Biomedical subjects

J W Kasckow

Publications and source records attributed to J W Kasckow.

At least 19 recordsLinked to original sources

PubMed2006

Aging associated changes in amygdalar corticotropin-releasing hormone (CRH) and CRH-binding protein in Fischer 344 rats.

Behavioral adaptation in aging may become impaired from abnormal expression of amygdalar corticotropin-releasing hormone (CRH) and/or CRH-binding protein (CRH-BP). In this study, we serially sectioned the amygdala in 4-, 12-, and 24-month-old Fischer 344 rats following perfusion with 4% paraformaldehyde. We determined the amount of CRH and CRH-BP containing cells as well as the density of fibers expressing CRH or CRH-BP utilizing densitometric methods. Images were digitized using Zeiss Axiovision software and densitometrically analyzed using Scion Image. Both sides were analyzed in sections cut at 30 mum thickness. Cell counts of CRH-BP containing cells in the basolateral and lateral nucleus of the amygdala were lower in 24-month-old rats vs. 4-month-old rats, respectively (mean cells/section +/- SE): 31 +/- 6 vs. 72 +/- 10 (n = 3; P < 0.05 via ANOVA and Fisher's PLSD). There was a trend for cell counts of CRH containing cells in the central nucleus of the amygdala to be lower in 24-month-old rats vs. 4-month-old rats, respectively 28 +/- 7 vs. 47 +/- 9 (n = 3; P = 0.07 via ANOVA). Densitometric analysis of the number of CRH-BP positive fibers revealed no age differences in CeA; however, with regards to CRH-positive fibers, both 4- and 12-month rats had greater CeA CRH immunoreactivity relative to 24-month-old rats (Ps < 0.05 via ANOVA and Fisher's PLSD). These changes may contribute to impaired adaptations to stress, cognitive decline, and other pathophysiological processes during aging.

Age Factors↗

PubMed2006

Neurocognitive functioning in dually diagnosed middle aged and elderly patients with alcoholism and schizophrenia.

BACKGROUND: Alcohol abuse and dependence have important clinical implications for managing patients with schizophrenia. Alcoholism in schizophrenia patients can interfere with the course and prognosis of the schizophrenic illness. OBJECTIVE: The purpose of the present study was to compare the cognitive status, symptom profile and quality of life of middle aged and older patients (>44 years old) with schizophrenia and alcohol abuse/dependence vs those without alcohol abuse/dependence. We initially hypothesized that more males in this age group with schizophrenia would exhibit alcoholism. We also examined the characteristics of the 45-54 year age group with those of the > or = 55 year old group and hypothesized that comorbidity with alcohol would be associated with worse cognition and quality of life in later life. METHODS: Data were obtained from a database from the Center for Services and Interventions research at the University of California, San Diego. Patients had diagnoses of schizophrenia or schizoaffective disorder. Data collected included demographic characteristics, cognitive status (tested with the Mattis Dementia Rating Scale learning, the Figural and Story Memory Test of the Wechsler Memory Scale-Revised and the California Verbal Learning Test [CVLT]). In addition, patients had undergone psychopathologic assessment and were screened for quality of life using the Quality of Well Being scale. RESULTS: We demonstrated that the older aged patients with alcoholism had worse scores assessing cognition relative to the same aged group without alcoholism. In addition, they had worse cognitive scores relative to the younger group (45-54 year old) with alcoholism. There was no significant difference with regards to quality of life. In addition, more males than females exhibited alcoholism. CONCLUSION: The results are consistent with the premise that the higher cognitive function in the younger schizophrenia patients with alcoholism appear to mask the effects of alcohol use on cognition at that age. However, for the older group of schizophrenia patients, the effects of alcohol use on neuropsychological functioning appear to be deleterious.

Alcoholism↗

PubMed2003

In vitro regulation of corticotropin-releasing hormone.

