Discovering selective antiferroptotic inhibitors of the 15LOX/PEBP1 complex noninterfering with biosynthesis of lipid mediators.

Programmed ferroptotic death eliminates cells in all major organs and tissues with imbalanced redox metabolism due to overwhelming iron-catalyzed lipid peroxidation under insufficient control by thiols (Glutathione (GSH)). Ferroptosis has been associated with the pathogenesis of major chronic degenerative diseases and acute injuries of the brain, cardiovascular system, liver, kidneys, and other organs, and its manipulation offers a promising new strategy for anticancer therapy. This explains the high interest in designing new small-molecule-specific inhibitors against ferroptosis. Given the role of 15-lipoxygenase (15LOX) association with phosphatidylethanolamine (PE)-binding protein 1 (PEBP1) in initiating ferroptosis-specific peroxidation of polyunsaturated PE, we propose a strategy of discovering antiferroptotic agents as inhibitors of the 15LOX/PEBP1 catalytic complex rather than 15LOX alone. Here we designed, synthesized, and tested a customized library of 26 compounds using biochemical, molecular, and cell biology models along with redox lipidomic and computational analyses. We selected two lead compounds, FerroLOXIN-1 and 2, which effectively suppressed ferroptosis in vitro and in vivo without affecting the biosynthesis of pro-/anti-inflammatory lipid mediators in vivo. The effectiveness of these lead compounds is not due to radical scavenging or iron-chelation but results from their specific mechanisms of interaction with the 15LOX-2/PEBP1 complex, which either alters the binding pose of the substrate [eicosatetraenoyl-PE (ETE-PE)] in a nonproductive way or blocks the predominant oxygen channel thus preventing the catalysis of ETE-PE peroxidation. Our successful strategy may be adapted to the design of additional chemical libraries to reveal new ferroptosis-targeting therapeutic modalities.

Small-molecule IKKß activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth.

Activation of inhibitor of nuclear factor NF-κB kinase subunit-ß (IKKß), characterized by phosphorylation of activation loop serine residues 177 and 181, has been implicated in the early onset of cancer. On the other hand, tissue-specific IKKß knockout in Kras mutation-driven mouse models stalled the disease in the precancerous stage. In this study, we used cell line models, tumor growth studies, and patient samples to assess the role of IKKß and its activation in cancer. We also conducted a hit-to-lead optimization study that led to the identification of 39-100 as a selective mitogen-activated protein kinase kinase kinase (MAP3K) 1 inhibitor. We show that IKKß is not required for growth of Kras mutant pancreatic cancer (PC) cells but is critical for PC tumor growth in mice. We also observed elevated basal levels of activated IKKß in PC cell lines, PC patient-derived tumors, and liver metastases, implicating it in disease onset and progression. Optimization of an ATP noncompetitive IKKß inhibitor resulted in the identification of 39-100, an orally bioavailable inhibitor with improved potency and pharmacokinetic properties. The compound 39-100 did not inhibit IKKß but inhibited the IKKß kinase MAP3K1 with low-micromolar potency. MAP3K1-mediated IKKß phosphorylation was inhibited by 39-100, thus we termed it IKKß activation modulator (IKAM) 1. In PC models, IKAM-1 reduced activated IKKß levels, inhibited tumor growth, and reduced metastasis. Our findings suggests that MAP3K1-mediated IKKß activation contributes to KRAS mutation-associated PC growth and IKAM-1 is a viable pretherapeutic lead that targets this pathway.

Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells.

