John ngell Veterans Affairs Medical Center

Detroit, United States

John ngell Veterans Affairs Medical Center

Detroit, United States
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Mateika J.H.,John ngell Veterans Affairs Medical Center | Mateika J.H.,Wayne State University | Komnenov D.,John ngell Veterans Affairs Medical Center | Komnenov D.,Wayne State University
Experimental Neurology | Year: 2017

Over the past three decades exposure to intermittent hypoxia (IH) has generally been considered a stimulus associated with a number of detrimental outcomes. However, there is sufficient evidence to link IH to many beneficial outcomes but they have largely been ignored, particularly in the field of sleep medicine in the United States. Recent reviews have postulated that this apparent contradiction is related to the severity and duration of exposure to IH; mild forms of IH initiate beneficial outcomes while severe forms of IH are coupled to detrimental consequences. In the present review we explore the role that IH has in initiating respiratory plasticity and the potential this form of plasticity has to mitigate obstructive sleep apnea (OSA) in humans. In taking this approach, we address the possibility that IH could serve as an adjunct therapy coupled with continuous positive airway pressure (CPAP) to treat OSA. Our working hypothesis is that exposure to mild IH leads to respiratory plasticity that manifests in increased stability of the upper airway, which could ultimately reduce the CPAP required to treat OSA. In turn, this reduction could increase CPAP compliance and extend the length of treatment each night, which might improve the magnitude of outcome measures. Improved treatment compliance coupled with the direct effect that IH has on numerous overlapping conditions (i.e. asthma, chronic obstructive pulmonary disease, spinal cord injury) may well lead to substantial improvements that exceed outcomes following treatment with CPAP alone. Overall, this review will consider evidence from the published literature which suggests that IH could serve as an effective multipronged therapeutic approach to treat sleep apnea and its overlapping co-morbidities. © 2016


Rhodes C.J.,University of Chicago | Kowluru R.A.,Wayne State University | Kowluru A.,John ngell Veterans Affairs Medical Center
Diabetes | Year: 2011

OBJECTIVE - To determine the subunit expression and functional activation of phagocyte-like NADPH oxidase (Nox), reactive oxygen species (ROS) generation and caspase-3 activation in the Zucker diabetic fatty (ZDF) rat and diabetic human islets. RESEARCH DESIGN AND METHODS - Expression of core components of Nox was quantitated by Western blotting and densitometry. ROS levels were quantitated by the 2′,7′- dichlorofluorescein diacetate method. Rac1 activation was quantitated using the gold-labeled immunosorbent assay kit. RESULTS - Levels of phosphorylated p47 phox, active Rac1, Nox activity, ROS generation, Jun NH 2-terminal kinase (JNK) 1/2 phosphorylation, and caspase-3 activity were significantly higher in the ZDF islets than the lean control rat islets. Chronic exposure of INS 832/13 cells to glucolipotoxic conditions resulted in increased JNK1/2 phosphorylation and caspase-3 activity; such effects were largely reversed by SP600125, a selective inhibitor of JNK. Incubation of normal human islets with high glucose also increased the activation of Rac1 and Nox. Lastly, in a manner akin to the ZDF diabetic rat islets, Rac1 expression, JNK1/2, and caspase-3 activation were also significantly increased in diabetic human islets. CONCLUSIONS - We provide the first in vitro and in vivo evidence in support of an accelerated Rac1-Nox-ROS-JNK1/2 signaling pathway in the islet β-cell leading to the onset of mitochondrial dysregulation in diabetes. © 2011 by the American Diabetes Association.


