Evidence for hypothalamo-growth hormone dysfunction in panic disorder: profile of growth hormone (GH) responses to clonidine, yohimbine, caffeine, glucose, GRF and TRH in panic disorder patients versus healthy volunteers.

Given the abrupt and time-limited nature of daytime-awake and nocturnal-sleep panic attacks, several chemical and neuroendocrine challenge tests have been employed to investigate the neurobiology of "spontaneous" panic attacks. Previously we demonstrated that panic disorder patients have blunted growth hormone (GH) responses to clonidine, an alpha 2-adrenergic agonist. However, the mechanism of this blunted response and the role of hypothalamic-GH dysfunction, if any, remains unclear. To further delineate the status of hypothalamic-GH function in panic disorder, we review the literature and present original data on the GH responses to a number of different chemical and neuroendocrine challenge paradigms. Although stress-mediated increases in GH are thought to be a common correlate of stress in humans, our findings indicate that panic disorder patients have significantly blunted GH responses to clonidine, yohimbine, growth-hormone releasing factor, and caffeine compared to normal control subjects. A similar trend was noted in the delayed rise in GH after glucose challenge. There was no difference in the rate of abnormal GH responses to thyrotropin-releasing hormone in panic disorder compared to normal control subjects. No drug or neuroendocrine challenge, even if associated with marked increases in anxiety, produced a significantly enhanced GH response compared to normal control subjects. These findings provide support for a hyporesponsive hypothalamic-GH system in panic disorder. These observations, combined with preliminary observations from our clinic of short stature in several cases of prepubescent children with anxiety disorders, also underscore the need for assessing early growth patterns in individuals with panic disorder. Strategies for investigating the site(s) of possible neurotransmitter or hypothalamic-GH-somatomedin dysfunction are discussed.     

A method for monitoring medication omission error rates

A study was conducted of the number of doses omitted on eight patient care units in a hospital which employs a decentralized unit dose system. Omitted doses were doses of drugs that were returned to the pharmacy and that, as subsequently determined, should have been administered to patients. The number of omitted doses was 0.048 per patient day. The number of omitted doses per patient day varied among the patient care units. The results were reported to the Medication Practices Review Committee, a subcommittee of the Pharmacy & Therapeutics Committee. Subsequently, educational efforts by the Departments of Nursing and Pharmacy were directed towards reducing the omitted-dose rate. The study was repeated five months later. The number of omitted doses had fallen to 0.011 doses per day, a significant difference from the previous study. All patient care units but one had significantly fewer omitted doses, with the other patient care unit showing no change. This study showed that the rate of omitted doses can be estimated without the use of trained observers. Additionally, this method can be used to determine the changes in the omitted dose rate within a hospital.     

Fine structure of pancreatic adenocarcinoma induced in rats by 7,12-dimethylbenz(a)anthracene.

We induced pancreatic adenocarcinomas in Long-Evans rats by placing crystals, 2-3 mg, of 7,12-dimethylbenz[a]anthracene (DMBA) in a 2- to 3-mm incision in the "head" of the pancreas approximately 1 cm from the duodenum. The incisions were closed with one or two silk sutures. The animals were killed 4-10 months after DMBA implantation, and nodules were removed and routinely prepared for light and/or electron microscopic study. Histologic organization varied from normal, through areas of tubule-like structures, to sheets of pleomorphic tumor cells. Electron microscopic study of tumor cells revealed large electron-lucent nuclei that frequently had irregular outlines and prominent nucleoli. The predominant feature of the cytoplasm was abundant rough endoplasmic reticulum. Zymogen granules were rare. Adjacent cells sometimes were jointed by an apical junctional complex to form a lumen into which projected irregular microvilli. A basal lamina sometimes occurred at the bases of the tumor cells. The fine structural similarity of these tumor cells to acinar cells was noted.     

The diets of preschool children in Newcastle upon Tyne, 1968-71.

1. Ninety-one families containing 140 children under 4 years of age at enrolment were studied. At 1-monthly intervals, the children were weighed and measured and qualitative information about feeding habits was obtained. Weighed dietary surveys for periods of 5 d were made at approximately 8 months, 3 years, and 5 years of age; there were forty-six failures in 260 surveys attempted. 2. At the four specified ages, mean energy intakes were 3-75, 5-03, 5-82 and 6-75 MJ (896, 1203, 1392 and 1613 kcal)/d respectively. At 8 months, milk products provided on average, 43% of the total energy intake, and commerical baby foods provided 17%. These values decreased to 21 and 2% respectively at 20 months and there was little further change therafter. 3. Average intake of energy and of most nutrients met recommended intakes (Department of Health and Social Security, 1969). Iron intakes were marginal, and vitamin D intakes were low. 4. The energy intake of boys was significantly higher than that of the girls at 3 years of age, but the boys were not significantly heavier. The energy intake of children from "manual-worker" families was higher than that from "non-manual" families. Similarly, the energy intake of children from larger families was higher than that of children from smaller families. 5. Energy intakes were correlated with body-weights and with rates of gain in weight. Irrespective of body-weight, "big eaters" at 20 months tended to be "big eaters" at 3 years also.     