The unfolded protein response (UPR) is an adaptation mechanism activated to resolve transient accumulation of unfolded/misfolded proteins in the endoplasmic reticulum. Failure to resolve the transient accumulation of such proteins results in UPR-mediated programmed cell death. Loss of tumor suppressor gene or oncogene addiction in cancer cells can result in sustained higher basal UPR levels; however, it is not clear if these higher basal UPR levels in cancer cells can be exploited as a therapeutic strategy. We hypothesized that covalent modification of surface-exposed cysteine (SEC) residues could simulate unfolded/misfolded proteins to activate the UPR, and that higher basal UPR levels in cancer cells would provide the necessary therapeutic window. To test this hypothesis, here we synthesized analogs that can covalently modify multiple SEC residues and evaluated them as UPR activators. We identified a spirocyclic dimer, SpiD7, and evaluated its effects on UPR activation signals, that is, XBP1 splicing, phosphorylation of eIF2α, and a decrease in ATF 6 levels, in normal and cancer cells, which were further confirmed by RNA-Seq analyses. We found that SpiD7 selectively induced caspase-mediated apoptosis in cancer cells, whereas normal cells exhibited robust XBP1 splicing, indicating adaptation to stress. Furthermore, SpiD7 inhibited the growth of high-grade serous carcinoma cell lines ~3-15-fold more potently than immortalized fallopian tube epithelial (paired normal control) cells and reduced clonogenic growth of high-grade serous carcinoma cell lines. Our results suggest that induction of the UPR by covalent modification of SEC residues represents a cancer cell vulnerability and can be exploited to discover novel therapeutics.

Molecular mechanisms of neuroprotective offerings by rosmarinic acid against neurodegenerative and other CNS pathologies.

Rosmarinic acid (RA) is a natural phenolic compound present in culinary herbs of the Boraginaceae, Lamiaceae/Labiatae, and Nepetoideae families. While the medicinal applications of these plants have been known for ages, RA has only been relatively recently established as an effective ameliorative agent against various disorders including cardiac diseases, cancer, and neuropathologies. In particular, several studies have confirmed the neuroprotective potential of RA in multiple cellular and animal models, as well as in clinical studies. The neuroprotective effects mediated by RA stem from its multimodal actions on a plethora of cellular and molecular pathways; including oxidative, bioenergetic, neuroinflammatory, and synaptic signaling. In recent years, RA has garnered tremendous interest as an ideal therapeutic candidate for treating neurodegenerative diseases. This review first briefly discusses the pharmacokinetics of RA and then proceeds to detail the neuroprotective mechanisms of RA at the molecular levels. Finally, the authors focus on the ameliorative potential of RA against several central nervous system (CNS) disorders, ranging from neuropsychological stress and epilepsy to neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, and amyotrophic lateral sclerosis.

Neurological Emergencies in the Intensive Care Unit.

Neurological emergencies carry significant morbidity and mortality, and it is necessary to have a multidisciplinary approach involving the emergency physician, the neurologist, the intensivist, and the critical care nursing staff. These disorders can be broadly divided into noninfectious and infectious etiologies. In this article, we review a few of the neurological emergencies that present to the neurological intensive unit, with emphasis on convulsive status epileptics, myasthenia gravis, Guillain-Barré syndrome, meningitis, encephalitis, and brain abscess.

Dimers of isatin derived α-methylene-γ-butyrolactone as potent anti-cancer agents.

The IKK-NFκB complex is a key signaling node that facilitates activation of gene expression in response to extracellular signals. The kinase IKKß and the transcription factor RELA have been targeted by covalent modifiers that bind to surface exposed cysteine residues. A common feature in well characterized covalent modifiers of RELA and IKKß is the Michael acceptor containing α-methylene-γ-butyrolactone functionality. Through synthesis and evaluation of a focused set of α-methylene-γ-butyrolactone containing spirocyclic dimers (SpiDs) we identified SpiD3 as an anticancer agent with low nanomolar potency. Using cell-free and cell-based studies we show that SpiD3 is a covalent modifier that generates stable RELA containing high molecular weight complexes. SpiD3 inhibits TNFα-induced IκBα phosphorylation resulting in the blockade of RELA nuclear translocation. SpiD3 induces apoptosis, inhibits colony formation and migration of cancer cells. The NCI-60 cell line screen revealed that SpiD3 potently inhibits growth of leukemia cell lines, making it a suitable pre-therapeutic lead for hematological malignancies.

Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax.

Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC50 = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition.

