Caramiphen edisylate as adjunct to standard therapy attenuates soman-induced seizures and cognitive deficits in rats.

The progression of epileptiform activity following soman (GD) exposure is characterized by a period of excessive cholinergic activity followed by excessive glutamatergic activity resulting in status epilepticus, which may lead to neuropathological damage and behavioral deficits. Caramiphen edisylate is an anticholinergic drug with antiglutamatergic properties, which conceptually may be a beneficial therapeutic approach to the treatment of nerve agent exposure. In the present study, rats were exposed to 1.2 LD50 GD or saline, treated with atropine sulfate (2mg/kg, im) and HI-6 (93.6mg/kg, im) 1min after GD exposure, and monitored for seizure activity. Rats were treated with diazepam (10mg/kg, sc) and caramiphen (0, 20 or 100mg/kg, im) 30min after seizure onset. Following GD exposure, performance was evaluated using a battery of behavioral tests to assess motor coordination and function, sensorimotor gating, and cognitive function. Caramiphen as adjunct to diazepam treatment attenuated GD-induced seizure activity, neuropathological damage, and cognitive deficits compared to diazepam alone, but did not attenuate the GD-induced sensorimotor gating impairment. These findings show that physiological, behavioral, and neuropathological effects of GD exposure can be attenuated by treatment with caramiphen as an adjunct to therapy, even if administration is delayed to 30min after seizure onset.

Unmasking masked hypertension: prevalence, clinical implications, diagnosis, correlates and future directions.

'Masked hypertension' is defined as having non-elevated clinic blood pressure (BP) with elevated out-of-clinic average BP, typically determined by ambulatory BP monitoring. Approximately 15-30% of adults with non-elevated clinic BP have masked hypertension. Masked hypertension is associated with increased risks of cardiovascular morbidity and mortality compared with sustained normotension (non-elevated clinic and ambulatory BP), which is similar to or approaching the risk associated with sustained hypertension (elevated clinic and ambulatory BP). The confluence of increased cardiovascular risk and a failure to be diagnosed by the conventional approach of clinic BP measurement makes masked hypertension a significant public health concern. However, many important questions remain. First, the definition of masked hypertension varies across studies. Further, the best approach in the clinical setting to exclude masked hypertension also remains unknown. It is unclear whether home BP monitoring is an adequate substitute for ambulatory BP monitoring in identifying masked hypertension. Few studies have examined the mechanistic pathways that may explain masked hypertension. Finally, scarce data are available on the best approach to treating individuals with masked hypertension. Herein, we review the current literature on masked hypertension including definition, prevalence, clinical implications, special patient populations, correlates, issues related to diagnosis, treatment and areas for future research.

The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: synergism with the benzodiazepine diazepam.

Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA(A)) receptors. However, seizure activity itself causes the endocytosis of GABA(A) receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-d-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20mg/kg, im) and DZP (10mg/kg, sc), administered both separately and in combination, at 10, 20 or 30min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD(50); 132µg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20-30min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity.

Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia.

We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine with high-dose busulfan followed by allogeneic stem cell transplantation (SCT) in patients with high-risk and refractory acute leukemia. Patients received intravenous busulfan 0.8 mg/kg every 6 h on days -6 to -3 and clofarabine 30-60 mg/m(2) per day on days -6 to -2. Graft-versus-host disease prophylaxis included sirolimus plus tacrolimus (days -2 to +180). A total of 15 patients, median age 48 (30-58) years, with acute leukemia that was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1), were treated at four clofarabine dose levels: 30 (n=3), 40 (n=3), 50 (n=3) and 60 mg/m(2) per day (n=6) with busulfan. All engrafted, and the MTD was not reached. Grades 3-4 non-hematological toxicities included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), acute renal failure (n=1) and reversible elevation of aspartate aminotransferase/alanine aminotransferase (n=10). The 1-year event-free survival was 53% (95% confidence interval: 33-86%), and the 1-year overall survival was 60% (95% confidence interval: 40-91%). Given the good tolerability and promising results, we recommend clofarabine 60 mg/m(2) per day × 5 days as a phase II dose in combination with busulfan (12.8 mg per kg total dose) for further study as a myeloablative regimen for allogeneic SCT for high-risk acute leukemia.