Community treatment orders: relationship to clinical care, medication compliance, behavioural disturbance and readmission

OBJECTIVE: The objective of this study was to investigate the readmission rate, and the level of patient disturbance and community care associated with readmission following Community Treatment Orders (CTOs) in New South Wales, Australia. METHOD: The readmission rates of all patients given CTOs within a 4-year period and a matched comparison group were investigated. The following factors were compared before, during and following a CTO: medication non-compliance, number of clinical services and duration of disturbed behaviour preceding hospitalisations. RESULTS: Of 123 patients on CTOs (mean length, 288 days; SD, 210 days), 38 were readmitted during the CTO, the majority in the first 3 months and a further 21 patients were readmitted following termination of the CTO. Evidence of lower severity of illness in the comparison patients prevented meaningful evaluation of the readmission rates of the two groups. While on CTOs, patients receiving depot medications showed high compliance and a significantly reduced readmission rate compared with that of patients receiving oral medications. In the 2 months prior to hospitalisations during CTOs, compared with those before or after CTOs, patients received more frequent consultations and showed a shorter duration of medication non-compliance and disturbed behaviour. The level of services in the 3 months following discharge were comparable for patients on CTOs and the comparison group. CONCLUSIONS: CTOs may reduce rehospitalisations by use of depot medication. Earlier and possibly more frequent readmissions in the CTO group shortened the disturbance associated with illness recurrence. It would appear that to establish a control group with equivalent severity of disorder necessary to evaluate the impact of CTOs requires a random allocation design.     

Adult medulloblastoma: prognostic factors and patterns of relapse

OBJECTIVE: To determine the patterns of relapse and the prognostic factors for adult medulloblastomas treated in the magnetic resonance imaging era. METHODS: Between 1986 and 1996, 32 adult patients (age, > or =16 yr) with medulloblastomas confined to the craniospinal axis were treated in our institutions. Twenty cases involved classic histological features and 12 involved the desmoplastic variant. The Chang staging distribution was as follows: T1, 2; T2, 17; T3, 10; T4, 3; M0, 24; M1, 1; M2, 4; M3, 3. Brainstem invasion was present in nine patients. Lesions were midline in 13 cases and lateral in 19. Resection was complete in 17 cases, subtotal in 6, and partial in 5, with biopsy only in 4 cases. All patients received postoperative radiotherapy, with median doses of 36 Gy to the entire craniospinal axis and 55 Gy to the posterior fossa. Twenty-four patients received chemotherapy (20 before radiotherapy, 3 after radiotherapy, and 1 before and after radiotherapy). RESULTS: With a median follow-up period of 5.4 years, 17 patients experienced recurrences. At 5 and 8 years, overall survival rates were 83 and 45% and disease-free survival rates were 57 and 40%, respectively. The 5- and 8-year posterior fossa control rates were 67 and 59%, respectively. Twenty-nine percent of all relapses occurred more than 5 years after treatment. The posterior fossa was the most common site of relapses. In univariate analyses, factors adversely affecting posterior fossa control were less than complete resection (P<0.001), the presence of brainstem invasion (P = 0.02), and the use of chemotherapy (P = 0.03). The overall radiotherapy duration was marginally significant in predicting posterior fossa control, with 5-year posterior fossa control rates of 81 and 49% for durations of less than 48 days and 48 days or more, respectively (P = 0.06). In a multivariate analysis, complete resection was predictive of improved posterior fossa control (P = 0.02) and disease-free survival (P = 0.02) rates. Of the eight low-risk patients who received radiotherapy alone, three experienced recurrences in the bone as the only site of relapse. CONCLUSION: Late relapse is common among adult patients with medulloblastomas, and long-term follow-up monitoring is important. Because of the high risk of systemic failure among the low-risk patients treated with radiotherapy alone, the role of chemotherapy for this group of patients needs to be further investigated. Complete resection, the absence of brainstem invasion, and an overall radiotherapy duration of less than 48 days are important prognostic factors.     

Thymic Function and Output of Recent Thymic Emigrant T Cells During Intracranial Glioma Progression

One of the hallmarks of patients with glioblastoma multiforme (GBM) is profound lymphopenia mostly confined to the T cell lineage. A deficiency in the production of naïve T cells from the thymus could contribute to the lymphopenia seen in GBM patients. In this study we asked whether thymic function and the production of recent thymic emigrant (RTE) T cells from the thymus was influenced by intracranial (i.c.) glioma progression. We found significant thymic involution in animals with progressive i.c. gliomas. Involuted thymi from animals with progressive i.c. T9.F gliomas showed dramatic losses of CD4⁺CD8⁺ (DP) thymocytes. Microscopic analysis complemented those findings by demonstrating a reversal of the typical cortico-medullary structure. Significant increases in apoptosis accompanied the rapid loss of viable thymocytes, which was prevented in part by adrenalectomy, suggesting a dominant role for endogenous glucocorticoids. This thymic involution was also associated with a significant decrease in peripheral RTE T cells, reflecting the diminished thymic function. Finally, we found that CD8⁺ RTE T cells were enriched in progressively growing T9 gliomas, which points to an immunological role for RTE's in anti-glioma immunity. Our findings may shed light on the significance of thymic function for anti-glioma immunity and the response to immunotherapeutic treatment paradigms.