Biomedical subjects

R A Cohen

Publications and source records attributed to R A Cohen.

At least 19 recordsLinked to original sources

PubMed2006

Obesity is associated with memory deficits in young and middle-aged adults.

Recent findings suggest obesity is associated with reduced memory performance in older adults. The present study examined whether similar deficits also exist in younger adults and the degree to which the relationship between body mass index (BMI) and memory varies as a function of age. Prior to inclusion, participants were rigorously screened and excluded for medical conditions known to impact cognitive functioning, including neurological disorders, head injury, cardiovascular disease, and diabetes. A total of 486 healthy adults completed a verbal list-learning task. Participants were categorized into normal weight, overweight, and obese groups based on their BMI. Performance on learning, delayed recall, and recognition performance were compared across BMI groups. Results showed obese individuals had poorer memory performance when comparing persons across the adult lifespan (age 21-82 yr), but also when examining only younger and middle-aged adults (age 21-50 yr). Regression analyses found no evidence of an interaction between BMI and age on any memory variable, suggesting the relationship between BMI and memory does not vary with age. These findings provide further support for an independent relationship between obesity and reduced memory performance and suggest these effects are not limited to older adults. Further research is needed to identify etiological factors.

Adult↗

PubMed2003

Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes.

Based on available evidence, we would propose the following. (i) Excesses of glucose and free fatty acids cause insulin resistance in skeletal muscle and damage to the endothelial cell by a similar mechanism. (ii) Key pathogenetic events in this mechanism very likely include increased fatty acid esterification, protein kinase C activation, an increase in oxidative stress (demonstrated to date in endothelium) and alterations in the inhibitor kappa B kinase/nuclear factor kappa B system. (iii) Activation of AMP-activated protein kinase (AMPK) inhibits all of these events and enhances insulin signalling in the endothelial cell. It also enhances insulin action in muscle; however, the mechanism by which it does so has not been well studied. (iv) The reported beneficial effects of exercise and metformin on cardiovascular disease and insulin resistance in humans could be related to the fact that they activate AMPK. (v) The comparative roles of AMPK in regulating metabolism, signalling and gene expression in muscle and endothelial cells warrant further study.

AMP-Activated Protein Kinases↗

PubMed2003

Toad venom poisoning: resemblance to digoxin toxicity and therapeutic implications.

A healthy man developed gastrointestinal symptoms after ingesting purported aphrodisiac pills. He had severe unrelenting bradycardia, hyperkalaemia, and acidosis. He rapidly developed severe life threatening cardiac arrhythmias and died after a few hours. He was found to have positive serum digoxin concentrations, although he was not taking digoxin. Toad venom poisoning is similar to digitalis toxicity and carries a high mortality. Cardiac glycoside poisoning can occur from ingestion of various plants and animal toxins, and the venom gland of cane toad (Bufo marinus) contains large quantities of cardiac glycosides. Toad venom, a constituent of an aphrodisiac, was considered responsible for the development of clinical manifestations and death in this patient. Digoxin specific Fab fragment has been reported to be beneficial in the treatment of toad venom poisoning. This report alerts physicians to the need to be aware of a new community toxic exposure, as prompt treatment with digoxin specific Fab fragment may be life saving. The treatment approach to patients with suspected toad venom poisoning is described.

Adult↗

PubMed2001

Reduced sarco/endoplasmic reticulum Ca(2+) uptake activity can account for the reduced response to NO, but not sodium nitroprusside, in hypercholesterolemic rabbit aorta.