Trimethoprim-sulfamethoxazole-induced rhabdomyolysis in an allogeneic stem cell transplant patient.

Trimethoprim-Rhabdomyolysis is a serious, potentially life-threatening complication diagnosed when creatine phosphokinase levels exceed 1000 U/L. Although many drugs are associated with rhabdomyolysis, the previous reports of trimethoprim-sulfamethoxazole (TMP/SMX)-induced rhabdomyolysis have involved patients with human immunodeficiency virus/acquired immunodeficiency syndrome. This is the first report, to our knowledge, of TMP/SMX-induced rhabdomyolysis in an allogeneic stem cell transplant patient.

Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia.

A total of 50 consecutive patients (median age, 57.5 years) with AML (n=30) or myelodysplasia (MDS, n=20) underwent HLA matched related donor (MRD, n=27) or unrelated donor (MUD, n=23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n=19)+/-mycophenolate mofetil (n=31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan-Meier analysis, year 1-4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P=0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.

Emotional reactivity to daily life stress in psychosis.

BACKGROUND: The vulnerability-stress model of psychotic disorders describes, in essence, an interaction between personal vulnerability and environmental stressors. The present study investigated this interaction and studied emotional reactivity to daily life stress as a vulnerability marker for psychotic illness. METHODS: Patients with psychotic illness (n = 42), their first-degree relatives (n = 47), and control subjects (n = 49) were studied with the Experience Sampling Method (a structured diary technique assessing thoughts, current context, and mood in daily life) to assess (1) appraised subjective stress of daily events and smaller disturbances in daily life and (2) emotional reactivity conceptualized as changes in both negative affect and positive affect. RESULTS: Multilevel regression analyses showed that an increase in subjective stress was associated with an increase in negative affect and a decrease in positive affect in all groups. However, the groups differed quantitatively in their pattern of reactions to stress. Patients with psychotic illness reacted with more intense emotions to subjective appraisals of stress in daily life than control subjects. The decrease in positive affect in the relatives was similar to that of the patients, while the increase in negative affect in this group was intermediary to that of patients and control subjects. CONCLUSIONS: Higher levels of familial risk for psychosis were associated with higher levels of emotional reactivity to daily life stress in a dose-response fashion. Subtle alterations in the way persons interact with their environment may constitute part of the vulnerability for psychotic illness.

Gender differences in associations of diurnal blood pressure variation, awake physical activity, and sleep quality with negative affect: the work site blood pressure study.

This study reports on the associations among depression, anxiety, awake physical activity, sleep quality (assessed by nocturnal physical activity), and diurnal blood pressure (BP) variation in a nonpsychiatric sample (The Work Site Blood Pressure Study). We conducted ambulatory BP (ABP) monitoring and actigraphy in 231 working men and women. Depression and anxiety were measured by the Brief Symptom Inventory. There were gender-specific associations between depression or anxiety and ABP parameters. In men, depression was associated positively with the sleep/awake systolic BP (SBP) ratio (r=0.24, P=0.006). After controlling for age, body mass index, and awake and sleep activity, depression remained significantly associated with the sleep/awake SBP ratio (r=0.25, P=0.005) and was also significantly related to sleep SBP (r=0.21, P=0.02). Anxiety, which was related to depression (r=0.73, P<0.0001), had a similar but slightly weaker pattern of associations with ABP and activity. These associations were not found in women, but there were associations of anxiety with awake SBP (r=0.24, P=0.01) and pulse rate (r=0.27, P=0.006). In conclusion, depression is associated with disrupted diurnal BP variation independent of ambulatory physical activity in working men, whereas anxiety is associated with awake SBP and pulse rate in women.

Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives.