Werth B.J.,Anti Infective Research Laboratory | Steed M.E.,Anti Infective Research Laboratory | Kaatz G.W.,Wayne State University | Kaatz G.W.,John ngell Veterans Affairs Medical Center | And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

A seesaw effect" in methicillin-resistant Staphylococcus aureus (MRSA) has been demonstrated, whereby susceptibility to β-lactam antimicrobials increases as glyco- and lipopeptide susceptibility decreases. We investigated this effect by evaluating the activity of the anti-MRSA cephalosporin ceftaroline against isogenic pairs of MRSA strains with various susceptibilities to vancomycin in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activities of ceftaroline at 600 mg every 12 h (q12h) (targeted free maximum concentration of drug in serum [fCmax], 15.2 μg/ml; half-life [t1/2], 2.3 h) and vancomycin at 1 g q12h (targeted fCmax, 18 μg/ml; t1/2, 6 h) were evaluated against 3 pairs of isogenic clinical strains of MRSA that developed increased MICs to vancomycin in patients while on therapy using a two-compartment hollow-fiber PK/PD model with a starting inoculum of ̃ 107 CFU/ml over a 96-h period. Bacterial killing and development of resistance were evaluated. Expression of penicillin- binding proteins (PBPs) 2 and 4 was evaluated by reverse transcription (RT)-PCR. The achieved pharmacokinetic parameters were 98 to 119% of the targeted values. Ceftaroline and vancomycin were bactericidal against 5/6 and 1/6 strains, respectively, at 96 h. Ceftaroline was more active against the mutant strains than the parent strains, with this difference being statistically significant for 2/3 strain pairs at 96 h. The level of PBP2 expression was 4.4higher in the vancomycin-intermediate S. aureus (VISA) strain in 1/3 pairs. The levels of PBP2 and PBP4 expression were otherwise similar between the parent and mutant strains. These data support the seesaw hypothesis that ceftaroline, like traditional β-lactams, is more active against strains that are less susceptible to vancomycin even when the ceftaroline MICs are identical. Further research to explore these unique findings is warranted. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Mateika J.H.,John ngell Veterans Affairs Medical Center | Mateika J.H.,Wayne State University | Syed Z.,John ngell Veterans Affairs Medical Center | Syed Z.,Wayne State University
Respiratory Physiology and Neurobiology | Year: 2013

This review examines the role that respiratory plasticity has in the maintenance of breathing stability during sleep in individuals with sleep apnea. The initial portion of the review considers the manner in which repetitive breathing events may be initiated in individuals with sleep apnea. Thereafter, the role that two forms of respiratory plasticity, progressive augmentation of the hypoxic ventilatory response and long-term facilitation of upper airway and respiratory muscle activity, might have in modifying breathing events in humans is examined. In this context, present knowledge regarding the initiation of respiratory plasticity in humans during wakefulness and sleep is addressed. Also, published findings which reveal that exposure to intermittent hypoxia promotes breathing instability, at least in part, because of progressive augmentation of the hypoxic ventilatory response and the absence of long-term facilitation, are considered. Next, future directions are presented and are focused on the manner in which forms of plasticity that stabilize breathing might be promoted while diminishing destabilizing forms, concurrently. These future directions will consider the potential role of circadian rhythms in the promotion of respiratory plasticity and the role of respiratory plasticity in enhancing established treatments for sleep apnea. © 2013.


Wei H.,Wayne State University | Vander Heide R.S.,Wayne State University | Vander Heide R.S.,John ngell Veterans Affairs Medical Center
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2010

Heat stress (HS)-induced cardioprotection is associated with the activation of focal adhesion kinase (FAK) and protein kinase B (Akt) in neonatal rat ventricular myocytes (NRVMs), suggesting that stress-induced activation of survival pathways may be important in protecting intact hearts from irreversible injury. The purposes of this study were 1) to examine the subcellular signaling pathways activated by HS and ischemic preconditioning (IP) in intact hearts, 2) to determine whether HS and IP activate an integrated survival pathway similar to that activated by HS in cultured NRVMs, and 3) to determine whether HS and IP reduce lethal cell injury in perfused intact hearts. Adult rat hearts perfused in the Langendorff mode were subjected to 25 min of global ischemia and 30 min of reperfusion (I/R) either 24 h after whole animal HS or following a standard IP protocol. Myocardial signaling was analyzed using Western blot analysis, whereas cell death was assayed by measuring lactate dehydrogenase release into the perfusate and confirmed by light microscopy. Similar to NRVMs, HS performed in the whole animal 24 h before I/R increased phosphorylation of FAK at tyrosine-397 and protein kinase B (Akt) and resulted in protection from cell death. Using IP as a myocardial stress also resulted in an increased phosphorylation/activation of both FAK and Akt and resulted in reduced cell death in adult perfused rat hearts subjected to I/R. In conclusion, 1) myocardial stress caused by whole animal HS activates cytoskeletal-based survival signaling pathways in whole heart tissue and reduces lethal I/R injury and 2) IP activates the same stress-induced survival pathway and the activation correlates with the well-known cardioprotective effect of IP on lethal I/R injury.


