Nerve-induced disruption and reformation of beta1-integrin aggregates during development of the neuromuscular junction

Assertive Community Treatment (ACT) is now recognized as the model proven to be most successful in working with clients with long-term, severe mental illness. The first documented research replication study of ACT was Harbinger of Grand Rapids, in Kent County, Michigan. The Harbinger program influenced significant programmatic changes throughout the public mental health system in Michigan. This paper describes this evolution in community mental health locally and why these changes came about. The state-level strategy to implement replications of Harbinger is described, as well as funding and monitoring mechanisms that have now resulted in over 100 successful ACT programs in Michigan. For mental health administrators, the implications discussed include the future of ACT promotion and implementation, within the reality of a managed care framework.     

Reduced response of the hypothalamo-pituitary-adrenal axis to alpha1-agonist stimulation during lactation

To determine whether altered noradrenergic activation of the hypothalamo-pituitary-adrenal (HPA) axis contributes to the attenuated neuroendocrine response to stress observed during lactation, the effect of intracerebroventricular injection of the alpha1-agonist methoxamine (100 microg) was compared between virgin and lactating rats. Virgin rats showed significant increases in plasma corticosterone after methoxamine, reaching 317 +/- 44 ng/ml at 10 min and remaining significantly elevated for more than 120 min, but lactating rats showed no significant increase in corticosterone levels. Furthermore, methoxamine induced an increase in paraventricular nucleus (PVN) CRF messenger RNA expression in virgin, but not lactating, animals. Both groups of rats exhibited comparable elevations in plasma PRL after methoxamine treatment. Arginine vasopressin messenger RNA expression within the parvocellular PVN was greater in the lactating animals than in the virgin controls, but methoxamine injection was without further effect. Studies performed on ovariectomized virgin rats and ovariectomized rats receiving estradiol or progesterone replacement failed to reproduce the attenuated HPA responses seen after methoxamine treatment, although methoxamine-induced PRL levels were greatly increased by estradiol, probably arising from an effect on hormone synthesis. In vitro electrophysiological recordings of PVN neurons in hypothalamic slices from proestrous virgin and lactating rats showed that 45-52% of neurons in both groups exhibited excitatory responses to 10(-4) M methoxamine, but there was a differential response to 10(-5) M methoxamine, with PVN neurons from lactating animals failing to show a response. These data show a selective down-regulation of alpha1-mediated activation of the HPA axis in lactating animals. This may contribute to the attenuated stress-induced activation of the HPA axis during lactation.     

Refractory giant cell arteritis with spinal cord infarction

We report an elderly patient with aggressive steroid-refractory giant cell arteritis manifesting as myelopathy and bilateral visual loss while on treatment. Pathologically, spinal cord infarction was observed and was due to extensive necrotizing granulomatous arteritis of spinal arteries. Spinal cord damage in giant cell arteritis is rare. One prior autopsy report of spinal cord infarction in giant cell arteritis did not identify vasculitic changes in the spinal arteries.     

Recent developments in assessing medical students

Most medical schools in the UK are revising their undergraduate courses in response to the recommendations published by the General Medical Council Education Committee in Tomorrow's doctors. However, achievement of the objectives of curricular change is attendant on revision of the assessment process. This paper reviews traditional and more recently developed methods for assessment of medical education in the light of the General Medical Council's recommendations which relate specifically to summative assessment of the core curriculum. The importance of reliability and validity is highlighted, and the case for criterion-referenced assessment is examined.     

Purification, characterization, and crystallization of Escherichia coli ribokinase

Ribokinase phosphorylates ribose to form ribose-5-phosphate in the presence of ATP and magnesium. The phosphorylated sugar can enter the pentose phosphate pathway or be used for the synthesis of nucleotides, histidine, and tryptophan. Ribokinase belongs to the PfkB family of carbohydrate kinases, for which no three-dimensional structure is currently known. We describe an improved purification protocol for Escherichia coli ribokinase and give evidence from light-scattering and gel filtration studies that the protein forms a dimer in solution. Several types of crystals are also described that have been obtained of apo ribokinase, ribokinase in the presence of ATP, and in a ternary complex with an ATP-analogue and ribose. The latter crystals give the best X-ray diffraction. A complete data set has been collected at the synchrotron source in Hamburg, to 2.6 A resolution using a frozen crystal. The crystals belong to space group P6(1)22 or P6(5)22 with cell parameters a = b = 95 A and c = 155 A.     