It remains uncertain whether abnormal dipping patterns of nocturnal blood pressure influence the prognosis for stroke. We studied stroke events in 575 older Japanese patients with sustained hypertension determined by ambulatory blood pressure monitoring (without medication). They were subclassified by their nocturnal systolic blood pressure fall (97 extreme-dippers, with >/=20% nocturnal systolic blood pressure fall; 230 dippers, with >/=10% but <20% fall; 185 nondippers, with >/=0% but <10% fall; and 63 reverse-dippers, with <0% fall) and were followed prospectively for an average duration of 41 months. Baseline brain magnetic resonance imaging (MRI) disclosed that the percentages with multiple silent cerebral infarct were 53% in extreme-dippers, 29% in dippers, 41% in nondippers, and 49% in reverse-dippers. There was a J-shaped relationship between dipping status and stroke incidence (extreme-dippers, 12%; dippers, 6.1%; nondippers, 7.6%; and reverse-dippers, 22%), and this remained significant in a Cox regression analysis after controlling for age, gender, body mass index, 24-hour systolic blood pressure, and antihypertensive medication. Intracranial hemorrhage was more common in reverse-dippers (29% of strokes) than in other subgroups (7.7% of strokes, P=0.04). In the extreme-dipper group, 27% of strokes were ischemic strokes that occurred during sleep (versus 8.6% of strokes in the other 3 subgroups, P=0.11). In conclusion, in older Japanese hypertensive patients, extreme dipping of nocturnal blood pressure may be related to silent and clinical cerebral ischemia through hypoperfusion during sleep or an exaggerated morning rise of blood pressure, whereas reverse dipping may pose a risk for intracranial hemorrhage.

Relation of blood pressure variability to carotid atherosclerosis and carotid artery and left ventricular hypertrophy.

The relationship of blood pressure (BP) variability to cardiovascular target-organ damage is controversial. Studies examining BP variability and left ventricular (LV) hypertrophy have been contradictory, and only limited data on the relation of BP variability to carotid atherosclerosis and carotid artery hypertrophy exist. BP variability was assessed as the standard deviation and coefficient of variation of awake and asleep pressures in 511 normotensive or untreated hypertensive subjects who underwent ambulatory BP monitoring and cardiac and carotid ultrasonography. Although the presence of focal carotid plaque was associated with an increase in ambulatory pressures and pressure variability, the differences in variability were eliminated by adjustment for age and absolute pressures. Similarly, LV mass was significantly related to BP variability, but the significance of this finding was eliminated after adjustment for important covariates. In multivariate analyses, age was the primary determinant of carotid artery cross-sectional area, with a weak but independent contribution from awake systolic and diastolic BP variability in addition to absolute pressure. BP variability was not independently related to either carotid or LV relative wall thickness, both measures of concentric remodeling. In the present study, awake BP variability was weakly but independently associated with carotid artery cross-sectional area, a measure of arterial hypertrophy. However, neither systolic nor diastolic BP variability was independently associated with carotid atherosclerotic plaque or LV mass.

Silent and clinically overt stroke in older Japanese subjects with white-coat and sustained hypertension.

OBJECTIVES: We investigated whether white-coat hypertension is a risk factor for stroke in relation to silent cerebral infarct (SCI) in an older Japanese population. BACKGROUND: It remains uncertain whether white-coat hypertension in older subjects is a benign condition or is associated with an increased risk of stroke. METHODS: We studied the prognosis for stroke in 958 older Japanese subjects (147 normotensives [NT], 236 white-coat hypertensives [WCHT] and 575 sustained hypertensives [SHT]) in whom ambulatory blood pressure monitoring was performed in the absence of antihypertensive treatment. In 585 subjects (61%), we also assessed SCI using brain magnetic resonance imaging. RESULTS: Silent cerebral infarcts were found in 36% of NT (n = 70), 42% of WCHT (n = 154), and 53% of SHT (n = 361); multiple SCIs (the presence of > or =2 SCIs) were found in 24% of NT, 25% of WCHT and 39% of SHT. During a mean 42-month follow-up period, clinically overt strokes occurred in 62 subjects (NT: three [2.0%]; WCHT: five [2.1%]; SHT: 54 [9.4%]), with 14 fatal cases (NT: one [0.7%]; WCHT: 0 [0%]; SHT: 13 [2.3%]). A Cox regression analysis showed that age (p = 0.0001) and SHT (relative risk, [RR] [95% confidence interval, CI]: 4.3 [1.3-14.2], p = 0.018) were independent stroke predictors, whereas WCHT was not significant. When we added presence/absence of SCI at baseline into this model, the RR (95% CI) for SCI was 4.6 (2.0-10.5) (p = 0.003) and that of SHT was 5.5 (1.8-18.9) versus WCHT (p = 0.004) and 3.8 (0.88-16.7) versus NT (p = 0.07). CONCLUSIONS: In older subjects the incidence of stroke in WCHT is similar to that of NT and one-fourth the risk in SHT. Although SCI is a strong predictor of stroke, the difference in stroke prognosis between SHT and WCHT was independent of SCI. It is clinically important to distinguish WCHT from SHT even after assessment of target organ damage in the elderly.

