Single-cell fate mapping reveals widespread clonal ignorance of low-affinity T cells exposed to systemic infection

T cell ignorance is a specific form of immunological tolerance. It describes the maintenance of naivety in antigen-specific T cells in vivo despite the presence of their target antigen. It is thought to mainly play a role during the steady state, when self-antigens are presented in absence of costimulatory signals and at low density or to T cells of low affinity. In how far antigen-specific T cells can also remain clonally ignorant to foreign antigens, presented in the inflammatory context of systemic infection, remains unclear. Using single-cell in vivo fate mapping and high throughput flow cytometric enrichment, we find that high-affinity antigen-specific CD8⁺ T cells are efficiently recruited upon systemic infection. In contrast, most low-affinity antigen-specific T cells ignore the priming antigen and persist in the naïve state while remaining fully responsive to subsequent immunization with a high-affinity ligand. These data establish the widespread clonal ignorance of low-affinity T cells as a major factor shaping the composition of antigen-specific CD8⁺ T cell responses to systemic infection.     

The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes

1. The antipsychotic drug haloperidol can induce a marked QT prolongation and polymorphic ventricular arrhythmias. In this study, we expressed several cloned cardiac K⁺ channels, including the human ether-a-go-go related gene (HERG) channels, in Xenopus oocytes and tested them for their haloperidol sensitivity.
2. Haloperidol had only little effects on the delayed rectifier channels Kv1.1, Kv1.2, Kv1.5 and I_sK, the A-type channel Kv1.4 and the inward rectifier channel Kir2.1 (inhibition <6% at 3 μM haloperidol).
3. In contrast, haloperidol blocked HERG channels potently with an IC₅₀ value of approximately 1 μM. Reduced haloperidol, the primary metabolite of haloperidol, produced a block with an IC₅₀ value of 2.6 μM.
4. Haloperidol block was use- and voltage-dependent, suggesting that it binds preferentially to either open or inactivated HERG channels. As haloperidol increased the degree and rate of HERG inactivation, binding to inactivated HERG channels is suggested.
5. The channel mutant HERG S631A has been shown to exhibit greatly reduced C-type inactivation which occurs only at potentials greater than 0 mV. Haloperidol block of HERG S631A at 0 mV was four fold weaker than for HERG wild-type channels. Haloperidol affinity for HERG S631A was increased four fold at +40 mV compared to 0 mV.
6. In summary, the data suggest that HERG channel blockade is involved in the arrhythmogenic side effects of haloperidol. The mechanism of haloperidol block involves binding to inactivated HERG channels.

     

Daytime sleep in myotonic dystrophy is not caused by sleep apnoea.

Daytime sleepiness is common in myotonic dystrophy and might be attributed to disturbed nocturnal breathing. Seventeen out of 22 patients complained of excessive daytime sleepiness, resembling "idiopathic hypersomnolence". Sleep apnoea might have contributed to daytime sleepiness in only three of 17 patients. Treatment with the central stimulant methylphenidate produced sustained benefit in seven out of 11 patients tested. Daytime sleepiness in myotonic dystrophy is usually caused by dysfunction of central sleep regulation and not by disturbed nocturnal breathing.     

Primary colorectal non-Hodgkin's lymphoma

Background: The gastrointestinal tract is the most common site of extranodal involvement in non-Hodgkin's lymphoma (NHL). Primary colorectal NHL comprises 13–18% of all gastrointestinal NHL but is not commonly reported as a separate entity. Methods: This was a retrospective review of the medical records of 19 patients over a 16-year period to evaluate the clinical features and behavior of colorectal NHL. Results: A pediatric group of seven male patients presented at an early stage with acute symptomatology. The primary tumor was located in the ileocecum in all cases and intussusception was common. An adult group of 12 patients presented at a later stage with chronic symptomatology. Staging study results were positive by bone marrow biopsy in four of 16 patients (25%), by lymphangiography in six of 11 patients (54.5%), and by gallium scan in eight of 10 patients (80%). Seven patients relapsed a median of 8 months after treatment. Three other patients died during treatment, one died of other causes, and one died without receiving treatment. The remaining seven patients are alive from 41 to 231 months without evidence of disease. Five of these patients are in the pediatric group, where the median survival was >72 months. The overall median survival was 45 months. Conclusion: Colorectal NHL is a disease that affects both the pediatric and adult population. Although pediatric patients have an excellent prognosis with anticipated long-term survival after treatment, long-term survival can be expected in 50% of adult patients. In both groups of patients, multimodality therapy with surgery, chemotherapy, and radiation is the treatment of choice.Presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

Unsuspected idiopathic mediastinal fibrosis complicating coronary bypass operation

A 66-year-old woman was referred for coronary bypass operation to the left anterior descending and the circumflex arteries. She had a systemic inflammatory process of unknown origin. On opening the pericardium, fibrotic plaques encircling the entire ascending aorta were found. Aortic cannulation and proximal anastomosis of the planned vein graft were impossible. The right internal mammary was anastomosed to the left anterior descending artery, the left to the obtuse marginal after femoral arterial cannulation. Pathologic examination revealed idiopathic mediastinal fibrosis.     