Postoperative hemodynamics after high spinal block with or without intrathecal morphine in cardiac surgical patients: a randomized-controlled trial.

PURPOSE: There is some evidence for the use of intrathecal morphine as a means to provide prolonged analgesia in selective cardiac surgical patients; however, the hemodynamic effects of intrathecal morphine are not well defined. This study was designed to study the effect of intrathecal morphine on hemodynamic parameters in cardiac surgery patients. METHODS: In a prospective, double-blind study, 100 adult cardiac surgical patients were randomized to receive either intrathecal 40 mg of 0.5% hyperbaric bupivacaine alone (intrathecal bupivacaine [ITB] group, n = 50) or intrathecal 250 µg of morphine added to 40 mg of 0.5% bupivacaine (intrathecal bupivacaine and morphine [ITBM] group, n = 50). Hemodynamic data, pain scores, rescue analgesic use, spirometry, and vasopressor use were recorded every four hours after surgery for 48 hr. The primary outcome was the incidence of vasoplegia in each group, which was defined as a cardiac index > 2.2 L·min-1·m-2 with the requirement of vasopressors to maintain the mean arterial pressure > 60 mmHg with the hemodynamic episode lasting > four hours. RESULTS: Eighty-seven patients were analyzed (ITB group, n = 42, and ITBM group, n =45). The incidence of vasoplegia was higher in the ITBM group than in the ITB group [14 (31%) vs 5 (12%), respectively; relative risk, 2.6; 95% confidence interval [CI], 1.0 to 6.6; P = 0.04]. The mean (standard deviation [SD]) duration of vasoplegia was significantly longer in the ITBM group than in the ITB group [8.9 (3.0) hr vs 4.3 (0.4) hr, respectively; difference in means, 4.6; 95% CI, 3.7 to 5.5; P < 0.001]. CONCLUSION: Intrathecal morphine added to bupivacaine for high spinal anesthesia increases the incidence and duration of vasoplegia in cardiac surgery patients. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02825056); registered 19 June 2016.

RéSUMé: OBJECTIF : Certaines données probantes appuient l'utilisation de morphine intrathécale pour une analgésie prolongée chez certains patients de chirurgie cardiaque; cependant, les effets hémodynamiques de la morphine intrathécale ne sont pas bien définis. Cette étude a été conçue pour évaluer l'effet de la morphine intrathécale sur les paramètres hémodynamiques de patients de chirurgie cardiaque. MéTHODE : Dans une étude prospective et à double insu, 100 patients adultes de chirurgie cardiaque ont été randomisés à recevoir 40 mg de bupivacaïne hyperbare 0,5 % intrathécale (groupe bupivacaïne intrathécale [BIT], n = 50) ou 250 µg de morphine intrathécale ajoutés à 40 mg de bupivacaïne 0,5 % (groupe bupivacaïne et morphine intrathécales [BMIT], n = 50). Les données hémodynamiques, les scores de douleur, l'utilisation d'analgésiques, la spirométrie et l'utilisation de vasopresseurs ont été enregistrés toutes les quatre heures après la chirurgie pendant 48 heures. Le critère d'évaluation principal était l'incidence de vasoplégie dans chaque groupe, définie comme un index cardiaque > 2,2 L·min-1·m2 nécessitant des vasopresseurs pour maintenir la tension artérielle moyenne > 60 mmHg avec une durée de plus de quatre heures. RéSULTATS : Quatre-vingt-sept patients ont été analysés (groupe BIT, n = 42, et groupe BMIT, n = 45). L'incidence de vasoplégie était plus élevée dans le groupe BMIT que dans le groupe BIT [14 (31%) vs 5 (12 %), respectivement; risque relatif, 2,6; intervalle de confiance [IC] 95 %, 1,0 à 6,6; P = 0,04]. La durée moyenne (écart type [ÉT]) de la vasoplégie était significativement plus longue dans le groupe BMIT que dans le groupe BIT [8,9 (3,0) h vs 4,3 (0,4) h, respectivement; différence de moyennes, 4,6; IC 95 %, 3,7 à 5,5; P < 0,001]. CONCLUSION : L'ajout de morphine intrathécale à la bupivacaïne pour une anesthésie rachidienne haute augmente l'incidence et la durée de la vasoplégie chez les patients de chirurgie cardiaque. ENREGISTREMENT DE L'éTUDE : www.clinicaltrials.gov ; (NCT02825056); enregistrée le 19 juin 2016.

