Comparative Study of Microbial Adhesion on Different Orthodontic Brackets - An In Vivo Study.

Aim: To study the microbial adhesion on different orthodontic brackets (conventional, ceramic, and self-ligating brackets). Materials and Methods: Three types of bracket systems i.e. self-ligating, conventional, and ceramic brackets were used consisting of 10 patients for each bracket system. Out of 30 patients 20 patients will be treated with conventional and ceramic brackets, in which, in one-half of the mouth steel ligature ties are placed and in the other half elastomeric rings would be placed. We collected swabs from the central incisors and first premolars of the both the right and left sides of both the maxillary and mandibular arches. The samples were collected three times from the above-mentioned teeth once prior to the placement of the brackets, the second and third samples after one and three months respectively. Result: Significant variations were between the pretreatment and after one and three months of bracket placement in all three groups. Significant increase in the microbial adhesion of aerobic and anaerobic bacteria in conventional bracket form pretreatment to one and three months after bracket placement is seen. Although the colony formed by anaerobic bacteria is more in number in comparison to the aerobic bacteria. Conclusion: Our study reveals that the most hygienic bracket is a self-ligating bracket that should be used in patients who have poor oral hygiene. We also found that using steel ligature is more suitable as compared to elastomeric ligature in both conventional and ceramic brackets.

Survival and health economic outcomes in heart failure diagnosed at hospital admission versus community settings: a propensity-matched analysis.

BACKGROUND AND AIMS: Most patients with heart failure (HF) are diagnosed following a hospital admission. The clinical and health economic impacts of index HF diagnosis made on admission to hospital versus community settings are not known. METHODS: We used the North West London Discover database to examine 34 208 patients receiving an index diagnosis of HF between January 2015 and December 2020. A propensity score-matched (PSM) cohort was identified to adjust for differences in socioeconomic status, cardiovascular risk and pre-diagnosis health resource utilisation cost. Outcomes were stratified by two pathways to index HF diagnosis: a 'hospital pathway' was defined by diagnosis following hospital admission; and a 'community pathway' by diagnosis via a general practitioner or outpatient services. The primary clinical and health economic endpoints were all-cause mortality and cost-consequence differential, respectively. RESULTS: The diagnosis of HF was via hospital pathway in 68% (23 273) of patients. The PSM cohort included 17 174 patients (8582 per group) and was matched across all selected confounders (p>0.05). The ratio of deaths per person-months at 24 months comparing community versus hospital diagnosis was 0.780 (95% CI 0.722 to 0.841, p<0.0001). By 72 months, the ratio of deaths was 0.960 (0.905 to 1.020, p=0.18). Diagnosis via hospital pathway incurred an overall extra longitudinal cost of £2485 per patient. CONCLUSIONS: Index diagnosis of HF through hospital admission continues to dominate and is associated with a significantly greater short-term risk of mortality and substantially increased long-term costs than if first diagnosed in the community. This study highlights the potential for community diagnosis-early, before symptoms necessitate hospitalisation-to improve both clinical and health economic outcomes.

A First Estimate of the Annual Prevalence of Basivertebral Nerve Ablation Candidates in a Spine Clinic.

BACKGROUND: Emerging literature supports the use of basivertebral nerve ablation (BVNA) for a specific cohort of patients with chronic low back pain and Type 1 or Type 2 Modic changes from vertebral levels L3-S1. The early literature warrants further evaluation. Studies establishing the efficacy of BVNA use highly selective patient criteria. OBJECTIVE: Provide a first estimate of the prevalence of BVNA candidates in a spine clinic over a year using the foundational studies patient selection criteria? METHODS: A retrospective review of four fellowhsip trained spine physiatrists patient encounters at a large academic medical center using relevant ICD-10 codes to isolate chronic low back pain without radiating symptoms from January 1, 2019 to January 1, 2020. Charts were then reviewed by a team of physicians for exclusionary criteria from the foundational studies which have demonstrated benefit from BVNA. MRI's from qualifying charts which did not meet exclusionary criteria were then independently reviewed by four physician for localization and characterization of Modic changes. RESULTS: The relevant diagnostic codes query yielded 338 unique patient records. Based on exclusionary criteria or lack of imaging availability, 318 charts were eliminated. The remaining 20 charts qualified for imaging review. There were 11 charts in which there was 100% agreement between all reviewers regarding the presence and either Type 1 or Type 2 Modic changes between vertebral levels L3 to S1. Accordingly, the prevalence of eligibility for BVNA was 3% (11/338, 95% CI 1-5%). CONCLUSION: The population which may benefit from BVNA is small. Our study demonstrated that over a year, the prevalence for BVNA candidacy using the foundational studies criteria was 3% (95% CI 1% - 5%). While physicians may be tempted to use less stringent selection criteria in practice, upon doing so they cannot cite the foundational studies as evidence for the outcomes they expect to achieve. Those outcomes will require more studies which formally assess the benefits of BVNA when selection criteria are relaxed.

