The role of anergy in peripheral T cell unresponsiveness

When a T cell's encounter with specific antigen results in good signaling through the T cell antigen receptor yet does not lead to a proliferative response, the T cell enters a state of nonresponsiveness, or anergy. Anergy induction can result from a number of different situations, including antigen presentation by costimulation-deficient or "non-professional" antigen presenting cells, pharmacological blocking of T cell proliferation, or chronic stimulation of the T cell receptor by antigen. Anergy is a long-lived but temporary state characterized by a profound inability of the T cell to produce IL-2. Other effector functions may be affected to variable degrees. Anergy has been characterized most carefully under in vitro conditions, but several experimental models have demonstrated that T cells can also become anergic in vivo. This mechanism for tolerance induction may help to ensure that any mature autoreactive T cells which escape thymic deletion are unable to respond to host tissues. Furthermore, an understanding of the mechanism of anergy induction will most certainly lead to beneficial clinical applications, including improving graft acceptance and avoiding such deleterious immune responses as autoimmunity and allergy.     

Long latency postural reflexes are under supraspinal dopaminergic control

Scaling of posturally stabilizing long latency (LL) reflexes in tibialis anterior muscles induced by "toe-up" rotational perturbations is abnormal in standing patients with Parkinson's disease. To investigate the contribution of dopaminergic pathways to abnormal scaling, we studied LL reflexes in 22 patients with selective hypodopaminergic syndromes: 10 psychiatric patients taking chronic neuroleptic medication (7 with mild parkinsonism), 8 patients with young-onset Parkinson's disease, and 4 patients with MPTP-induced parkinsonism. Results were compared with those of 10 healthy controls. Stimuli consisted of (a) 10 serial (predictable) perturbations of 4 degrees amplitude, (b) 10 serial (predictable) perturbations of 10 degrees amplitude, and (c) 20 randomly mixed (unpredictable) perturbations of either 4 or 10 degrees amplitude. In normal subjects, LL reflex amplitudes were adapted to match predictable variations in stimulus size, whereas under unpredictable conditions a "default" response emerged that anticipated the 10 degrees perturbation. LL reflex scaling under predictable conditions was intact in patients with neuroleptic-induced parkinsonism and young-onset Parkinson's disease, but the large default LL response under unpredictable conditions was absent. In patients with MPTP-induced parkinsonism, LL reflex scaling was absent during both predictable and unpredictable conditions. We conclude that abnormal scaling of posturally stabilizing LL reflexes is related to decreased supraspinal dopaminergic influence.     

Prognostic factors in resectable gastric cancer: results of EORTC study no. 40813 on FAM adjuvant chemotherapy

BACKGROUND: The high incidence of locoregional recurrences and distant metastases after curative surgery for gastric cancer calls for improved locoregional control and systemic adjuvant treatment. METHODS: In a randomized clinical trial on adjuvant FAM2 chemotherapy, quality of surgery was evaluated by comparing surgical and pathology data. Univariate and multivariate analysis was made to evaluate the effect of prognostic factors on survival and time of recurrence in relation to patients, tumor, and therapy. RESULTS: Of 314 patients randomized from 28 European institutions, 159 comprised the control and 155 the FAM2 group. After a median follow-up of 80 months, no statistically significant difference was found between survivals. However, for recurrence time, treated patients had a significant advantage over controls (p = 0.02). At univariate analysis, statistically significant differences in survival and time to progression emerged for T, N, disease stage and "adequacy" of surgery. The multivariate analysis retained preoperative Hb level, T, N, and "adequacy" of surgery for time of survival; and T, N, "adequacy" of surgery and adjuvant chemotherapy for recurrence time. CONCLUSIONS: Disease stage is the most important prognostic factor. "Adequate" surgery has an important effect. Adjuvant FAM2 delayed time of recurrence, but did not influence overall survival.     