Clinical characteristics and clinical predictors of mortality in hospitalised patients of COVID 19 : An Indian study.

BACKGROUND: The rapid spread of the coronavirus disease 2019 (COVID-19) with high mortality rate necessitates disease characterization and accurate prognostication for prompt clinical decision-making. The aim of this study is to study clinical characteristics and predictors of mortality in hospitalized patients with COVID-19 in India. METHODS: Retrospective cohort study was conducted in a tertiary care hospital in northern India. All consecutive confirmed hospitalized COVID-19 cases aged 15 years and older from 13 Apr till 31 Aug 2020 are included. Primary end point was 30-day mortality. RESULTS: Of 1622 patients ,1536 cases were valid. Median age was 36 years, 88.3% were men and 58.1% were symptomatic. Fever (37.6%) was commonest presenting symptom. Dyspnea was reported by 15.4%. Primary hypertension (8.5%) was commonest comorbidity, followed by diabetes mellitus (6.7%). Mild, moderate, and severe hypoxemia were seen in 3.4%, 4.3%, and 0.8% respectively. Logistic regression showed greater odds of moderate/severe disease in patients with dyspnea, hypertension, Chronic Kidney Disease (CKD), and malignancy. Seventy six patients died (4.9%). In adjusted Cox proportional hazards model for mortality, patients with dyspnea (hazard ratio [HR]: 14.449 [5.043-41.402]), altered sensorium (HR: 2.762 [1.142-6.683]), Diabetes Mellitus (HR: 1.734 [1.001-3.009]), malignancy (HR:10.443 [4.396-24.805]) and Chronic Liver Disease (CLD) (HR: 14.432 [2.321-89.715]) had higher risk. Rising respiratory rate (HR: 1.098 [1.048-1.150]), falling oxygen saturation (HR: 1.057 per unit change 95% CI: 1.028-1.085) were significant predictors. CONCLUSION: Analysis suggests that age, dyspnea, and malignancy were associated with both severe disease and mortality. Diabetes Mellitus and Chronic Liver Disease were associated with increased the risk of fatal outcome. Simple clinical parameters such as respiratory rate and oxygen saturation are strong predictors and with other risk factors at admission can be effectively used to triage patients.

To Maintain Formulation Composition Similarity of Coated Tablets of Different Strengths: Should Coating be Based on Core Tablet Weight or Surface Area?

PURPOSE: As per the Japanese or SUPAC guidance to maintain formulation composition similarity across tablet strengths, the coating should be applied based on the core tablet surface area or weight, respectively. These two coating approaches were compared by evaluating protective effects of coating on the light stability of three model compounds. METHODS: Core tablets of three light sensitive drugs, nifedipine, rosuvastatin calcium, and montelukast sodium were coated either with PVA-based Opadry® II white or Opadry® II beige. The coated tablets were exposed to light up to three ICH cycles. RESULTS: For Opadry® II white, the surface area based coating provided consistent light protection across tablet strengths when the coating amount was more than 0.1 mg/mm2 compared to that based on core tablet weights. For Opadry® II beige, both approaches gave comparable and better light protection due to presence of iron oxides. The light protection by Opadry® II white could be because of physical barrier of coating, which was uniform across the strengths when it was based on core tablet surface area. CONCLUSION: For a routine tablet formulation development with Opadry color coating, it does not matter whether the coating is applied based on the core tablet surface area or weight.

Synthesis and SAR studies of novel 1,2,4-oxadiazole-sulfonamide based compounds as potential anticancer agents for colorectal cancer therapy.