Development of a Cadaver Laboratory Curriculum for Interventional Spine Procedures for Physical Medicine and Rehabilitation Residents.

ABSTRACT: There is no standardized curriculum for teaching interventional spine procedures during residency. The objective of this protocol was to share a curriculum using a cadaver laboratory for teaching Physical Medicine and Rehabilitation residents interventional spine procedures, which can be an effective and safe medium to train residents. This protocol provides a checklist that can guide the residents while they are in the cadaver laboratory with a focus on some of the most common lumbar procedures. Twelve physical medicine and rehabilitation resident's confidence in their ability to maneuver the x-ray image intensifier (C-arm), identify spine anatomy under fluoroscopy, and drive the needle improved after the training curriculum (P < 0.005). Although the cadaver laboratory curriculum is not a replacement for the required Accreditation Council for Graduate Medical Education training, it may serve as a tool to improve resident preparedness for spine procedures.

Balloon aortic valvuloplasty to improve candidacy of patients evaluated for transcatheter aortic valve replacement.

OBJECTIVES: Evaluate the role of balloon aortic valvuloplasty (BAV) in improving candidacy of patients for transcatheter aortic valve replacement (TAVR). BACKGROUND: Patients who are not candidates for TAVR may undergo BAV to improve functional and clinical status. METHODS: 117 inoperable or high-risk patients with critical aortic stenosis underwent BAV as a bridge-to-decision for TAVR. Frailty measures including gait speed, serum albumin, hand grip, activities of daily living (ADL); and NYHA functional class before and after BAV were compared. RESULTS: Mean age was 81.6 ± 8.5 years and the mean Society of Thoracic Surgeons predicted risk of mortality was 9.57 ± 5.51, with 19/117 (16.2%) patients non-ambulatory. There was no significant change in mean GS post-BAV, but all non-ambulatory patients completed GS testing at follow-up. Albumin and hand grip did not change after BAV, but there was a significant improvement in mean ADL score (4.85 ± 1.41 baseline to 5.20 ± 1.17, P = 0.021). The number of patients with Class IV congestive heart failure (CHF) was significantly lower post BAV (71/117 [60.7%] baseline versus 18/117 [15.4%], P = 0.008). 78/117 (66.7%) of patients were referred to definitive valve therapy after BAV. CONCLUSIONS: When evaluating frailty measures post BAV, we saw no significant improvement in mean GS, however, we observed a significant improvement in non-ambulatory patients and ADL scores. We also describe improved Class IV CHF symptoms. With this improved health status, the majority of patients underwent subsequent valve therapy, demonstrating that BAV may improve candidacy of patients for TAVR.

Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain.

Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders.

Subtype-selective regulation of IP(3) receptors by thimerosal via cysteine residues within the IP(3)-binding core and suppressor domain.

IP(3)R (IP(3) [inositol 1,4,5-trisphosphate] receptors) and ryanodine receptors are the most widely expressed intracellular Ca(2+) channels and both are regulated by thiol reagents. In DT40 cells stably expressing single subtypes of mammalian IP(3)R, low concentrations of thimerosal (also known as thiomersal), which oxidizes thiols to form a thiomercurylethyl complex, increased the sensitivity of IP(3)-evoked Ca(2+) release via IP(3)R1 and IP(3)R2, but inhibited IP(3)R3. Activation of IP(3)R is initiated by IP(3) binding to the IBC (IP(3)-binding core; residues 224-604) and proceeds via re-arrangement of an interface between the IBC and SD (suppressor domain; residues 1-223). Thimerosal (100 µM) stimulated IP(3) binding to the isolated NT (N-terminal; residues 1-604) of IP(3)R1 and IP(3)R2, but not to that of IP(3)R3. Binding of a competitive antagonist (heparin) or partial agonist (dimeric-IP(3)) to NT1 was unaffected by thiomersal, suggesting that the effect of thimerosal is specifically related to IP(3)R activation. IP(3) binding to NT1 in which all cysteine residues were replaced by alanine was insensitive to thimerosal, so too were NT1 in which cysteine residues were replaced in either the SD or IBC. This demonstrates that thimerosal interacts directly with cysteine in both the SD and IBC. Chimaeric proteins in which the SD of the IP(3)R was replaced by the structurally related A domain of a ryanodine receptor were functional, but thimerosal inhibited both IP(3) binding to the chimaeric NT and IP(3)-evoked Ca(2+) release from the chimaeric IP(3)R. This is the first systematic analysis of the effects of a thiol reagent on each IP(3)R subtype. We conclude that thimerosal selectively sensitizes IP(3)R1 and IP(3)R2 to IP(3) by modifying cysteine residues within both the SD and IBC and thereby stabilizing an active conformation of the receptor.