Surgical management of total anomalous pulmonary venous drainage: impact of coexisting cardiac anomalies

BACKGROUND: Recent reports have cited improving results for surgical management of isolated total anomalous pulmonary venous drainage. Complex cases (with other cardiac anomalies) are less frequently reported and are associated with higher mortality. METHODS: Retrospective review identified 170 consecutive patients treated for total anomalous pulmonary venous drainage from 1982 to 1996: 44 cases were "complex" (with significant associated cardiac lesions) and 126 cases were "simple." RESULTS: Operative mortality for simple cases decreased from 26% to 8%, and mortality for complex cases remained constant at 52%. Age, size, and the presence of atrial isomerism were univariate predictors of mortality. Multivariable analysis identified only univentricular hearts and associated cardiac lesions as predictors of operative mortality. Pulmonary artery (n = 16) and arteriopulmonary (n = 7) shunting strategies for complex cases resulted in less than 30% long-term survival. CONCLUSIONS: Despite improvement in survival for simple cases, management of total anomalous pulmonary venous drainage with single-ventricle hearts or other associated cardiac lesions remains problematic.     

Passive but not active CD8+ T cell-based immunotherapy interferes with liver tumor progression in a transgenic mouse model

To evaluate tumor immunotherapies, we used transgenic mice that harbor a progressive liver tumor associated with the expression of the SV40 large tumor T oncoprotein (SV40-T). To induce "self" tumor Ag-specific CD8+ T cells, mice were injected with an immunodominant SV40-T CTL epitope mixed with a heterologous helper peptide. Despite repeated injections, this vaccine failed to raise a tumor-specific CD8+ T cell response that was efficient enough to counteract tumors. Although coimmunization with SV40-T CTL epitope and heterologous helper peptide efficiently recruited the respective Th cells, only low-avidity SV40-T-specific CD8+ T cells were activated. Furthermore, major alterations in SV40-T-specific B and Th cell responses were characterized. In contrast, transfers of higher-avidity CTLs specific for the same SV40-T epitope were effective in counteracting tumors. These results suggest that passive therapies targeted to self tumor Ag may be more suitable than active immunization in the treatment of spontaneous tumors.     

Measurement of amide hydrogen exchange by MALDI-TOF mass spectrometry

Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) was used to determine amide proton/deuteron (H/D) exchange rates. The method has broad application to the study of protein conformation and folding and to the study of protein-ligand interactions and requires no modifications of the instrument. Amide protons were allowed to exchange with deuterons in buffered D2O at room temperature, pD 7.25. Exchanged deuterons were "frozen" in the exchanged state by quenching at pH 2.5, 0 degree C and analyzed by MALDI-TOF MS. The matrix mixture consisted of 5 mg/mL alpha-cyano-4-hydroxycinnamic acid, acetonitrile, ethanol, and 0.1% TFA. The matrix was adjusted to pH 2.5, and the chilled MALDI target was rapidly dried. Deuteration of amide protons on cyclic AMP-dependent protein kinase was measured after short times of incubation in deuterium by pepsin protein digestion and MALDI-TOF MS analysis. The unseparated peptic digest was analyzed in a single spectrum of the mixture. From five spectra, H/D exchange rates were determined for some 40 peptides covering 65% of the protein sequence.     

Isolation and characterization of a novel facultatively alkaliphilic Nitrobacter species, N. alkalicus sp. nov

BACKGROUND: The American College of Rheumatology (ACR) established criteria to discriminate among patients with seven types of vasculitis. Although designated as "classification criteria" for research, these criteria are often used for diagnosis. OBJECTIVE: To examine the operating characteristics of the 1990 ACR classification criteria in the diagnosis of Wegener granulomatosis, giant-cell arteritis, polyarteritis nodosa, and hypersensitivity vasculitis. DESIGN: Prospective cohort study. SETTING: University medical center and Veterans Affairs medical center. PATIENTS: 198 consecutive patients referred to rheumatologists for evaluation of possible vasculitis. Measurements: Blinded chart audits were done to classify patients according to the 1990 ACR classification criteria for Wegener granulomatosis, polyarteritis nodosa, giant-cell arteritis, and hypersensitivity vasculitis on the basis of the patients' initial presentation. Chart audits done 2 to 8 months after baseline provided the patients' final diagnoses, which were considered the gold standard, as in the development of the ACR criteria. Test operating characteristics of the ACR classification criteria were calculated according to 2 x 2 tables for the entire cohort and for only the patients with a final diagnosis of vasculitis. RESULTS: Vasculitis was diagnosed in 51 (26%) patients. Thirty-eight (75%) of 51 patients with vasculitis and 31 (21%) of 147 patients without vasculitis met ACR criteria for one or more types of vasculitis. The positive predictive values for the four vasculitides according to ACR criteria were 17% to 29% for the entire cohort and 29% to 75% for only the patients with a final diagnosis of vasculitis. CONCLUSION: The 1990 ACR classification criteria function poorly in the diagnosis of specific vasculitides.     