Studies involving regulation of corticotropin-releasing hormone (CRH) in vitro have been used to validate findings obtained in vivo and more importantly have been used as model systems to better understand signalling mechanisms responsible for the expression of the CRH gene and peptide. Many in vitro studies examining CRH have utilized hypothalamic tissue while a few have focused on the amygdala. Clonal cell lines have also been utilized as models of central nervous system CRH neurons. Stimuli that have been implicated in regulating hypothalamic CRH regulation in vitro include protein kinase A (PKA) and protein kinase C (PKC) activators, glucocorticoids, biogenic amines, cytokines and the gaseous neurotransmitters. Amygdalar CRH levels in vitro are affected by some of the same stimuli that regulate hypothalamic CRH; however there is evidence supporting differential regulation of CRH in these two brain regions by some of the same stimuli. Only a few studies in aggregate have investigated signal transduction mechanisms and these studies have focused on PKA- and glucocorticoid-mediated changes in CRH expression. Thus, much more investigative work in better understanding CRH regulation in vitro is needed.

Amygdala↗

PubMed2001

Health-related quality of well-being in chronically hospitalized patients with schizophrenia: comparison with matched outpatients.

Quantifying the functional consequences of illness in terms of quality of life can enhance our understanding of both mental and physical disorders. However, little is known about the quality of life among older inpatients vs. outpatients with schizophrenia. We present the results of health-related quality of life assessments in 54 middle-aged and elderly long-term inpatients with schizophrenia and a demographically matched outpatient sample. Assessments were performed using the Quality of Well-Being (QWB) scale, along with standard measures of psychopathology and global cognitive impairment. Compared with outpatients, the inpatients had a significantly lower health-related quality of life, as measured by the QWB. In the inpatient and outpatient groups, higher levels of positive symptoms were associated with lower health-related quality of life. Health-related quality of life remained fairly stable among the inpatients who remained hospitalized over 6 months. In both inpatients and outpatients, baseline cognitive status and psychopathology predicted QWB scores at the 6-month follow-up. These findings further support the use of the QWB in severely mentally ill populations; implications for improving health-related quality of life among older patients with schizophrenia are discussed.

Adult↗

PubMed2001

The effect of feeding on cerebrospinal fluid corticotropin-releasing hormone levels in humans.

Corticotropin-releasing hormone (CRH) is a neuropeptide thought to play a role in appetite regulation. In this report, we used a serial cerebrospinal fluid (CSF) sampling technique to examine the relationship between CSF CRH, plasma ACTH and cortisol and perceptions of hunger and satiety in fasting and sated volunteers. CSF was withdrawn continuously from 11:00 AM to 5:00 PM via an indwelling subarachnoid catheter. Blood was withdrawn every 10 min via an antecubital vein catheter. Fed subjects received a meal at 1:00 PM. Subjects who were fed had lower post-prandial ratings on hunger scales and higher ratings on satiety scales. Fed subjects also had slightly lower levels of CSF CRH after feeding. Furthermore, fed subjects had higher ACTH and cortisol concentrations in the first 3 h; by the fourth h the opposite was true. Our findings do not support the hypothesis that CNS CRH is a central satiety factor in the human. Instead our findings of slightly diminished CSF CRH levels after feeding may be accounted for by the rises in glucocorticoids and their associated negative feedback effects on CNS CRH. Alternatively, our findings could also reflect changes in CRH levels associated with feeding in multiple brain areas and in the spinal cord with the net effect being in the negative direction.

Adrenocorticotropic Hormone↗

PubMed2001

Circulating human corticotropin-releasing factor-binding protein levels following cortisol infusions.