Structural and functional conservation of key domains in InsP3 and ryanodine receptors.

Inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca(2+) channels. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP(3)R gating is initiated by InsP(3) binding to the InsP(3)-binding core (IBC, residues 224-604 of InsP(3)R1) and it requires the suppressor domain (SD, residues 1-223 of InsP(3)R1). Here we present structures of the amino-terminal region (NT, residues 1-604) of rat InsP(3)R1 with (3.6 Å) and without (3.0 Å) InsP(3) bound. The arrangement of the three NT domains, SD, IBC-ß and IBC-α, identifies two discrete interfaces (α and ß) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP(3)R and of the ABC domains docked into RyR are remarkably similar. The importance of the α-interface for activation of InsP(3)R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations. Binding of InsP(3) causes partial closure of the clam-like IBC, disrupting the ß-interface and pulling the SD towards the IBC. This reorients an exposed SD loop ('hotspot' (HS) loop) that is essential for InsP(3)R activation. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP(3)R, and an InsP(3)R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP(3) and blocked by ryanodine. Activation mechanisms are conserved between InsP(3)R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-ß or B domain), to gate the pore.

HPA axis, respiration and the airways in stress--a review in search of intersections.

Given clear connections between respiratory distress and subjective anxiety, it is not surprising that respiratory psychophysiologists have been interested in the psychobiology of anxiety. Given parallel links between anxiety and stress, it is not surprising that the hypothalamic-pituitary adrenal (HPA) stress system has also been a focus in anxiety research. However, despite extensive work in respiratory psychophysiology and stress neuroendocrinology--and evidence that these systems are jointly dysregulated in anxiety disorders--direct studies of their interactions are rare. This paper reviews evidence for scientific intersections, providing an overview of the HPA axis, its psychobiology, and shared neural substrates for HPA and respiratory control. We examine HPA hormone effects on respiration, immune/inflammatory mediators, and lung maturation. We also examine respiratory/dyspnea effects on HPA axis. There are clear points of intersection in the neuroscience of respiration and stress. Given the importance of both systems to an organism's ability to survive and adapt in challenging and changing environments, further study of their interactions is needed.

Cognitive modulation of endocrine responses to CRH stimulation in healthy subjects.

BACKGROUND: The hypothalamic-pituitary adrenal (HPA) axis is critical for biobehavioral adaptation to challenge and appears dysregulated in a range of psychiatric disorders. Its precise role in psychopathology remains unclear and discrepant and difficult to explain findings abound in the clinical literature. Basic research suggests this system is sensitive to psychosocial cues, but psychosocial milieu factors are rarely controlled or examined in psychiatric studies using biological probes of the HPA axis. To test the hypothesis that psychological factors might complicate HPA study results even in direct, pharmacological challenge paradigms, endocrine responses to corticotropin-releasing hormone (CRH) were examined under two different cognitive preparation conditions. METHODS: Healthy subjects (n=32) received standard instructions or a cognitive intervention (CI) prior to injection with CRH and placebo, given on separate days in random order. The CI combined access to control over drug exposure with novelty reduction and coping enhancement. Blood samples were obtained via intravenous catheter before and after CRH. RESULTS: Cognitive intervention reduced corticotropin (ACTH) levels, but only when CRH was given first (intervention by order interaction). It did not reduce cortisol response. The CI and visit (1st or 2nd) both impacted cortisol levels on placebo day. CONCLUSIONS: Modifiable psychological factors may amplify or inhibit HPA axis activity in pharmacological activation paradigms, including CRH stimulation tests. The factors manipulated by the CI (novelty/familiarity, control and coping) may have particular salience to the HPA axis. Differential sensitivity to such factors could impact results in studies applying biological HPA probes to psychiatric populations.