Rhesus brain gas tension and learned task performance responses to normoxic and hyperoxic breathing

The impact of extended exposure to 21 and 100% O2 breathing mixtures on brain tissue oxygenation and performance of a learned task was studied in seven rhesus monkeys. Trained in the Sidman Avoidance Task, the animals were exposed to either breathing mixture for a period of 3.5 h in which brain tissue PO2, PCO2, and PN2 were observed. With 100% O2, PO2 and PCO2 rose significantly (less than 0.01 and less than 0.05, respectively) above control levels while PN2 fell significantly (less than 0.01) below its baseline value. With 100% O2 no statistically significant difference in gas tension values was shown for performance vs. nonperformance conditions. There was no difference in the number of shocks received with either breathing mixture. Lever press response frequency decreased throughout the experiment for both groups. During the last performance session, response frequency for the 100% O2 group leveled off, whereas for the 21% O2 group it continued to decrease.     

A breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated from different open reading frames

Infusion of TIL586 along with IL-2 into the autologous patient with metastatic melanoma resulted in the objective regression of tumor. Here, we report that screening a cDNA library from the 586mel cell line using CTL clones derived from TIL586 resulted in the isolation of a gene, CAG-3 (cancer Ag gene 3). Sequence analysis revealed that CAG-3 encodes an open reading frame identical to NY-ESO-1, which was recently reported to be recognized by autologous serum from a patient with esophageal cancer. Thus, NY-ESO-1 appears to be an immune target for both Ab- and T cell-mediated responses. Significantly, NY-ESO-1-specific CTL clones were capable of recognizing two HLA-A31-positive fresh and cultured breast tumors. To our knowledge, this represents the first direct demonstration that tumor-specific CTL clones can recognize both breast and melanoma tumor cells. A 10-mer antigenic peptide ESO10-53 (ASGPGGGAPR) was identified from the normal open reading frame of NY-ESO-1 based on its ability to sensitize HLA-A31-positive target cells for cytokine release and specific lysis. Interestingly, two additional CTL clones that were sensitized with NY-ESO-1 recognized two overlapping antigenic peptides derived from an alternative open reading frame of the same gene. These findings indicate that CTLs simultaneously responded to two different gene products translated from the normal and alternative reading frames of the same gene. Understanding of this mechanism by which the alternative reading frame is translated may have important implications in tumor immunology.     

Respiratory effects of kynurenic acid microinjected into the ventromedullary surface of the rat

Several studies demonstrate that, within the ventral medullary surface (VMS), excitatory amino acids are necessary components of the neural circuits involved in the tonic and reflex control of respiration and circulation. In the present study we investigated the cardiorespiratory effects of unilateral microinjections of the broad spectrum glutamate antagonist kynurenic acid (2 nmol/200 nl) along the VMS of urethane-anesthetized rats. Within the VMS only one region was responsive to this drug. This area includes most of the intermediate respiratory area, partially overlapping the rostral ventrolateral medulla (IA/RVL). When microinjected into the IA/RVL, kynurenic acid produced a respiratory depression, without changes in mean arterial pressure or heart rate. The respiratory depression observed was characterized by a decrease in ventilation, tidal volume and mean inspiratory flow and an increase in respiratory frequency. Therefore, the observed respiratory depression was entirely due to a reduction in the inspiratory drive. Microinjections of vehicle (200 nl of saline) into this area produced no significant changes in breathing pattern, blood pressure or heart rate. Respiratory depression in response to the blockade of glutamatergic receptors inside the rostral VMS suggests that neurons at this site have an endogenous glutamatergic input controlling the respiratory cycle duration and the inspiratory drive transmission.