A diverse series of 1,2,4-oxadiazoles based substituted compounds were designed, synthesized and evaluated as anticancer agents targeting carbonic anhydrase IX (CAIX). Initial structure-activity analysis suggested that the thiazole/thiophene-sulfonamide conjugates of 1,2,4-oxadiazoles exhibited potent anticancer activities with low µM potencies. Compound OX12 exhibited antiproliferative activity (IC50 = 11.1 µM) along with appreciable inhibition potential for tumor-associated CAIX (IC50 = 4.23 µM) isoform. Therefore, OX12 was structurally optimized and its SAR oriented derivatives (OX17-27) were synthesized and evaluated. This iteration resulted in compound OX27 with an almost two-fold increase in antiproliferative effect (IC50 = 6.0 µM) comparable to the clinical drug doxorubicin and significantly higher potency against CAIX (IC50 = 0.74 µM). Additionally, OX27 treatment decreases the expression of CAIX, induces apoptosis and ROS production, inhibited colony formation and migration of colon cancer cells. Our studies provide preclinical rational for the further optimization of identified OX27 as a suitable lead for the possible treatment of CRC.

Rapid Arterial Occlusion Evaluation Scale Agreement between Emergency Medical Services Technicians and Neurologists.

BACKGROUND: Rapid arterial occlusion evaluation (RACE) scale is a valid prehospital tool used to predict large vessel occlusion of major cerebral arteries in patients with suspected acute stroke. RACE scale administered by Emergency medicine services (EMS) technicians in the prehospital setting correlates well with NIH Stroke Scale score after patient arrival at a hospital. Despite this, the RACE scale is often characterized as too difficult for EMS technicians to accurately utilize. There are no data examining RACE scale accuracy in the prehospital setting comparing EMS technicians with neurologists. We sought to examine agreement between RACE scores calculated by EMS technicians and stroke neurologists in the prehospital setting during telestroke consultation. METHODS: Data for this observational cohort study were prospectively collected and retrospectively analyzed. EMS technicians in person and stroke specialized neurologists via televideo connection independently assessed suspected stroke patients and calculated RACE scores in the prehospital setting. We used a linearly weighted Cohen's kappa (kw) to estimate the extent of agreement for RACE score between EMS technicians and stroke neurologists. RESULTS: Thirty-one patients with stroke symptoms were independently examined and assessed with the RACE scale by EMS technicians and stroke neurologists in the prehospital setting. Exact agreement on the RACE score was found in 24 of 31 (77%) patients. We found very good agreement between EMS technicians and stroke neurologists, kw = .818 (95% CI, .677-.960), P< .001. CONCLUSIONS: EMS technicians provide reliable RACE assessments in patients with suspected stroke, with agreement similar to stroke specialized neurologists in the prehospital setting.

CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax.

Developing small molecules that indirectly regulate Mcl-1 function has attracted a lot of attention in recent years. Here, we report the discovery of an aminopyrazole, 2-([1,1'-biphenyl]-4-yl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)acetamide (analog 24), which selectively inhibited cyclin-dependent kinase (CDK) 5 over CDK2 in cancer cell lines. We also show that analog 24 reduced Mcl-1 levels in a concentration-dependent manner in cancer cell lines. Using a panel of doxycycline inducible cell lines, we show that CDK5 inhibitor 24 selectively modulates Mcl-1 function while the CDK4/6 inhibitor 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-day]pyrimidin-7(8H)-one does not. Previous studies using RNA interference and CRISPR showed that concurrent elimination of Bcl-xL and Mcl-1 resulted in induction of apoptosis. In pancreatic cancer cell lines, we show that either CDK5 knockdown or expression of a dominant negative CDK5 results in synergistic induction of apoptosis. Moreover, concurrent pharmacological perturbation of Mcl-1 and Bcl-xL in pancreatic cancer cell lines using a CDK5 inhibitor analog 24 that reduced Mcl-1 levels and 4-(4-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl] benzamide (navitoclax), a Bcl-2/Bcl-xL/Bcl-w inhibitor, resulted in synergistic inhibition of cell growth and induction of apoptosis. In conclusion, we demonstrate targeting CDK5 will sensitize pancreatic cancers to Bcl-2 protein inhibitors. SIGNIFICANCE STATEMENT: Mcl-1 is stabilized by CDK5-mediated phosphorylation in pancreatic ductal adenocarcinoma, resulting in the deregulation of the apoptotic pathway. Thus, genetic or pharmacological targeting of CDK5 sensitizes pancreatic cancers to Bcl-2 inhibitors, such as navitoclax.