CRH-stimulated cortisol release and food intake in healthy, non-obese adults.

BACKGROUND: There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamic-pituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans. METHODS: We infused healthy adults with corticotropin-releasing hormone (CRH) at a dose that is subjectively undetectable but elicits a robust endogenous cortisol response, and measured subsequent intake of snack foods, allowing analysis of HPA reactivity effects on food intake without the complex psychological effects of a stress paradigm. RESULTS: CRH elevated cortisol levels relative to placebo but did not impact subjective anxious distress. Subjects ate more following CRH than following placebo and peak cortisol response to CRH was strongly related to both caloric intake and total consumption. CONCLUSIONS: These data show that HPA axis reactivity to pharmacological stimulation predicts subsequent food intake and suggest that cortisol itself may directly stimulate food consumption in humans. Understanding the physiological mechanisms that underlie stress-related eating may prove useful in efforts to attack the public health crises created by obesity.

Effects of perceived control and cognitive coping on endocrine stress responses to pharmacological activation.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis may mediate negative health effects of stress. It is sensitive to cognitive/emotional factors like novelty, perceived control, and coping. Psychological intervention that reduces novelty and enhances cognitive coping and sense of control can reduce cortisol responses to pentagastrin, a pharmacological HPA activator. This study attempted to identify the core factors that modulate HPA axis activity in this model. METHODS: Varying instructions were administered prior to drug exposure in a two-visit (placebo first) pentagastrin infusion paradigm. Healthy subjects (n = 40) were randomly assigned to one of four instruction groups: 1) standard instruction (SI); 2) full cognitive intervention (CI); 3) the CI control component alone; or 4) the CI novelty reduction/coping components alone. Blood samples were obtained via intravenous catheter before and after pentagastrin. RESULTS: Subjects receiving an intervention had smaller cortisol responses than subjects receiving standard instructions. Coping alone had as strong an impact as the more complex intervention that combined coping and control. Control alone also reduced cortisol but its HPA impact appeared less robust. CONCLUSIONS: Brief psychological manipulation can significantly reduce HPA activation in challenge paradigms. Cognitive preparation that focused on side effects, reduced potential surprise, and enhanced cognitive coping modulated HPA axis activity as effectively as a previously tested intervention that combined coping and control manipulations. A sense of control alone also reduced cortisol release. The results support development of control or coping techniques to combat negative health effects of stress that are mediated by HPA axis activation.

Downregulation of CCR5 on activated CD4 T cells in HIV-infected Indians.

BACKGROUND: HIV infection in India is unique as it occurs predominantly by CCR5-utilizing isolates that exhibit no co-receptor switch. OBJECTIVES: To study HIV-1 co-receptor dynamics on T cells and monocytes following viral infection. STUDY DESIGN: HIV co-receptor expression was evaluated by flow cytometry on various cell subsets in HIV-infected Indians and in vitro in human peripheral blood mononuclear cells infected with CCR5- or CXCR4-utilizing HIV-1. Transfection of the T cell line CEM-CCR5 (which expresses CD4, CCR5 and CXCR4) with HIV-1 Nef or Vpu expression vectors, or treatment with recombinant soluble gp120 from CCR5- and CXCR4-tropic HIV-1, was carried out to determine their effects on co-receptor expression. RESULTS: Indian HIV patients had fewer CD4+CCR5+ T cells and CCR5-expressing activated CD4+ T cells, but higher CXCR4-expressing activated CD4+ T cells compared with controls. Expression of CCR5 was not different on monocytes in HIV patients as compared to controls. The CCR5 downregulation on T cells was HIV infection specific and was governed by the co-receptor-utilization phenotype of the virus. The Nef and soluble gp120 proteins induced CCR5 downregulation, the latter in a co-receptor-utilization phenotype specific manner. CONCLUSIONS: The HIV-1 co-receptor dynamics in Indian patients is distinct from western patients and depends upon the virus surface protein. We propose this to be a viral survival strategy.

Cerebral ischemic preconditioning induces lasting effects on CA1 neuronal survival, prevents memory impairments but not ischemia-induced hyperactivity.

