: Baseline, Post Sham, AIH Day 1 and AIH Day 10. Significant improvements in airflow generated in response to applied IRL were found after AIH treatment compared to Baseline. There were no significant changes in the respiratory perceptual sensitivity to applied IRL after AIH treatment.

Clinical relevance

Rehabilitative interventions after SCI demand restoration of the respiratory motor function. However, they must also ensure that the respiratory perceptual sensitivity of the injured individual does not hinder their capability to compensate to ventilatory challenges.     

Study of placenta in sickle cell disorders

Remarkable changes are seen on gross and microscopic examination of placenta of patients with sickle cell disorders, hence the present study was undertaken to find out the pathological changes seen in the placenta of sickle cell disorder patients, as compared to control and to study the effect of maternal sickling on the fetus. It includes total 73 cases, of which 10 were of control group and 63 were from patients with sickle cell disorders, which included 47 sickle cell trait (AS) and 16 sickle cell disease (SS) patients. In group II, 9 (14.28%) patients with SS pattern developed complications during pregnancy, in the form of vaso-occlusive and hemolytic crises. Pregnancy induced hypertension was seen in 4 (25%) out of 16 SS and 11 (23.40%) of the 47 AS patients. Urinary tract infection (UTI) was seen in 6 (37.5%) out of 16 SS and 8 (17.02%) out of 47 AS patients. Placentae in sickle cell disorders showed pathological changes in the form of infarction, calcification, sickled red blood cells and hemorrhage in intervillous spaces, increased syncytial knots, fibrinoid necrosis, stromal fibrosis, hyalinised villi and compensatory proliferation of trophoblastic cells.     

Development and evaluation of an in vitro isolation of street rabies virus in mouse neuroblastoma cells as compared to conventional tests used for diagnosis of rabies

In vitro isolation of rabies virus using mouse neuroblastoma cells (MNA) was evaluated. The sensitivity and reliability of in vitro procedure was performed in comparison with mouse inoculation test (MIT), the in vivo method of virus isolation, direct fluorescent antibody test (FAT) and Sellers staining. Of the 33 animal brain samples tested, 24 (72.72%) were positive by MIT. Sensitivity of Sellers stain, FAT and rapid tissue culture infection test (RTCIT) was found to be 54.16, 100 and 91.6% respectively. Concordance of Sellers stain, FAT, RTCIT with MIT was found to be 66.6, 100 and 93.93% respectively. Two samples which were positive by FAT and MIT showed gross contamination in cell lines, which is one of the drawbacks of RTCIT. However, rabies virus could be isolated in MNA cells from two of the eight human cerebrospinal fluid (CSF) samples from clinico-epidemiologically suspected cases of rabies. Both MIT and FAT showed negative results in the two CSF samples. RTCIT appears to be a fast and reliable alternative to MIT and holds promise in antemortem diagnosis of rabies, which is otherwise, a challenging task for a reference laboratory.     

Non‐peptide‐based new class of platelet aggregation inhibitors: Design,synthesis, bioevaluation,SAR, and in silico studies

A series of 2‐oxo‐2‐phenylethylidene linked 2‐oxo‐benzo[1,4]oxazine analogues 17a–x and 18a–o , incorporated with a variety of electron‐withdrawing as well as electron‐donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a–x and 18a–o were evaluated for their arachidonic acid (AA)‐induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC₅₀ = 21.34 ± 1.09 µg/mL). Among all the screened compounds, eight analogues, 17i , 17x , 18f , 18g , 18h , 18i , 18l , and 18o , were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3T₃ fibroblast cell lines by MTT assay of the promising compounds ( 17i , 17x , 18f–18i , 18l , and 18o ) were also performed and the compounds were found to be non‐toxic in nature. Furthermore, the results on the AA‐induced platelet aggregation inhibitory activities of these compounds ( 17i , 17x , 18f–18i , 18l , and 18o ) were validated via in silico molecular docking simulation studies. To the best of our knowledge, this is the first report of the identification of non‐peptide‐based functionalized 2‐oxo‐benzo[1,4]oxazines as platelet aggregation inhibitors.

     

Quantitative structure–activity relationship (QSAR) studies as strategic approach in drug discovery

Drug design is a process which is driven by technological breakthroughs implying advanced experimental and computational methods. Nowadays, the techniques or the drug design methods are of paramount importance for prediction of biological profile, identification of hits, generation of leads, and moreover to accelerate the optimization of leads into drug candidates. Quantitative structure–activity relationship (QSAR) has served as a valuable predictive tool in the design of pharmaceuticals and agrochemicals. From decades to recent research, QSAR methods have been applied in the development of relationship between properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. Classical QSAR studies include ligands with their binding sites, inhibition constants, rate constants, and other biological end points, in addition molecular to properties such as lipophilicity, polarizability, electronic, and steric properties or with certain structural features. 3D-QSAR has emerged as a natural extension to the classical Hansch and Free–Wilson approaches, which exploit the three-dimensional properties of the ligands to predict their biological activities using robust chemometric techniques such as PLS, G/PLS, and ANN. This paper provides an overview of 1-6 dimension-based developed QSAR methods and their approaches. In particular, we present various dimensional QSAR approaches, such as comparative molecular field analysis (CoMFA), comparative molecular similarity analysis, Topomer CoMFA, self-organizing molecular field analysis, comparative molecule/pseudo receptor interaction analysis, comparative molecular active site analysis, and FLUFF-BALL, 4D-QSAR, and G-QSAR approaches.     