BACKGROUND: Hypercholesterolemia (HC) impairs acetylcholine-induced relaxation but has little effect on that caused by the NO donor sodium nitroprusside (SNP), suggesting that acetylcholine releases less NO from the endothelium in HC. The relaxation to authentic NO gas, however, is also impaired in HC aortic smooth muscle, indicating an abnormal smooth muscle response. NO relaxes arteries by both cGMP-dependent and -independent mechanisms, and the response involves calcium (Ca(2+)) store refilling via the sarco/endoplasmic reticulum calcium ATPase (SERCA). We studied the involvement of cGMP and SERCA in the smooth muscle response to NO and SNP in HC rabbit aorta. METHODS AND RESULTS: A selective guanylyl cyclase inhibitor, 1H-[1,2,4]-oxadiazole-[4,3-a]quinoxalin-1-one, eliminated SNP-induced relaxation but only partially blocked NO-induced relaxation in both normal and HC aorta. The residual relaxation to NO was still less in HC and, in both normal and HC aorta, was abolished by concomitant administration of the SERCA inhibitor cyclopiazonic acid (CPA). In contrast, CPA did not affect SNP-induced relaxation in either normal or HC aorta. SERCA activity measured by (45)Ca(2+) uptake was markedly decreased in HC, although SERCA2 protein expression did not change significantly. CONCLUSIONS: These data suggest that NO-induced relaxation but not that to SNP is partially mediated by cGMP-independent Ca(2+) uptake into sarco/endoplasmic reticulum and that reduced sarco/endoplasmic reticulum Ca(2+) pump function can account for the impaired response to NO in HC.

Acetylcholine↗

PubMed2001

Characterization of a long-term survivor with Stüve-Wiedemann syndrome and mosaicism of a supernumerary marker chromosome.

Stüve-Wiedemann syndrome (SWS) is typically lethal in the neonatal period; only two patients have been reported with a longer survival. We report a new patient with SWS, who at 9 years of age is one of the longest survivors with this disorder. In addition to the characteristic features of SWS, she has a number of unique clinical signs, including lack of corneal and patellar reflexes, a smooth tongue with no fungiform papillae, chronic gingival abscesses, mottled, poor dentition, blotchy pigmentation of the skin, unusual infections, multiple fractures, and progressive scoliosis. Cytogenetic analysis identified mosaicism for a supernumerary marker chromosome (SMC), seen in the majority of amniocytes, blood, and skin fibroblasts. The SMC was shown to be derived from chromosome 5 and contains euchromatin. The significance of the SMC to the etiology of SWS is unknown. This patient further demonstrates that SWS is not universally lethal.

Abnormalities, Multiple↗

PubMed2001

Role of NADPH oxidase in the vascular hypertrophic and oxidative stress response to angiotensin II in mice.

Oxygen-derived free radicals are involved in the vascular response to angiotensin II (Ang II), but the role of NADPH oxidase, its subunit proteins, and their vascular localization remain controversial. Our purpose was to address the role of NADPH oxidase in the blood pressure (BP), aortic hypertrophic, and oxidant responses to Ang II by taking advantage of knockout (KO) mice that are genetically deficient in gp91(phox), an NADPH oxidase subunit protein. The baseline BP was significantly lower in KO mice than in wild-type (WT) (92+/-2 [KO] versus 101+/-1 [WT] mm Hg, P<0.01), but infusion of Ang II for 6 days caused similar increases in BP in the 2 strains (33+/-4 [KO] versus 38+/-2 [WT] mm Hg, P>0.4). Ang II increased aortic superoxide anion production 2-fold in the aorta of WT mice but did not do so in KO mice. Aortic medial area increased in WT (0.12+/-0.02 to 0.17+/-0.02 mm(2), P<0.05), but did not do so in KO mice (0.10+/-0.01 to 0.11+/-0.01 mm(2), P>0.05). Histochemistry and polymerase chain reaction demonstrated gp91(phox) localized in endothelium and adventitia of WT mice. Levels of reactive oxidant species as indicated by 3-nitrotyrosine immunoreactivity increased in these regions in WT but not in KO mouse aorta in response to Ang II. These results indicate an essential role in vivo of gp91(phox) and NADPH oxidase-derived superoxide anion in the regulation of basal BP and a pressure-independent vascular hypertrophic and oxidant stress response to Ang II.