In ischemic preconditioning, prior exposure to a short 3-min global ischemia provides substantial protection against the deleterious effects of a subsequent prolonged ischemic insult in rats. The objective of the present study was to determine if the neuronal protection induced by ischemic preconditioning influence functional recovery following a 6-min ischemic insult in rats. Animals received either sham-operation, a 3-min ischemia, a preconditioning 3-min global ischemia followed 3 days later by a 6-min global ischemia or a single 6-min global ischemia. Open field habituation, memory performance in the 8-arm radial maze and object recognition were assessed at different intervals following ischemia. Our findings revealed that preconditioning reversed ischemia-induced spatial memory deficits in the 8-arm radial maze, as suggested by significant reduction of working memory errors in preconditioned as compared to ischemic animals. Preconditioning also attenuated ischemia-induced object recognition deficits at short-term intervals. Nonetheless, preconditioning failed to alter ischemia-induced hyperactivity as demonstrated by enhanced behavioral activity in the open field in both preconditioned and ischemic animals compared to 3-min ischemic and sham-operated rats. CA1 cell counts revealed significant neuronal sparing in preconditioned animals that was observed 6-month following reperfusion. Together, these findings suggest that neuronal survival in preconditioned rats is associated with significant improvements of hippocampal-dependent memory functions and, further support that ischemia-induced hyperactivity may not solely depend on selective neuronal damage to hippocampal neurons.

Effect of time of preparation on pentagastrin-induced symptom, endocrine and cardiovascular responses.

Pentagastrin is a cholecystokinin (CCK)-B agonist and laboratory panicogenic agent that produces endocrine (ACTH and cortisol), symptom (anxiety, panic) and cardiovascular (heart rate) responses. Although in vitro data have supported its chemical stability, preliminary data suggested that increasing time between drug preparation and drug infusion could reduce the magnitude of endocrine and symptom responses. The current study examined this possibility. Twenty-one healthy subjects presented at the University of Michigan General Clinical Research Center (GCRC) and had an intravenous catheter inserted. Heart rate, cortisol levels and subjective anxiety were measured before and after pentagastrin and placebo injections. Pentagastrin was prepared either within 60 min of IV infusion (Normal Preparation group) or at least 3.5 h prior to infusion (Early Preparation group). Relative to the Normal Preparation group, Early Preparation subjects had similar heart rate responses but significantly smaller cortisol and subjective anxiety responses. Early preparation of pentagastrin thus appears to weaken endocrine and subjective anxiety responses, highlighting the importance of attending to often overlooked procedural variables (e.g., time between preparation and administration) in studies of this type. The sensitivity of cortisol and anxiety responses to preparation time, but insensitivity of heart rate, is consistent with previous studies suggesting different thresholds of activation for the three response modalities. These differential sensitivities may suggest different and separable CCK-B stimulated pathways for each response, which combine to produce panic, rather than a single, unified CCK-B mediated panicogenic response.

Respiratory irregularity and stress hormones in panic disorder: exploring potential linkages.

Dysregulation within both respiratory control systems and the hypothalamic-pituitary adrenal (HPA) axis has been implicated in the pathophysiological of panic disorder. However, potential linkages between respiration and the HPA axis have rarely been examined in panic patients. We have previously published neuroendocrine and psychophysiological response data from a laboratory panic model using the respiratory stimulant doxapram. We now present a new, theoretically driven re-examination of linkages between HPA axis and respiratory measures in this model. Previous analyses showed elevated corticotropin (ACTH) and persistent tidal volume irregularity in panic patients, due to a high frequency of sighs. Regression analyses now show that tidal volume irregularity and sigh frequency were strongly predicted by pre-challenge ACTH levels, but not by subjective distress or panic symptoms. We predicted this relationship on the basis of our hypothesis that both the HPA axis and respiratory control systems may be reactive to contextual cues such as novelty or anticipation of future challenge. Follow-up work is needed to directly test this hypothesis.