Tester N.J.,Brain Rehabilitation Research Center | Tester N.J.,University of Florida | Fuller D.D.,University of Florida | Fromm J.S.,University of Florida | And 6 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: Intermittent stimulation of the respiratory system with hypoxia causes persistent increases in respiratory motor output (i.e., long-term facilitation) in animals with spinal cord injury. This paradigm, therefore, has been touted as a potential respiratory rehabilitation strategy. Objectives: To determine whether acute (daily) exposure to intermittent hypoxia can also evoke long-term facilitation of ventilation after chronic spinal cord injury in humans, and whether repeated daily exposure to intermittent hypoxia enhances the magnitude of this response. Methods: Eight individuals with incomplete spinal cord injury (>1 yr; cervical [n = 6], thoracic [n = 2]) were exposed to intermittent hypoxia (eight 2-min intervals of 8% oxygen) for 10 days. During all exposures, end-tidal carbon dioxide levels were maintained, on average, 2 mm Hg above resting values. Minute ventilation, tidal volume, and breathing frequency were measured before (baseline), during, and 30 minutes after intermittent hypoxia. Sham protocols consisted of exposure to room air and were administered to a subset of the participants (n = 4). Measurements and Main Results: Minute ventilation increased significantly for 30 minutes after acute exposure to intermittent hypoxia (P < 0.001), but not after sham exposure. However, the magnitude of ventilatory long-term facilitation was not enhanced over 10 days of intermittent hypoxia exposures. Conclusions: Ventilatory long-term facilitation can be evoked by brief periods of hypoxia in humans with chronic spinal cord injury. Thus, intermittent hypoxia may represent a strategy for inducing respiratory neuroplasticity after declines in respiratory function that are related to neurological impairment. Clinical trial registered with www.clinicaltrials.gov (NCT01272011). Copyright © 2014 by the American Thoracic Society.


Barber K.E.,Wayne State University | Werth B.J.,Wayne State University | McRoberts J.P.,Wayne State University | Rybaka M.J.,John ngell Veterans Affairs Medical Center
Antimicrobial Agents and Chemotherapy | Year: 2014

Medical device infections frequently require combination therapy. Beta-lactams combined with glycopeptides/lipopeptides are bactericidal against methicillin-resistant Staphylococcus aureus (MRSA). Novel macrowell kill-curve methods tested synergy between ceftaroline or cefazolin plus daptomycin, vancomycin, or rifampin against biofilm-producing MRSA. Ceftaroline combinations demonstrated the most pronounced bacterial reductions. Ceftaroline demonstrated greatest kill with daptomycin (4.02±0.59 log10 CFU/cm 2), compared to combination with vancomycin (3.36±0.35 log10 CFU/cm2) or rifampin (2.68±0.61 log10 CFU/cm2). These data suggest that beta-lactam combinations are useful against MRSA biofilms.© 2014, American Society for Microbiology.