Primary motor cortex long‐term plasticity in multiple system atrophy

In humans, intermittent and continuous theta‐burst stimulation (iTBS and cTBS) elicit long‐term changes in motor‐evoked potentials (MEPs) reflecting long‐term potentiation (LTP)‐ and depression (LTD)‐like plasticity in the primary motor cortex (M1). In this study, we used TBS to investigate M1 plasticity in patients with MSA. We also assessed whether responses to TBS reflect M1 excitability as tested by short‐interval intracortical inhibition (SICI), intracortical facilitation (ICF), short‐interval intracortical facilitation (SICF), and the input/output curves. We studied 20 patients with MSA and 20 healthy subjects (HS). Patients were clinically evaluated with the Unified Multiple System Atrophy Rating Scale. The left M1 was conditioned with TBS. Twenty MEPs were recorded from the right first dorsal interosseous muscle before TBS and 5, 15, and 30 minutes thereafter. In a subgroup of 10 patients, we also tested MEPs elicited by SICI, ICF, SICF, and input/output curves, before TBS. Between‐group analysis of variance showed that at all time points after iTBS MEPs increased, whereas after cTBS they decreased only in HS. In both subgroups tested, patients with predominant parkinsonian and cerebellar features, iTBS and cTBS left MEPs unchanged. MSA patients had reduced SICI, but normal ICF, SICF, and input/output curves. No correlation was found between patients' clinical features and responses to TBS and M1 excitability variables. These findings suggest impaired M1 plasticity in MSA. © 2013 International Parkinson and Movement Disorder Society     

The flavoprotein FOXRED2 reductively activates nitro-chloromethylbenzindolines and other hypoxia-targeting prodrugs

The nitro-chloromethylbenzindoline prodrug SN29428 has been rationally designed to target tumour hypoxia. SN29428 is metabolised to a DNA minor groove alkylator via oxygen-sensitive reductive activation initiated by unknown one-electron reductases. The present study sought to identify reductases capable of activating SN29428 in tumours. Expression of candidate reductases in cell lines was modulated using forced expression and, for P450 (cytochrome) oxidoreductase (POR), by zinc finger nuclease-mediated gene knockout. Affymetrix microarray mRNA expression of flavoreductases was correlated with SN29428 activation in a panel of 23 cancer cell lines. Reductive activation and cytotoxicity of prodrugs were measured using mass spectrometry and antiproliferative assays, respectively. SN29428 activation under hypoxia was strongly attenuated by the pan-flavoprotein inhibitor diphenyliodonium, but less so by knockout of POR suggesting other flavoreductases contribute. Forced expression of 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), as well as POR, increased activation of SN29428 in hypoxic HCT 116 cells. SN29428 activation strongly correlated with expression of POR and also FAD-dependent oxidoreductase domain containing 2 (FOXRED2), in cancer cell lines. This association persisted after removing the effect of POR enzyme activity using first-order partial correlation. Forced expression of FOXRED2 increased SN29428 activation and cytotoxicity in hypoxic HEK293 cells and also increased activation of hypoxia-targeted prodrugs PR-104A, tirapazamine and SN30000, and increased cytotoxicity of the clinical-stage prodrug TH-302. Thus this study has identified three flavoreductases capable of enzymatically activating SN29428, one of which (FOXRED2) has not previously been implicated in xenobiotic metabolism. These results will inform future development of biomarkers predictive of SN29428 sensitivity.     

A review on current advances in machine learning based diabetes prediction

Diabetes is a metabolic disorder comprising of high glucose level in blood over a prolonged period in the body as it is not capable of using it properly. The severe complications associated with diabetes include diabetic ketoacidosis, nonketotic hypersmolar coma, cardiovascular disease, stroke, chronic renal failure, retinal damage and foot ulcers. There is a huge increase in the number of patients with diabetes globally and it is considered a major health problem worldwide. Early diagnosis of diabetes is helpful for treatment and reduces the chance of severe complications associated with it. Machine learning algorithms (such as ANN, SVM, Naive Bayes, PLS-DA and deep learning) and data mining techniques are used for detecting interesting patterns for diagnosing and treatment of disease. Current computational methods for diabetes diagnosis have some limitations and are not tested on different datasets or peoples from different countries which limits the practical use of prediction methods. This paper is an effort to summarize the majority of the literature concerned with machine learning and data mining techniques applied for the prediction of diabetes and associated challenges. This report would be helpful for better prediction of disease and improve in understanding the pattern of diabetes. Consequently, the report would be helpful for treatment and reduce risk of other complications of diabetes.     

Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs

Over the past decades, a multitude of experimental drugs have been shown to delay disease progression in preclinical animal models of amyotrophic lateral sclerosis (ALS) but failed to show efficacy in human clinical trials or are still waiting for approval under Phase I–III trials. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug approved by the USA Food and Drug Administration for ALS treatment with modest benefits on survival. Recently, an antioxidant drug, edaravone, developed by Mitsubishi Tanabe Pharma was found to be effective in halting ALS progression during early stages. The newly approved drug edaravone is a force multiplier for ALS treatment. This short report provides an overview of the two drugs that have been approved for ALS treatment and highlights an update on the timeline of drug development, how clinical trials were done, the outcome of these trials, primary endpoint, mechanism of actions, dosing information, administration, side effects, and storage procedures. Moreover, we also discussed the pressing issues and challenges of ALS clinical trials and drug developments as well as future outlook.     

Scapulothoracic and scapholunate dissociation in the ipsilateral upper limb of a trauma victim

Scapulothoracic dissociation is a rare and complex injury pattern with varied presentation.Here we describe a case of a 32-year-old male who presented with scapulothoracic dissociation associated with brachial plexus injury,along with scapholunate dissociation.We also propose an injury mechanism that might link the two injury patterns,suggesting that the association might be more than by chance.The patient was managed according to established trauma care and resuscitation protocols followed by open reduction and internal fixation of the clavicle fracture,and fixation of scapholunate dissociation and had a successful outcome at follow-up.