Angiotensin II↗

PubMed2001

Neurocognitive performance enhanced by highly active antiretroviral therapy in HIV-infected women.

OBJECTIVE: To determine whether highly active retroviral therapy (HAART) is associated with better neurocognitive outcome over time among HIV-infected women with severely impaired immune function. METHODS: A semiannual neurocognitive examination on four tasks was administered: Color Trail Making, Controlled Oral Word Association, Grooved Pegboard and Four-Word Learning. This protocol was initiated in the HIV Epidemiological Research study (HERS) study when a woman's CD4 cell count fell to < 100 x 10(6) cells/l. Immune function (CD4), viral load status and depression severity (CESD) were also assessed semi-annually, along with an interview to determine medication intake and illicit drug use. RESULTS: HAART was not available to any participant at the time of enrollment (baseline), while 44% reported taking HAART at their most recent visit (mean duration of HAART 36.3 +/- 12.6 months). HAART-treated women had improved neurocognitive performance compared with those not treated with HAART. Women taking HAART for 18 months or more showed the strongest neurocognitive performance with improved verbal fluency, psychomotor and executive functions. These functions worsened among women not taking HAART. Substance abuse status, severity of depressive symptoms, age and educational level did not influence the HAART treatment effects on neurocognitive performance. Neurocognitive improvements were strongly associated with the magnitude of CD4 cell count increases. CONCLUSIONS: HAART appeared to produce beneficial effect on neurocognitive functioning in HIV-infected women with severely impaired immune systems. Benefits were greatest for women who reported receiving HAART for more than 18 months.

Adolescent↗

PubMed2001

Quality of life and well-being of patients with myasthenia gravis.

The cardinal symptom of myasthenia gravis (MG) is weakness of voluntary muscles, a feature that may restrict full participation in life activities. In turn, such limitations may negatively affect quality of life (QOL) and well-being among individuals with the disease. In the present study, we administered a measure of QOL to 27 patients with generalized MG. Results revealed that functional status was negatively impacted in the domains of physical functioning, energy, and general health. However, a clinically meaningful difference was evident only on perceived ability to accomplish physical tasks. The results suggest that although MG requires accommodations in physical activities, general QOL and well-being does not differ markedly from the general population.

Adult↗

PubMed2001

What have we learned about cognition in myasthenia gravis?: a review of methods and results.

Most individuals with myasthenia gravis (MG) complain of cognitive impairment, but empirical studies of cognition in MG have produced mixed results. In the present review, we critically examined the methodology and results of previous studies that investigated cognition in MG. Results from our review revealed that none of the studies met at least 50% of criteria under review. The most common shortcomings of previous studies included small sample size, no exclusion for visual difficulties in patients, inadequate assessment of mood, and poor control for prednisone use. Despite these methodological difficulties, mild impairments on measures of learning have been identified. These findings need to be replicated with adequate control of potential confounds before any conclusions can be made regarding cognition in this disease. Suggestions for design of future studies are provided.

Cognition↗

PubMed2001

Emotional and personality changes following cingulotomy.

The effects of bilateral anterior cingulate cortex (ACC) lesions on emotional and personality functioning were studied. Patients undergoing cingulotomy for chronic intractable pain were assessed on the Minnesota Multiphasic Personality Inventory (MMPI), the Profile of Mood States (POMS), cognitive tests, and pain ratings, pre- and postsurgically. Patients with intractable pain, not treated with cingulotomy, served as controls. Cingulotomy patients experienced reductions in POMS-Tension, POMS-Anger, and MMPI Scale 7 (Psychasthenia) compared with baseline and the controls. POMS-Tension was significantly correlated with attention-intention performance. The results indicate that the ACC modulates emotional experience, related to self-perceived tension, and that there is relationship between the emotional and the attentional effects of cingulotomy.

Adult↗

PubMed2001

Single photon emission computed tomography, magnetic resonance imaging hyperintensity, and cognitive impairments in patients with vascular dementia.