Selective degradation of CDK6 by a palbociclib based PROTAC.

Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.

Myocardial protection and clinical outcomes in Tetralogy of Fallot patients undergoing intracardiac repair: a randomized study of two cardioplegic techniques.

BACKGROUND: Myocardial protection in Tetralogy of Fallot patients undergoing intracardiac repair is suboptimal due to hypertrophied right ventricle. Hypertrophied myocardium is more susceptible to poor myocardial preservation because of inadequate capillary density as compared to the myocytes. There is a capillary to myocyte ratio mismatch. But del Nido Cardioplegia owing to its less viscosity is able to get more evenly distributed under hypothermic cardiopulmonary bypass as opposed to blood Cardioplegia. We hypothesized that the del Nido Cardioplegia technique, would be beneficial in myocardial protection because of its composition and method of delivery, leading into better early and late clinical outcomes in patients undergoing Tetralogy of Fallot repair as compared to blood cardioplegia reconstituted using St Thomas Cardioplegia solution. The objective of the study was to identify a better technique of myocardial preservation in Tetralogy of Fallot patient. METHODS: In total, 56 Tetralogy of Fallot patients undergoing intracardiac repair under mild hypothermic cardiopulmonary bypass were randomly allocated to receive antegrade Cardioplegia with either standard blood Cardioplegia (Group I) or del Nido Cardioplegia (Group II). Preoperative as well as postoperative data including echocardiographic parameters for right ventricle functions, creatine kinase MB level, inotropic requirement, mechanical ventilation duration, intensive care unit stay and hospital mortality were evaluated. RESULTS: Inotropic score in the first 24 hours postoperatively was significantly lower in Group II compared to Group I (13.4 ± 7.2 vs. 21.2 ± 9.6, p = 0.003). Creatine kinase MB level (ng/mL) was comparable between the groups. Echocardiographic parameters for right ventricle functions were also comparable between the groups during early as well as after 3 to 6 months postoperatively. CONCLUSION: Del Nido Cardioplegia is equally efficacious in providing myocardial protection during intracardiac repair under mild hypothermic cardiopulmonary bypass in Tetralogy of Fallot patients as compared to blood Cardioplegia solution with the added benefit of reducing inotropic requirement in first 24 hours postoperative period.

Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy.

We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution for the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.

Variation in properties of tender jackfruit during different stages of maturity.

This research was conducted on two varieties of tender jackfruit [hard (HV) and soft variety (SV)]. The tender jackfruit was divided into four stages (i.e. Stage 1, 2, 3 and 4) and their physical, mechanical, chemical and textural properties were determined for both the varieties. Physical properties like weight, length, diameter, geometric mean and arithmetic mean diameter were increases with increase in size for both the varieties. There was a significant increase in TSS in both the varieties (HV: 1.5 ± 0.02 to 5.1 ± 0.03; SV: 2.7 ± 0.05 to 7.1 ± 0.05 oBrix) from stage 1 to 4 because of ripening of fruit. The hardness, fracturability and springiness increases with maturity but on the counterpart, there is a decrease in adhesiveness, cohesiveness, chewiness and gumminess. The nutritional properties and the energy (kj) values were inevitable increases whereas vitamins content was decreases from stage 1 to 4 in both the varieties. The measured properties will be helpful in planning, design and fabrication of post-harvest processing equipment for tender jackfruits.

Nasal mask ventilation is better than face mask ventilation in edentulous patients.