Corticotropin-releasing factor-binding protein (CRF-BP) is a 37 kDa protein present in the brain and plasma and is known to regulate the actions of CRF. It has been demonstrated that CRF-BP in the brain and the pituitary appears to be positively regulated by glucocorticoids. In this study, the effect of various doses of hydrocortisone infusions on plasma CRF-BP levels was assessed. Four groups of 10 age-matched males received a 100 min infusion of either placebo (saline), 40 microg/kg/h, 300 microg/kg/h or 600 microg/kg/h hydrocortisone. CRF-BP levels were measured via a LIRMA. In addition, levels of plasma ACTH and cortisol were measured by standard radioimmunoassay. As expected, plasma cortisol levels increased and plasma ACTH levels were suppressed following the infusion. When expressed as proportion of pre-infusion baseine, no significant changes in plasma CRF-BP levels were observed following the infusion for all hydrocortisone groups relative to the control group. However, a significant time-averaged positive correlation was found between CRF-BP and cortisol levels at low to moderate, but not high, cortisol levels. The data obtained in this study indicate that CRF binding protein levels within the time course examined may slightly appear to be affected in the peripheral circulation in response to pronounced, sustained hypercortisolemia.

Adult↗

PubMed2001

Citalopram augmentation of antipsychotic treatment in older schizophrenia patients.

BACKGROUND: Depressive symptoms are common in older patients with schizophrenia; yet, few studies have examined the usefulness of antidepressants in this population. OBJECTIVE: We conducted a 10-week single-blind trial of citalopram (20-40 mg/day) vs no citalopram augmentation in 19 middle-aged and elderly patients with schizophrenia hospitalized for more than six of the last 12 months. At study-entry, the patients had been on stable doses of antipsychotics for at least two weeks, and had a 17-item Hamilton Depression Rating (HAM-D) scale score of 12 or greater. Nine patients were randomly assigned to citalopram augmentation, and 10 to no augmentation of antipsychotics. RESULTS: Patients in both groups improved on positive and negative symptoms, but the citalopram group had significantly greater improvement in HAM-D and Clinical Global Impression Scale scores than the control group. There were no major side effects. CONCLUSION: Larger double-blind studies are needed to follow up on these preliminary findings.

Aged↗

PubMed2001

Regulation of corticotropin-releasing hormone in vitro.

Studies examining regulation of corticotropin-releasing hormone (CRH) in vitro have been used to validate findings obtained in vivo and more importantly have been used as model systems to better understand signalling mechanisms responsible for the expression of the CRH gene and peptide. Most in vitro studies examining CRH have utilized hypothalamic tissue while a few have focused on the amygdala. Furthermore, clonal cell lines have also been utilized as models of central nervous system CRH neurons. Stimuli that have been implicated in regulating hypothalamic CRH in vitro include protein kinase A (PKA) and protein kinase C (PKC) activators, glucocorticoids, biogenic amines, cytokines and the gaseous neurotransmitters. CRH levels in the amygdala in vitro are affected by some of the same stimuli that regulate hypothalamic CRH; however there is evidence supporting differential regulation of CRH in these two brain regions by some of the same stimuli. Only a few studies in aggregate have investigated the signal transduction mechanisms responsible for CRH expression. These mechanistic studies have focused on PKA- and glucocorticoid-mediated changes in CRH expression. Clearly much more investigative work in better understanding CRH regulation in vitro is needed.

Animals↗

PubMed2001

Corticotropin-releasing hormone in depression and post-traumatic stress disorder.

Corticotropin-releasing hormone (CRH) has been implicated in the regulation of a wide range of behaviors including arousal, motor function, feeding, and reproduction. Because depressed patients are often hypercortisolemic and intracerebroventricular administration of CRH to experimental animals produces a syndrome reminiscent of depression, dysregulation of this compound has been suggested to be involved in the pathogenesis of depressive and anxiety disorders. Studies of cerebrospinal fluid CRH levels and clinical neuroendocrine tests in patients with anxiety and affective disorders have supported this hypothesis. This review discusses these neuroendocrine findings in melancholic and atypical depression as well as post-traumatic stress disorder (PTSD). Overall, the data suggest that melancholic depression is characterized by hyperactive central CRH systems with overactivity of the pituitary-adrenal (HPA) axis. On the other hand, atypical depression is characterized by hypoactive central CRH systems and accompanying underactivity of the hypothalamic-pituitary-adrenal axis. Furthermore, the neuroendocrinology of PTSD appears to be unique, in that patients have hyperactive central CRH systems with underactivity of the pituitary-adrenal axis.