BACKGROUND: The relationship between subcortical hyperintensity (SH) on magnetic resonance imaging (MRI), cortical perfusion on single photon emission computed tomography (SPECT), and cognitive function is not well understood. The authors examined these relationships in individuals with vascular dementia (VaD), paying particular attention to frontal lobe function to determine whether the presence of SH on MRI was associated with frontal hypoperfusion on SPECT, which in turn would be associated with impairments of executive-attention function. METHODS: Patients with vascular dementia (n = 26) were assessed on neurocognitive tests and brain MRI and SPECT. SH volume was quantified from the axial T2-weighted fluid attenuated inversion recovery MRI. Total counts of activation across voxels for 12 cortical regions of interest were determined from SPECT. Perfusion ratios of both total cortical and frontal activation relative to cerebellum activation were derived, and regression analyses were performed to determine the relationships between cognitive, MRI, and SPECT indices. RESULTS: SH volume on MRI was significantly associated with frontal lobe perfusion, but not with global cortical perfusion as measured by SPECT. Frontal lobe perfusion did not consistently correlate with performance on measures of executive-attention function, although both total and frontal perfusion ratios were significantly associated with other cognitive functions. CONCLUSIONS: These results suggest that a functional "disconnection" between the frontal lobes and subcortical structures does not fully account for the magnitude of global cognitive impairment in VaD. Cortical perfusion as measured by SPECT appears to be associated with cognitive performance, but not specifically executive-attention dysfunction. Additional studies are needed to further examine the relationship between subcortical and cortical function in VaD.

Aged↗

PubMed2001

Abnormal platelet function and calcium handling in Dahl salt-hypertensive rats.

The effect of dietary salt on platelet function and Ca(2+) homeostasis was studied in Dahl (DS) rats, a genetic model of salt-sensitive hypertension. DS rats were fed a high-salt (DSHS) or a low-salt diet (DSLS) for up to 4 weeks, and the effects of salt loading on systolic blood pressure, platelet P-selectin expression, and platelet Ca(2+) homeostasis were measured. The high-salt diet increased blood pressure and markedly increased the amount of ionomycin (IM)-releasable Ca(2+) in platelet intracellular stores (Ca(2+)/IM). The alteration in Ca(2+) stores was not prevented when the hypertension was prevented by treatment with hydralazine and reserpine. The Ca(2+) store filling during platelet exposure to 1 mmol/L Ca(2+) for 5 minutes and the rate of sarcoplasmic/endoplasmic Ca(2+) ATPase-dependent Ca(45) uptake were higher in DSHS compared with that in DSLS. There was a decrease in thrombin-induced Ca(2+) influx in platelets from DSHS; consistent with this, agonist-induced P-selectin expression was decreased. In DSLS, nitric oxide accelerated reloading of platelet Ca(2+) stores after their emptying by thrombin but failed to do so in DSHS. These results indicate that in DS rats, a high-salt diet increases sarcoplasmic/endoplasmic Ca(2+) ATPase activity and the Ca(2+)/IM but decreases the reuptake of Ca(2+) caused by nitric oxide. Decreases in Ca(2+) influx and platelet P-selectin expression might be explained by changes in intracellular Ca(2+) stores in DSHS rats, which apparently is a heritable response to a high-salt diet.

Analysis of Variance↗

PubMed2001

S17834, a new inhibitor of cell adhesion and atherosclerosis that targets nadph oxidase.