Relation of age to left ventricular function and systemic hemodynamics in uncomplicated mild hypertension.

Previous studies in normotensive subjects have shown a slight decline in resting left ventricular pump function and midwall contractility with aging. We examined the relations of age to these variables and to peripheral resistance and vascular stiffness in 272 asymptomatic, unmedicated adults (25 to 80 years old) who had uncomplicated essential hypertension. Cardiac and carotid ultrasound and carotid pressure waveforms were obtained to measure left ventricular dimensions, endocardial and midwall left ventricular shortening, stroke index and cardiac index, end-systolic stress, and pulse pressure/stroke index and beta, pressure-dependent and independent measures of vascular stiffness, respectively. Endocardial and midwall stress-corrected left ventricular shortening assessed ventricular performance. Cardiac index and TPRI did not change with age in either gender, with age-related increases in systolic pressure offset by increasingly concentric ventricular geometry in women and enhanced ventricular systolic function in men. In contrast to the lack of age-related change in traditional hemodynamic indexes, pulse pressure/stroke volume and beta strongly increased with age (P<0.001). Thus, in uncomplicated, relatively mild essential hypertension, neither cardiac index nor peripheral resistance is associated with age. This hemodynamic stability is associated with age-related increased concentricity of ventricular geometry in women and increased ventricular performance indexes in hypertensive men. Vascular stiffness progressively increases with age, independent of change in mean pressure or resistance, possibly contributing to increased rates of cardiovascular events in older individuals.

Prevalence and relation to risk factors of carotid atherosclerosis and left ventricular hypertrophy in systemic lupus erythematosus and antiphospholipid antibody syndrome.

The prevalence of preclinical cardiovascular disease was determined in women with systemic lupus erythematosus (SLE) and control subjects matched for traditional risk factors. Compared with control subjects, patients with SLE had a higher prevalence of carotid atherosclerosis (41% vs 9%, p < 0.005) and left ventricular hypertrophy (32% vs 5%, p < 0.005), supporting the possibility that chronic inflammation predisposes to premature cardiovascular disease in SLE.

Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine.

BACKGROUND: Acute rejection is a serious and frequent complication of renal transplantation, and its diagnosis is contingent on the invasive procedure of allograft biopsy. A noninvasive diagnostic test for rejection could improve the outcome of transplantation. METHODS: We obtained 24 urine specimens from 22 renal-allograft recipients with a biopsy-confirmed episode of acute rejection and 127 samples from 63 recipients without evidence of acute rejection. RNA was isolated from the urinary cells. Messenger RNA (mRNA) encoding the cytotoxic proteins perforin and granzyme B and a constitutively expressed cyclophilin B gene were measured with the use of a competitive, quantitative polymerase chain reaction, and the level of expression was correlated with allograft status. RESULTS: The log-transformed mean (+/-SE) levels of perforin mRNA and granzyme B mRNA, which encode cytotoxic proteins, but not the levels of constitutively expressed cyclophiiin B mRNA, were higher in the urinary cells from the 22 patients with a biopsy-confirmed episode of acute rejection than in the 63 recipients without an episode of acute rejection (perforin, 1.4+/-0.3 vs. -0.6+/-0.2 fg per microgram of total RNA; P<0.001; and granzyme B, 1.2+/-0.3 vs. -0.9+/-0.2 fg per microgram of total RNA; P<0.001). Analysis involving the receiver-operating-characteristic curve demonstrated that acute rejection can be predicted with a sensitivity of 83 percent and a specificity of 83 percent with the use of a cutoff value of 0.9 fg of perforin mRNA per microgram of total RNA, and with a sensitivity of 79 percent and a specificity of 77 percent with the use of a cutoff value of 0.4 fg of granzyme B mRNA per microgram of total RNA. Sequential urine samples were obtained from 37 patients during the first nine days after transplantation; and measurements of the levels of mRNA that encoded cytotoxic proteins identified those in whom acute rejection developed. CONCLUSIONS: Measurement of mRNA encoding cytotoxic proteins in urinary cells offers a noninvasive means of diagnosing acute rejection of renal allografts.

Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study.

Disordered breathing during sleep is associated with acute, unfavorable effects on cardiovascular physiology, but few studies have examined its postulated association with cardiovascular disease (CVD). We examined the cross-sectional association between sleep- disordered breathing and self-reported CVD in 6,424 free-living individuals who underwent overnight, unattended polysomnography at home. Sleep-disordered breathing was quantified by the apnea-hypopnea index (AHI)-the average number of apneas and hypopneas per hour of sleep. Mild to moderate disordered breathing during sleep was highly prevalent in the sample (median AHI: 4.4; interquartile range: 1.3 to 11.0). A total of 1,023 participants (16%) reported at least one manifestation of CVD (myocardial infarction, angina, coronary revascularization procedure, heart failure, or stroke). The multivariable-adjusted relative odds (95% CI) of prevalent CVD for the second, third, and fourth quartiles of the AHI (versus the first) were 0.98 (0.77-1.24), 1.28 (1.02-1.61), and 1.42 (1.13-1.78), respectively. Sleep-disordered breathing was associated more strongly with self-reported heart failure and stroke than with self-reported coronary heart disease: the relative odds (95% CI) of heart failure, stroke, and coronary heart disease (upper versus lower AHI quartile) were 2.38 (1.22-4.62), 1.58 (1.02- 2.46), and 1.27 (0.99-1.62), respectively. These findings are compatible with modest to moderate effects of sleep-disordered breathing on heterogeneous manifestations of CVD within a range of AHI values that are considered normal or only mildly elevated.

Psychological variables in hypertension: relationship to casual or ambulatory blood pressure in men.

OBJECTIVE: The evidence linking hypertension with personality or psychological characteristics, such as anger, anxiety, or depression, remains equivocal. This may be due in part to limitations of personality theory, confounding by awareness of hypertension, and/or inherent difficulties in measuring blood pressure. This study was designed to investigate the association between mild hypertension as defined by both ambulatory and casual (clinic) blood pressure measurements and various measures of personality and psychological characteristics. METHODS: We examined this association in a population-based sample of 283 men between the ages of 30 and 60 years from eight work sites in New York City, using an ambulatory blood pressure monitor and controlling for age, race/ethnicity, and body mass index. RESULTS: We found no consistent difference between participants with mild hypertension and those with normal blood pressure on any of the psychological variables assessed, including Type A behavior pattern, state and trait anger, anger expression, anxiety, symptoms of psychological distress, locus of control, or attributional style. Results were not due to the use of antihypertensive medication by some of the participants with hypertension nor to the dichotomization of blood pressure into those with and without mild hypertension. This contrasts with previous findings from this study showing a sizable association of ambulatory blood pressure and hypertension with job strain (a situational measure), age, and body mass index. CONCLUSIONS: These null results suggest that situational, biological, and perhaps behavioral factors are the primary determinants of mild hypertension and that the predictive significance of psychological or dispositional factors is low or negligible in those without overt cardiovascular disease.

Individual differences in the diurnal cycle of salivary free cortisol: a replication of flattened cycles for some individuals.

Free cortisol measured in saliva has been shown to have the same diurnal rhythm as serum cortisol, one that typically declines rapidly throughout the waking day. A recent study showed that over 15% of a sample of community individuals who were monitored over two days did not show the typical diurnal rhythm. The present study specifically tested the hypothesis that there is significant between-subject variation (individual differences) in diurnal rhythms using multi-level, random regression models. Analyses of participants from four studies were conducted; studies varied in terms of the number of saliva samples taken per day, the number of days studied, and participants' demographic and health status. Significant individual differences of diurnal cycle in each of the four samples were found. In at least 10% of each sample no significant diurnal cycles was detected; however, the overall mean level of cortisol of those with flat cycles differed among the samples. These results suggest that some people do not have the expected diurnal rhythm of cortisol secretion. It is not clear what the determinants of this finding are or if there are any health consequences of having a flat cycle.