Adrenocorticotropic Hormone↗

PubMed2001

Interaction of neuropeptide Y and corticotropin-releasing factor signaling pathways in AR-5 amygdalar cells.

Corticotropin-releasing factor (CRF) is a 41 amino acid neuropeptide which is involved in the stress response. CRF and neuropeptide Y (NPY) produce reciprocal effects on anxiety in the central nucleus of the amygdala. The molecular mechanisms of possible CRF-NPY interactions in regulating anxiety behavior is not known. In the central nervous system, the action of NPY leads to inhibition of cAMP production while CRF is known to stimulate levels of cAMP in the brain. Consequently, we hypothesized that NPY may antagonize anxiety-like behavior by counter-regulating CRF-stimulated cAMP accumulation and activation of the protein kinase A pathway. We have engineered an immortalized amygdalar cell line (AR-5 cells) which express via RT-PCR, the CRF(2alpha), Y(1) and Y(5) NPY receptor. In addition, in these cells CRF treatment results in significant concentration-dependent increases in cAMP production. Furthermore, incubation of 3 microM CRF with increasing concentrations of NPY was able to significantly inhibit the increases in cAMP compared to that observed with 3 microM CRF treatment alone. These findings suggest that CRF and NPY may counter-regulate each other in amygdalar neurons via reciprocal effects on the protein kinase A pathway.

Amygdala↗

PubMed2001

Cerebrospinal fluid and plasma testosterone levels in post-traumatic stress disorder and tobacco dependence.

BACKGROUND: Little is known about the relationship between endogenous central nervous system (CNS) testosterone and any psychiatric syndrome. The goal of this study was to screen for potential abnormalities in CNS testosterone levels in patients with post-traumatic stress disorder (PTSD) and/or tobacco dependence. METHODS: We sampled cerebrospinal fluid (CSF) via a subarachnoid catheter over six hours and determined hourly basal CSF concentrations of testosterone in 11 combat veterans with PTSD and 12 normal volunteers. Smokers were abstinent for 11-17 h. Testosterone in CSF and matching plasma samples was assayed by radioimmunoassay. RESULTS: A factor analysis for effects of PTSD status, smoking status and sample time revealed significant effects of PTSD or smoking status, but not time, on CSF testosterone. CSF testosterone levels were lower in individuals with PTSD as compared with normal volunteers. When divided by smoking status, abstinent smokers had mean CSF testosterone levels higher than those of non-smokers. A similar analysis of plasma testosterone revealed no significant effects of any factor on plasma testosterone. CONCLUSIONS: These results indicate that CSF testosterone is significantly influenced by PTSD and smoking status. The exposure of the brain to altered levels of testosterone in smokers and patients with PTSD may have pathophysiologic significance in these conditions.

Adult↗

PubMed2001

A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder.

The relative efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder was studied. Sixty-two patients (29 depressed type; 33 bipolar type) entered a three-site, randomized, double-blind, 6-week trial of risperidone (up to 10 mg/day) or haloperidol (up to 20 mg/day). Trained raters assessed baseline, weekly, and end-of-study levels of psychopathology with the Positive and Negative Syndrome Scale (PANSS), the 24-item Hamilton Rating Scale for Depression (HAM-D-24) and the Clinician-Administered Rating Scale for Mania (CARS-M). The authors were unable to statistically distinguish between risperidone and haloperidol in the amelioration of psychotic and manic symptoms. In addition, there was no difference in worsening of mania between the two agents in either subgroup (i.e., depressed or bipolar subgroups). For the total PANSS, risperidone produced a mean decrease of 16 points from baseline compared with a 14-point decrease with haloperidol. For the total CARS-M scale, risperidone and haloperidol produced mean change scores of 5 and 8 points, respectively, and for the CARS-M Mania subscale, 3 and 7 points, respectively. Additionally, risperidone produced a mean decrease of 13 points from the baseline 24-item HAM-D, compared with an 8-point decrease with haloperidol. In those patients who had more severe depressive symptoms (i.e., HAM-D baseline score >20), risperidone produced at least a 50% mean improvement in 12 (75%) of 16 patients in comparison to 8 (38%) of 21 patients receiving haloperidol. Haloperidol produced significantly more extrapyramidal side effects and resulted in more dropouts caused by any side effect. There was no difference between risperidone and haloperidol in reducing both psychotic and manic symptoms in this group of patients with schizoaffective disorder. Risperidone did not demonstrate a propensity to precipitate mania and was better tolerated than haloperidol. In those subjects with higher baseline HAM-D scores (i.e., >20), risperidone produced a greater improvement in depressive symptoms than haloperidol.