microdant stress is involved in the events that accompany endothelial cell expression of adhesion molecules and leukocyte adherence in many disease states, including atherosclerosis. A recently discovered benzo(b)pyran-4-one derivative, S17834 (10 to 50 micromol/L), reduced tumor necrosis factor-stimulated vascular cell adhesion molecule-1 (VCAM) mRNA accumulation and protein expression in human umbilical vein endothelial cells. Intercellular cell adhesion molecule-1 and E-selectin were also inhibited by S17834, but platelet endothelial cell adhesion molecule-1 was not. Adherence of U937 monocytic cells to the endothelial cells as well as to plastic plates coated with soluble VCAM, intercellular cell adhesion molecule-1, P-selectin, and E-selectin was also decreased. Consistent with an antioxidant mechanism of action, S17834 (10 to 50 micromol/L) inhibited tumor necrosis factor-stimulated release of superoxide from endothelial cells measured by cytochrome c reduction. S17834 had no effect on superoxide produced by xanthine oxidase, indicating that rather than by acting as a scavenger of superoxide anion, the drug acts by inhibiting the production of free radicals. Indeed, S17834 inhibited NADPH oxidase activity of endothelial cell membranes. The ability to inhibit superoxide anion production appears to be key in the effect of S17834 on superoxide anion production and VCAM expression, because these actions were mimicked by adenovirus-mediated overexpression of superoxide dismutase. Furthermore, these actions may be relevant in vivo, because S17834 reduced aortic superoxide anion levels by 40% and aortic atherosclerotic lesions by 60% in apolipoprotein E-deficient mice. These results indicate that S17834 inhibits adhesion molecule expression and adherence of leukocytes to endothelial cells as well as aortic atherogenesis and that perhaps these effects can be explained by its ability to inhibit endogenous superoxide anion production.

Animals↗

PubMed2001

Persistent activation of nuclear factor-kappaB by interleukin-1beta and subsequent inducible NO synthase expression requires extracellular signal-regulated kinase.

The role of extracellular signal-regulated kinase (ERK) was studied in the signaling pathway by which interleukin-1beta (IL-1beta) increases the expression of inducible NO synthase (iNOS) in rat vascular smooth muscle cells. IL-1beta induced a rapid and transient activation of nuclear factor-kappaB (NF-kappaB), followed by a prolonged activation of NF-kappaB that was required to induce iNOS expression. Either PD98059 or U0126, selective inhibitors of ERK activation, did not influence IL-1beta-induced early activation but effectively reduced the prolonged activation of NF-kappaB and significantly reduced IL-1beta induction of iNOS. Transfection with antisense, but not sense, phosphorothioate-modified oligodeoxynucleotides directed toward ERK also reduced IL-1beta-induced prolonged NF-kappaB activation and iNOS expression. IkappaBbeta, but not IkappaBalpha degradation, induced by IL-1beta was markedly attenuated when ERK activation was inhibited and could be partially responsible for the persistent NF-kappaB activation. These data suggest that ERK activity is required for persistent NF-kappaB activation by IL-1beta that is necessary for iNOS gene expression.

Animals↗

PubMed2001

Performance on the Mattis Dementia Rating Scale in patients with vascular dementia: relationships to neuroimaging findings.

Impairment on screening measures such as the Mattis Dementia Rating Scale (MDRS) provides evidence of dementia in patients with cerebrovascular disease. However, the relationships between neuroimaging findings and performance on the MDRS in vascular dementia (VD) have not been determined. In the present study, we examined the relationships between subcortical hyperintensity (SH) volume and whole brain volume (WBV) on the subscales and total score of the MDRS. Results revealed that SH accounted for a significant amount of variance on the Initiation/Perseveration and Construction subscales, whereas WBV accounted for a significant amount of variance on the Memory subscale. The total score on the MDRS was found to be significantly related to WBV but not SH. These results suggest that subcortical damage and brain volume account for different aspects of cognitive decline in VD and that overall cognitive impairment may reflect cortical and subcortical involvement.

Aged↗

PubMed2000

Properties of a native cation channel activated by Ca2+ store depletion in vascular smooth muscle cells.