The rotator cuff-deficient arthritic shoulder: diagnosis and surgical management

The symptomatic rotator cuff-deficient, arthritic glenohumeral joint poses a complex problem for the orthopaedic surgeon. Surgical management can be facilitated by classifying the disorder in one of three diagnostic categories: (1) rotator cuff-tear arthropathy, (2) rheumatoid arthritic shoulder with cuff deficiency, or (3) degenerative arthritic (osteoarthritic) shoulder with cuff deficiency. If it is not possible to repair the cuff defect, surgical management may include prosthetic arthroplasty, with the recognition that only limited goals are attainable, particularly with respect to strength and active motion. Glenohumeral arthrodesis is a salvage procedure when other surgical measures have failed. Arthrodesis is also indicated in patients with deltoid muscle deficiency. Humeral hemiarthroplasty avoids the complications of glenoid loosening and is an attractive alternative to arthrodesis, resection arthroplasty, and total shoulder arthroplasty. The functionally intact coracoacromial arch should be preserved to reduce the risk of anterosuperior subluxation. Care should be taken not to "overstuff" the gleno-humeral joint with a prosthetic component. In cases of significant internal rotation contracture, subscapularis lengthening is necessary to restore anterior and posterior rotator cuff balance. If the less stringent criteria of Neer's "limited goals" rehabilitation are followed, approximately 80% to 90% of patients treated with humeral hemiarthroplasty can have satisfactory results.     

DDAVP use during pregnancy: an analysis of its safety for mother and child

Synthetic 1-deamino-8-D-arginine-vasopressin (DDAVP) is used in the management of diabetes insipidus (DI). We conducted a systematic literature review of DDAVP use during pregnancy, with particular attention to its safety for both mother and infant. Studies were identified through Ovid MEDLINE from 1976 to July 1997 using the combined terms "desmopressin," "DDAVP," and "pregnancy". Review articles and published letters were also explored. One hundred one articles were retrieved, of which 20 met all the inclusion criteria. Included in the 20 articles were 53 cases with the use of DDAVP for the management of DI. The therapeutic daily dose of DDAVP was approximately 29 micrograms intranasally (range 7.5-100 micrograms), with adequate DI control observed. Three of 14 women with sufficient information developed preeclampsia, a nonsignificant difference from the expected rate of 5 percent (the Fisher exact test, 2-P = .08). The mode of delivery was defined for 22 cases, with 16 uneventful vaginal births, and six cesarean delivery. There was no evidence of a drug interaction among the five women who received both DDAVP and intravenous oxytocin. Information was available on 49 live births born to DI mothers on DDAVP. The mean gestational age at delivery was 37.4 weeks (SD 1.3 weeks), with an estimated mean birth weight of 2963.8 gm (range 2000-4420 gm). Forty-three offspring were reported as healthy (event rate 87.8 percent; 95 percent CI 77.2-95.3 percent). Of the remaining six infants, one developed DI at 18 months of age; a second was under 2500 gm at birth, but survived; the third developed hypotonia and failure to thrive at 21 months, two others had Down syndrome; and the sixth died of severe cardiac anomalies. Similar data were seen among the 41 infants whose mothers had used DDAVP throughout pregnancy. In conclusion, DDAVP use during pregnancy seems to be safe for both mother and child. Delivery does not seem to be augmented by its use, nor are there likely any associated adverse neonatal effects. A large database of DDAVP use during pregnancy is needed to confirm these findings.