HPA axis activity in patients with panic disorder: review and synthesis of four studies.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may play a role in panic disorder. HPA studies in patients with panic disorder, however, have produced inconsistent results. Seeking to understand the inconsistencies, we reexamined endocrine data from four studies of patients with panic disorder, in light of animal data highlighting the salience of novelty, control, and social support to HPA axis activity. Patients with panic disorder were studied (1) at rest over a full circadian cycle, (2) before and after activation by a panicogenic respiratory stimulant (doxapram) that does not directly stimulate the HPA axis, and (3) before and after a cholecystokinin B (CCK-B) agonist that is panicogenic and does directly stimulate the HPA axis. Patients with panic disorder had elevated overnight cortisol levels, which correlated with sleep disruption. ACTH and cortisol levels were higher in a challenge paradigm (doxapram) than in a resting state study, and paradigm-related ACTH secretion was exaggerated in patients with panic disorder. Panic itself could be elicited without HPA axis activation. Patients with panic disorder showed an exaggerated ACTH response to pentagastrin stimulation, but this response was normalized by prior exposure to the experimental context or psychological preparation to reduce novelty and enhance sense of control. Novelty is one of a number of contextual cues known from animal work to activate the HPA axis. The HPA axis abnormalities seen in patients with panic disorder in the four experiments reviewed here might all be due to exaggerated HPA axis reactivity to novelty cues. Most of the published panic/HPA literature is consistent with the hypothesis that HPA axis dysregulation in panic is due to hypersensitivity to contextual cues. This hypothesis requires experimental testing.

The CRH1 antagonist CP154,526 failed to alter ischemia-induced neurodegeneration and spatial memory deficits in rats but inhibited behavioral activity in the novel open field.

Corticotropin-releasing hormone (CRH) has been implicated in ischemia-induced neurotoxicity, due in part to excitatory effects at the hippocampus, and the demonstrated neuroprotective effects of centrally administered, non-specific CRH antagonists. However, a number of issues remain to be clarified from these studies, including the relative contribution of CRH receptor subtypes, and the efficacy of these compounds to alter ischemia-induced behavioral impairments. In the current study, a highly selective, systemically administered CRH1 antagonist (CP154,526) failed to reverse global ischemia-induced cell death in hippocampal CA1 neurons or spatial memory impairments as assessed in the radial arm maze. Similarly, central administration of alpha-helical CRH failed to confer protection against ischemic damage. Interestingly, CRH1 antagonism reversed ischemia-induced hyperactivity in a novel open field, suggesting that modulation of this behavior is independent of effects on hippocampal CA1 cell loss. Failure of the current study to demonstrate neuroprotective effects of either the selective or non-selective CRH antagonists tested challenges the proposed neurotoxic role of CRH in global ischemia. These findings are discussed in relationship to recent findings reconsidering the participation of CRH in excitotoxic-mediated cellular damage.

Cognitive modulation of the endocrine stress response to a pharmacological challenge in normal and panic disorder subjects.

CONTEXT: The hypothalamic-pituitary-adrenal (HPA) axis may mediate the deleterious effects of stress on health. It is sensitive to cognitive and emotional aspects of organism-environment interactions, such as familiarity, control, and social support. Scientific study of how such factors moderate human HPA axis activity has been limited. Their relevance to HPA axis disturbances in psychiatric patients is largely unexplored. OBJECTIVE: To determine whether cognitive manipulation can alter HPA axis activity in laboratory studies and whether patients with panic disorder are differentially sensitive to the manipulated factors. DESIGN: Pharmacological activation paradigm (cholecystokinin-B agonist pentagastrin) by which we examined symptom and endocrine effects on subjects randomly assigned to a standard introduction or a cognitive intervention. SETTING: Clinical research center. PARTICIPANTS: Recruited from university clinic and newspaper advertisements. Fourteen patients with panic disorder and 14 controls, individually matched for age and sex. Intervention Half of each group received a 9-minute cognitive intervention designed to reduce novelty, increase cognitive coping, and provide a sense of control. MAIN OUTCOME MEASURES: Corticotropin (ACTH) and cortisol levels. RESULTS: The cognitive intervention significantly reduced cortisol (P = .02) and ACTH (P = .01) levels, despite pentagastrin's robust stimulation of both hormones (P<.001). The intervention effect was evident in patients and controls, who did not differ in basal HPA axis activity or response to pentagastrin. They did differ in panic symptom responses, which were unaffected by the intervention, and in ACTH effects of the intervention. Patients' exaggerated anxiety responses to pentagastrin were normalized by the intervention. CONCLUSIONS: Cognitive/emotional manipulation can substantially modulate HPA axis responses to pharmacological activation in humans, and HPA disturbances in panic disorder may be secondary to manipulable cognitive/emotional sensitivities. Further study of such factors as novelty, control, and coping may help clarify the origins of HPA axis disturbance in psychiatric disorders and the mediators linking psychosocial stress to disease.