Solarewicz J.Z.,John ngell Veterans Affairs Medical Center
American journal of physiology. Regulatory, integrative and comparative physiology | Year: 2015

We examined the role that serotonin has in the modulation of sleep and wakefulness across a 12-h:12-h light-dark cycle and determined whether temperature and motor activity are directly responsible for potential disruptions to arousal state. Telemetry transmitters were implanted in 24 wild-type mice (Tph2(+/+)) and 24 mice with a null mutation for tryptophan hydroxylase 2 (Tph2(-/-)). After surgery, electroencephalography, core body temperature, and motor activity were recorded for 24 h. Temperature for a given arousal state (quiet and active wake, non-rapid eye movement, and paradoxical sleep) was similar in the Tph2(+/+) and Tph2(-/-) mice across the light-dark cycle. The percentage of time spent in active wakefulness, along with motor activity, was decreased in the Tph2(+/+) compared with the Tph2(-/-) mice at the start and end of the dark cycle. This difference persisted into the light cycle. In contrast, the time spent in a given arousal state was similar at the remaining time points. Despite this similarity, periods of non-rapid-eye-movement sleep and wakefulness were less consolidated in the Tph2(+/+) compared with the Tph2(-/-) mice throughout the light-dark cycle. We conclude that the depletion of serotonin does not disrupt the diurnal variation in the sleep-wake cycle, motor activity, and temperature. However, serotonin may suppress photic and nonphotic inputs that manifest at light-dark transitions and serve to shorten the ultraradian duration of wakefulness and non-rapid-eye-movement sleep. Finally, alterations in the sleep-wake cycle following depletion of serotonin are unrelated to disruptions in the modulation of temperature.


Van Dyke S.A.,John ngell Veterans Affairs Medical Center | Axelrod B.N.,John ngell Veterans Affairs Medical Center | Schutte C.,John ngell Veterans Affairs Medical Center
Military Medicine | Year: 2010

The Traumatic Brain Injury Screening Instrument (TBISI) was implemented in Veterans Affairs medical facilities in an attempt to identify Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans with possible mild TBI. Despite its widespread implementation, the reliability and validity of the screening tool has not yet been established. The current study reports preliminary findings on the test-retest reliability of the TBISI in 44 OEF/OIF veterans referred for neuropsychological evaluation following a positive TBI screen. Results suggest overall poor testretest reliability of the TBI screening tool with regard to type of event, injuries sustained, and resulting sequelae. These findings underscore the importance of further investigation of its psychometric properties to promote accurate identification and referral of veterans with possible TBI. Copyright © Association of Military Surgeons of the US. All rights reserved.


Wang S.,Michigan State University | Wang S.,John ngell Veterans Affairs Medical Center | Basson M.D.,Michigan State University | Basson M.D.,John ngell Veterans Affairs Medical Center
American Journal of Physiology - Cell Physiology | Year: 2011

Although focal adhesion kinase (FAK) is typically considered upstream of Akt, extracellular pressure stimulates cancer cell adhesion via Akt-dependent FAK activation. How Akt regulates FAK is unknown. We studied Akt-FAK interaction in colon cancer cells under 15 mmHg increased extracellular pressure. Pressure enhanced Akt-FAK association, blocked by inhibiting FAK or silencing Akt1 but not Akt2, and stimulated FAK serine phosphorylation in Caco-2 and human colon cancer cells from surgical specimens Akt1-dependently. FAK includes three serine (S517/601/695) and one threonine (T600)-containing consensus sequences for Akt phosphorylation. Studying S->A nonphosphorylatable point mutants suggests that these sites coordinately upregulate FAK Y397 tyrosine phosphorylation, which conventionally initiates FAK activation, and mediate pressure-induced cancer cell adhesion. FAK(T600A) mutation did not prevent pressure-induced FAK(Y397) phosphorylation or adhesion. Akt1 appeared to directly bind FAK, and this binding did not depend on the FAK autophosphorylation site (Y397). In addition, our results demonstrated that Akt phosphorylated FAK at three novel serine phosphorylation sites, which were also not required for FAK-Akt binding. This novel interaction suggests that FAK and Akt may be dual kinase targets to prevent cancer cell adhesion and metastasis.

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