BACKGROUND AND AIMS: Face mask ventilation of the edentulous patient is often difficult as ineffective seating of the standard mask to the face prevents attainment of an adequate air seal. The efficacy of nasal ventilation in edentulous patients has been cited in case reports but has never been investigated. MATERIAL AND METHODS: Consecutive edentulous adult patients scheduled for surgery under general anesthesia with endotracheal intubation, during a 17-month period, were prospectively evaluated. After induction of anesthesia and administration of neuromuscular blocker, lungs were ventilated with a standard anatomical face mask of appropriate size, using a volume controlled anesthesia ventilator with tidal volume set at 10 ml/kg. In case of inadequate ventilation, the mask position was adjusted to achieve best-fit. Inspired and expired tidal volumes were measured. Thereafter, the face mask was replaced by a nasal mask and after achieving best-fit, the inspired and expired tidal volumes were recorded. The difference in expired tidal volumes and airway pressures at best-fit with the use of the two masks and number of patients with inadequate ventilation with use of the masks were statistically analyzed. RESULTS: A total of 79 edentulous patients were recruited for the study. The difference in expiratory tidal volumes with the use of the two masks at best-fit was statistically significant (P = 0.0017). Despite the best-fit mask placement, adequacy of ventilation could not be achieved in 24.1% patients during face mask ventilation, and 12.7% patients during nasal mask ventilation and the difference was statistically significant. CONCLUSION: Nasal mask ventilation is more efficient than standard face mask ventilation in edentulous patients.

Irreversible binding of an anticancer compound (BI-94) to plasma proteins.

1. We investigated the mechanisms responsible for the in vivo instability of a benzofurazan compound BI-94 (NSC228148) with potent anti-cancer activity. 2. BI-94 was stable in MeOH, water, and in various buffers at pHs 2.5-5, regardless of the buffer composition. In contrast, BI-94 was unstable in NaOH and at pHs 7-9, regardless of the buffer composition. BI-94 disappeared immediately after spiking into mice, rat, monkey, and human plasma. BI-94 stability in plasma can be only partially restored by acidifying it, which indicated other mechanisms in addition to pH for BI-94 instability in plasma. 3. BI-94 formed adducts with the trapping agents, glutathione (GSH) and N-acetylcysteine (NAC), in vivo and in vitro via nucleophilic aromatic substitution reaction. The kinetics of adduct formation showed that neutral or physiological pHs enhanced and accelerated GSH and NAC adduct formation with BI-94, whereas acidic pHs prevented it. Therefore, physiological pHs not only altered BI-94 chemical stability but also enhanced adduct formation with endogenous nucleophiles. In addition, adduct formation with human serum albumin-peptide 3 (HSA-T3) at the Cys34 position was demonstrated. 4. In conclusion, BI-94 was unstable at physiological conditions due to chemical instability and irreversible binding to plasma proteins.

Environmental and occupational risk factors for amyotrophic lateral sclerosis: a case-control study.

BACKGROUND/AIMS: Environmental and occupational exposures are implicated as risk factors for amyotrophic lateral sclerosis (ALS), the etiology of which is largely unknown, although no causal relationships have been established. OBJECTIVE: The aim of the study was to evaluate the associations of personal risk factors and self-reported environmental and occupational exposures with risk of ALS. METHODS: The cases involved ALS patients (n = 66) identified from major neurological centers in Pittsburgh and Philadelphia, Pa., USA, from 2008 to 2010. The age-, race- and sex-matched controls included outpatient hospital and population-based controls (n = 66). A detailed questionnaire obtaining data on occupation, vocational and avocational exposure as well as personal lifestyle factors was administered. RESULTS: Occupational exposure to metals (odds ratio, OR = 3.65; 95% CI: 1.15, 11.60) and pesticides (OR = 6.50; 95% CI: 1.78, 23.77) was related to increased risk of ALS after controlling for smoking and education. No associations were found for occupational exposure to organic or aromatic solvents. CONCLUSION: Workers exposed to metals and pesticides may be at greater risk of ALS. Future research should involve more accurate exposure assessment through the use of job exposure matrices, confirmation of occupation and biomarkers.