Depletion of intracellular Ca(2+) stores activates capacitative Ca(2+) influx in smooth muscle cells, but the native store-operated channels that mediate such influx remain unidentified. Recently we demonstrated that calcium influx factor produced by yeast and human platelets with depleted Ca(2+) stores activates small conductance cation channels in excised membrane patches from vascular smooth muscle cells (SMC). Here we characterize these channels in intact cells and present evidence that they belong to the class of store-operated channels, which are activated upon passive depletion of Ca(2+) stores. Application of thapsigargin (TG), an inhibitor of sarco-endoplasmic reticulum Ca(2+) ATPase, to individual SMC activated single 3-pS cation channels in cell-attached membrane patches. Channels remained active when inside-out membrane patches were excised from the cells. Excision of membrane patches from resting SMC did not by itself activate the channels. Loading SMC with BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), which slowly depletes Ca(2+) stores without a rise in intracellular Ca(2+), activated the same 3-pS channels in cell-attached membrane patches as well as whole cell nonselective cation currents in SMC. TG- and BAPTA-activated 3-pS channels were cation-selective but poorly discriminated among Ca(2+), Sr(2+), Ba(2+), Na(+), K(+), and Cs(+). Open channel probability did not change at negative membrane potentials but increased significantly at high positive potentials. Activation of 3-pS channels did not depend on intracellular Ca(2+) concentration. Neither TG nor a variety of second messengers (including Ca(2+), InsP3, InsP4, GTPgammaS, cyclic AMP, cyclic GMP, ATP, and ADP) activated 3-pS channels in inside-out membrane patches. Thus, 3-pS nonselective cation channels are present and activated by TG or BAPTA-induced depletion of intracellular Ca(2+) stores in intact SMC. These native store-operated cation channels can account for capacitative Ca(2+) influx in SMC and can play an important role in regulation of vascular tone.

Animals↗

PubMed2000

Cognitive dysfunction in individuals with myasthenia gravis.

In the present study we administered a battery of cognitive measures that examined attention, response fluency, information processing, and verbal and visual learning and retention to 28 individuals with generalized myasthenia gravis (MG) and 18 demographically similar control subjects. Results revealed that MG patients performed significantly more poorly than control subjects on the measures of response fluency, information processing and most measures of verbal and visual learning. Significant group differences were not evident on the measure of attention span or on the indices of retention of information. Cognitive performances of the MG group were not related to mood disturbance, disease duration, or daily dose of prednisone. While these results suggest central involvement in MG, previous studies have not provided evidence that MG antibodies bind to central nicotinic receptors. Possible alternative mechanisms underlying cognitive dysfunction in MG are discussed.

Adult↗

PubMed2000

Calcium influx factor directly activates store-operated cation channels in vascular smooth muscle cells.

Recently, we described a novel 3-pS Ca(2+)-conducting channel that is activated by BAPTA and thapsigargin-induced passive depletion of intracellular Ca(2+) stores and likely to be a native store-operated channel in vascular smooth muscle cells (SMC). Neither Ca(2+) nor inositol 1,4,5-trisphosphate or other second messengers tested activated this channel in membrane patches excised from resting SMC. Here we report that these 3-pS channels are activated in inside-out membrane patches from SMC immediately upon application of Ca(2+) influx factor (CIF) extracted from mutant yeast, which has been previously shown to activate Ca(2+) influx in Xenopus oocytes and Ca(2+) release-activated Ca(2+) current in Jurkat cells. In bioassay experiments depletion of Ca(2+) stores in permeabilized human platelets resulted in the release of endogenous factor, which activated 3-pS channels in isolated inside-out membrane patches excised from SMC and exposed to permeabilized platelets. The same 3-pS channels in excised membrane patches were also activated by acid extracts of CIF derived from human platelets with depleted Ca(2+) stores, which also stimulated Ca(2+) influx upon injection into Xenopus oocytes. Specific high pressure liquid chromatography fractions of platelet extracts were found to have CIF activity when injected into oocytes and activate 3-pS channels in excised membrane patches. These data show for the first time that CIF produced by mammalian cells and yeast with depleted Ca(2+) stores directly activates native 3-pS cation channels, which in intact SMC are activated by Ca(2+) store depletion.

Animals↗