Adult↗

PubMed2001

Plasma and cerebrospinal fluid interleukin-6 concentrations in posttraumatic stress disorder.

BACKGROUND: Interleukin-6 (IL-6) secretion is suppressed by glucocorticoids and stimulated by catecholamines. Patients with posttraumatic stress disorder (PTSD) have decreased cortisol and increased catecholamine secretion. The purpose of this study was to assess the relation of IL-6 levels and hypothalamic-pituitary-adrenal and noradrenergic activity in patients with well-characterized PTSD. METHODS: Cerebrospinal fluid (CSF) was withdrawn via a lumbar subarachnoid catheter over 6 h from 11 combat veterans with PTSD and 8 age- and sex-matched healthy controls. Blood was withdrawn concurrently. We measured IL-6, CRH and norepinephrine concentrations in the CSF and IL-6, ACTH, cortisol and norepinephrine in plasma. RESULTS: Mean and median CSF IL-6 concentrations were higher in PTSD than in controls (mean = 24.0 vs. 14.6, p = 0.05; median = 26.7 vs. 14.3, p < 0.03): plasma IL-6 concentrations, however, were not different between the two groups. Plasma IL-6 and norepinephrine were positively correlated in the PTSD group (r = +0.74, p < 0.04), but not in normals (r = -0.55, p = 0.20). CONCLUSIONS: PTSD patients have increased CSF concentrations of IL-6. Their plasma IL-6 is not elevated but is more tightly associated with noradrenergic output in these patients than in normals. Both findings might be explained by the low cortisol secretion previously reported in PTSD as a result of lowered glucocorticoid suppression of IL-6 secretion. High levels of CSF IL-6 may reflect neurodegeneration or compensatory neuroprotection.

Adrenocorticotropic Hormone↗

PubMed2001

CSF norepinephrine concentrations in posttraumatic stress disorder.

OBJECTIVE: Despite evidence of hyperresponsive peripheral and central nervous system (CNS) noradrenergic activity in posttraumatic stress disorder (PTSD), direct measures of CNS norepinephrine in PTSD have been lacking. The goal of this study was to determine serial CSF norepinephrine levels in patients with PTSD. METHOD: CSF samples were obtained serially over a 6-hour period in 11 male combat veterans with chronic PTSD and eight healthy men through an indwelling subarachnoid catheter. Thus the authors were able to determine hourly CSF norepinephrine concentrations under baseline (unstressed) conditions. Severity of the patients' PTSD symptoms was assessed with the Clinician-Administered PTSD Scale. RESULTS: CSF norepinephrine concentrations were significantly higher in the men with PTSD than in the healthy men. Moreover, CSF norepinephrine levels strongly and positively correlated with the severity of PTSD symptoms. Plasma norepinephrine concentrations showed no significant relationship with the severity of PTSD symptoms. CONCLUSIONS: These findings reveal the presence of greater CNS noradrenergic activity under baseline conditions in patients with chronic PTSD than in healthy subjects and directly link this pathophysiologic observation with the severity of the clinical posttraumatic stress syndrome.

Adult↗

PubMed2000

Age-related alterations in emotional behaviors and amygdalar corticotropin-releasing factor (CRF) and CRF-binding protein expression in aged Fischer 344 rats.