Coronary artery bypass procedures in septuagenarians are justified. Short and long-term results

BACKGROUND: Elective coronary artery bypass surgery can be performed with low operative mortality. There is a controversial discussion whether short-term and long-term results of CABG justify this procedure in elderly patients. METHODS: To add to this discussion, we evaluated retrospectively, the clinical profile, operative technique, short- and long-term results of 1127 patients over 70 years of age who underwent myocardial revascularization between January 1985 and December 1996. RESULTS: Mean age of the cohort was 73.9 years and it rose continuously. In 1996, septuagenarians represented 21.5% of our coronary patients, in comparison to 6.4% in 1985. Analysis of risk factors showed an increasing prevalence of renal failure, obesity, hyperuricemia and a history of smoking. Preoperatively, 87% of our patients were in NYHA-class III or IV, and thus operated to relieve severe symptoms. The percentage of emergent operations decreased over the observed period by 10.3%. The internal mammary artery was used with rising frequency (44.8% in 1985-1992 vs 61.5% in 1993-1996). The number of simultaneous valve replacements increased, too. Postoperatively, we noted a rising incidence of respiratory failure (17.1%) and neurological disorders (13.7%). On the other hand, the need for intra-aortic balloon pumping and hemofiltration declined by 6.6% and 2.9%, respectively. Perioperative mortality (< or =24 hrs) was 3.65%, hospital mortality (< or =30 days) was 9.64%. The actuarial survival (standard error) at 1 year was 82% (+/-4.3%), and 65.7% (+/-3.8%) at 5 years. CONCLUSIONS: Our data suggest that coronary artery bypass grafting can be performed in septuagenarians at an acceptable risk. Since the large majority of patients improve symptomatically, surgery is a recommendable option for a growing number of elderly patients suffering from severe angina.     

Incarcerated postraumatic intercostal lung hernia. Case report and review of the literature

Traumatic lung hernia is a rare diagnosis. A 52-year-old female motorvehicle passenger was admitted as a trauma patient after a motorvehicle accident. She was found to have an incarcerated lung hernia. Size of the hernia, incarceration and respiratory insufficiency mandated immediate surgical intervention with reposition, drainage and stabilisation of the chest wall. The postoperative course was uneventful. The management of the patient is discussed and the available literature reviewed.     

Activity of standard and investigational cytotoxic drugs in primary cultures of tumor cells from patients with kidney and urinary bladder carcinomas

PURPOSE: In vitro tumor models could support the process of development of new cytotoxic drugs and selection of suitable drugs for the individual patient. We investigated whether the testing of tumor cells from patients with kidney or urinary bladder carcinoma by fluorometric microculture cytotoxicity assay (FMCA) could provide clinically relevant data for these tumor types. MATERIALS AND METHODS: A total of 45 tumor samples from patients with kidney or urinary bladder carcinoma were compared with 247 samples of other tumor types with respect to sensitivity to 8 standard and 6 investigational cytotoxic drugs in the FMCA, a 72 hour assay based on the concept of total cell kill. In bladder carcinomas, sensitivity to standard drugs was correlated to various tumor characteristics. RESULTS: The technical success rate for kidney and bladder carcinomas was high; approximately 90% of the samples could be analyzed successfully. Kidney carcinomas were highly resistant to standard drugs and bladder carcinomas essentially as sensitive as carcinomas of the breast and ovary but with a steeper dose-response relationship. In bladder carcinoma there was no clear relationship between tumor stage, grade, ploidy, mitoses or p53 expression and drug sensitivity. Except for suramin, kidney carcinomas were poorly sensitive to the investigational drugs CdA, gemcitabine, paclitaxel, vinorelbine and topotecan. In bladder carcinomas paclitaxel, gemcitabine and suramin showed promising activity. CONCLUSIONS: The FMCA seems suitable for cytotoxic drug sensitivity testing of urinary tract carcinomas. This technique may have a role in new drug development in these tumor types.