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.     

Comorbid dysthymia and substance disorder: treatment history and cost

OBJECTIVE: The purpose of this study was to determine the treatment history and cost of previous treatment among patients with comorbid substance-related disorder and dysthymia, as compared to patients with substance-related disorder only. METHOD: Retrospective data were obtained regarding past treatment. Treatment cost was calculated on the basis of the 1996 cost of various treatment modalities. The setting was alcohol-drug programs located within departments of psychiatry in two centers. A total of 642 patients were assessed, of whom 39 had substance-related disorder and dysthymia and 308 had substance-related disorder only (the remaining patients had other comorbid conditions). Data collection instruments included an interview-based questionnaire regarding previous psychiatric and substance abuse treatment. Current cost of treatment in various settings was assessed on the basis of a survey of facilities used by patients in this area. RESULTS: Patients with substance-related disorder and dysthymia had received more substance-related disorder treatment in 18 of 20 measures. Patients with substance-related disorder and dysthymia used 4.7 times more substance-related disorder treatment dollars than patients with substance-related disorder only, although their demographic characteristics were similar. Past self-help activities and pharmacotherapy were remarkably similar for both groups. Although substance-related disorder treatment differed considerably between the two groups of patients, other types of psychiatric treatment (i.e., non-substance-related treatment) did not differ between the two groups. CONCLUSIONS: Patients with substance-related disorder and dysthymia are referred to (or seek) substance-related disorder treatment more often than patients with substance-related disorder only but are referred to (or seek) non-substance-related psychiatric treatment no more often than patients with substance-related disorder only. The cost of previous substance-related disorder treatment was several times higher for the patients with substance-related disorder and dysthymia.     

Boosting with recombinant vaccinia increases immunogenicity and protective efficacy of malaria DNA vaccine

To enhance the efficacy of DNA malaria vaccines, we evaluated the effect on protection of immunizing with various combinations of DNA, recombinant vaccinia virus, and a synthetic peptide. Immunization of BALB/c mice with a plasmid expressing Plasmodium yoelii (Py) circumsporozoite protein (CSP) induces H-2Kd-restricted CD8+ cytotoxic T lymphocyte (CTL) responses and CD8+ T cell- and interferon (IFN)-gamma-dependent protection of mice against challenge with Py sporozoites. Immunization with a multiple antigenic peptide, including the only reported H-2Kd-restricted CD8+ T cell epitope on the PyCSP (PyCSP CTL multiple antigenic peptide) and immunization with recombinant vaccinia expressing the PyCSP induced CTL but only modest to minimal protection. Mice were immunized with PyCSP DNA, PyCSP CTL multiple antigenic peptide, or recombinant vaccinia expressing PyCSP, were boosted 9 wk later with the same immunogen or one of the others, and were challenged. Only mice immunized with DNA and boosted with vaccinia PyCSP (D-V) (11/16: 69%) or DNA (D-D) (7/16: 44%) had greater protection (P < 0. 0007) than controls. D-V mice had significantly higher individual levels of antibodies and class I-restricted CTL activity than did D-D mice; IFN-gamma production by ELIspot also was higher in D-V than in D-D mice. In a second experiment, three different groups of D-V mice each had higher levels of protection than did D-D mice, and IFN-gamma production was significantly greater in D-V than in D-D mice. The observation that priming with PyCSP DNA and boosting with vaccinia-PyCSP is more immunogenic and protective than immunizing with PyCSP DNA alone supports consideration of a similar sequential immunization approach in humans.