Corticotropin-releasing factor (CRF) coordinates the mammalian response to stress. In the amygdala, the CRF system appears to be responsible, at least in part, for the behavioral responses resulting from stress. Associated with amygdalar CRF is a 37 kDa binding protein (CRF-BP) which may also play a role in regulating stressful stimuli. Aging has been shown to be associated with abnormal neuroendocrine stress systems and little is known with regards to how amygdalar stress systems change with aging. In our study, we have assessed levels of amygdalar CRF and CRF-BP mRNA in Fischer 344 rats of 4, 12 or 24 months of age following 14 days of hourly restraint. Prior to sacrifice, rats were also tested for anxiety-like behaviors on the elevated plus maze. After behavioral testing, rats were perfused with 4% paraformaldehyde and the brains were processed for in situ hybridization. Twenty micron sections were hybridized with a CRF as well as a CRF-BP riboprobe. Following hybridization, tissue sections were oppossed to X-ray film and relative amounts of mRNA in the amygdala were quantitated. Levels of CRF mRNA in the amygdala of 12 and 24 month-old rats following chronic restraint were significantly lower relative to rats which were handled for 14 days. There were no significant differences in amygdalar CRF gene expression between stressed and handled 4 month-old rats. At 12 and 24 months of age but not 4 months, there were also significant effects of restraint associated with decreases in amygdalar CRF-BP gene expression. Furthermore, there were reciprocal decreases in anxiety-like behaviors in the 12 and 24 month-old rats which were significant; the changes in anxiety-like behaviors between restrained vs. handled 4 month-old rats were not significantly different. The decreased gene expression of CRF in the amygdala in concert with decreased anxiety-like behaviors following restraint is consistent with the known behavioral effects of exogenously applied intra-amygdalar CRF. The changes in amygdalar CRF-BP observed may be secondary to the known regulatory effects that CRF exhibits on its binding-protein. These studies have relevance to better understanding the molecular basis of aging related changes in neuroendocrine stress systems.

Aging↗

PubMed1999

Changes in brain corticotropin-releasing factor messenger RNA expression in aged Fischer 344 rats.

Adaptation in aging may become impaired from abnormal expression of corticotropin-releasing factor (CRF) and altered CRF receptor function. In this study, we measured CRF mRNA levels in Fischer 344 rats at various ages. The brains of these rats were processed for in situ hybridization. Relative to 3-month-old rats, levels of CRF mRNA were significantly decreased in the following brain areas at the following ages: at 24 months in the paraventricular hypothalamus, at 11, 17, and 24 months in the amygdala and at 17 and 24 months in the bed nucleus of the stria terminalis. These changes may contribute to impaired adaptations to stress, cognitive decline and other pathophysiological processes during aging.

Aging↗

PubMed1999

Steroidal regulation of portal arginine-vasopressin levels in aged Fischer 344 rats.

Levels of hypophysial portal arginine-vasopressin (AVP), plasma ACTH and plasma corticosterone (B) were measured in four and 24 month old Fischer 344 rats. Portal levels of AVP were lower in older rats whereas plasma ACTH levels were elevated. Older rats given adrenalectomies with physiologic replacement doses of B exhibited levels of AVP, but not ACTH, which were comparable to that observable in younger rats. The findings suggest that altered AVP, but not ACTH, can be accounted for by higher B levels which are commonly demonstrable in aging rats.

Adrenocorticotropic Hormone↗

PubMed1999

Regulation of corticotropin-releasing factor messenger RNA by nicotine in an immortalized amygdalar cell line.

Preliminary data suggest that amygdalar corticotropin-releasing factor (CRF) is regulated by nicotinic agonists. We sought to confirm and extend these observations by determining the effects of various concentrations of nicotine on CRF messenger RNA expression in the AR-5 immortalized amygdalar cell line. Nicotine produced concentration- and time-dependent increases in CRF mRNA. This cell line thus confirms that nicotinic agonists stimulate amygdalar CRF and appears to be a useful model for studying molecular factors important in this interaction.

Amygdala↗