Expansion of mycobacterium-reactive gamma delta T cells by a subset of memory helper T cells.

Human gamma delta T cells expressing the V gamma 9/V delta 2 T-cell receptor have been previously found to proliferate in response to certain microorganisms and to expand throughout life, presumably because of extrathymic activation by foreign antigens. In vitro expansion of V gamma 9/V delta 2 cells by mycobacteria has been previously shown to be dependent on accessory cells. In order to gain an insight into the mechanisms involved in the expansion of these cells, we have undertaken to identify the peripheral blood subset of cells on which proliferation of V gamma 9/V delta 2 cells in response to mycobacteria is dependent. Contrary to their role in antigen presentation to alpha beta T cells, professional antigen-presenting cells, such as monocytes, B cells, and dendritic cells, were unable to provide the cellular support for the expansion of V gamma 9/V delta 2 cells. Selective depletion of T-cell subsets, as well as the use of highly purified T-cell populations, indicated that the only subset of peripheral blood cells that could expand V gamma 9/V delta 2 cells were CD4+ CD45RO+ CD7- alpha beta T cells. These cells underwent distinct intracellular signaling events after stimulation with the mycobacterial antigen. Expansion of V gamma 9/V delta 2 cells by alpha beta T cells was dependent on cell-cell contact. This is the first evidence that a small subset of the memory helper T-cell population is exclusively responsible for the peripheral expansion of V gamma 9/V delta 2 cells. These data illustrate a unique aspect of antigen recognition by gamma delta T cells and provide new means to study their immune defense role.     

Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes

Thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) are the two key enzymes in mitochondrial DNA (mtDNA) precursor synthesis. Deficiencies in TK2 or dGK activity, due to genetic alteration, have been shown to cause tissue-specific depletion of mtDNA. In the case of TK2 deficiency, affected individuals suffer severe myopathy and, in the case of dGK deficiency, devastating liver or multi-systemic disease. Here, we report clinical and biochemical findings from two patients with mtDNA depletion syndrome. Patient A was a compound heterozygote carrying the previously reported T77M mutation and a novel mutation (R161K) in the TK2 gene. Patient B carried a novel mutation (L250S) in the dGK gene. The clinical symptoms of patient A included muscular weakness and exercise intolerance due to a severe mitochondrial myopathy associated with a 92% reduction in mtDNA. There was minimal involvement of other organs. Patient B suffered from rapidly progressive, early onset fatal liver failure associated with profoundly decreased mtDNA levels in liver and, to a lesser extent, in skeletal muscle. Site-directed mutagenesis was used to introduce the mutations detected in patients A and B into the TK2 and dGK cDNAs, respectively. We then characterized each of these recombinant enzymes. Catalytic activities of the three mutant enzymes were reduced to about 2-4% for TK2 and 0.5% for dGK as compared to the wild-type enzymes. Altered competition between dCyd and dThd was observed for the T77M mutant. The residual activities of the two mitochondrial enzymes correlated directly with disease development.     

Evidence for a reserpine-affected mechanism of resistance to tetracycline in Neisseria gonorrhoeae

The presence of a reserpine-affected mechanism of tetracycline resistance was investigated in 17 Neisseria gonorrhoeae clinical isolates. To establish this fact the MIC of tetracycline in the presence and absence of reserpine was determined, and, in addition, mechanisms of tetracycline resistance were analyzed by PCR. The results showed that reserpine affects the MIC of tetracycline at least 4-fold in all isolates, including those containing the tetM gene. An inhibitory effect of reserpine against the MtrCDE efflux system was ruled out by using strains either with an inactive or with an unrepressed MtrCDE system. The results suggest the presence of a constitutive system of resistance to tetracycline, by a possible efflux pump, which may be inhibited by reserpine. Further studies are required to determine the exact nature of the action of reserpine on the MIC of tetracycline.     

Psychopathology and quality of life for adolescents with asthma and their parents

Asthma is known to have a direct impact on the quality of life of children with asthma and their families as a consequence of the attacks on day-to-day life. Psychopathological factors may be associated with poor quality of life by modulating the handicap and the patient's experience of it. The authors' objective was to evaluate the relationship between emotional and behavioral problems and quality of life, as assessed by the Pediatric Asthma Quality of Life Questionnaire and the Pediatric Asthma Caregiver's Quality of Life Questionnaire. The study group consisted of 100 adolescent outpatients with asthma who were undergoing regular checkups: 70 boys and 30 girls, ages 12 to 19. They were evaluated by means of self-administered questionnaires completed by their parents. Path analysis was used to propose a model of relationships between psychopathology and quality of life. The quality of life of the children with asthma and their parents was clearly associated with the presence or absence of psychological problems in the patients. Emotional problems were associated with the quality of life of both the patients and their parents; behavioral problems had a smaller effect on the quality of life of the parents only. The authors proposed a structural model of the quality of life of adolescents with asthma and their parents in which quality of life is dependent on psychological variables and is responsible for emotional problems. Multivariate analyses indicated that the quality of life of the children with asthma and their parents and the correlation between quality of life and psychopathology depended little on medical variables such as the duration of illness, its pretreatment severity, or hospitalizations in the past year. In contrast, the quality of life of the parents depended on that of the children and vice versa. This study showed that scores on the Pediatric Asthma Quality of Life Questionnaire and the Pediatric Asthma Caregiver's Quality of Life Questionnaire reflected not only the medical status of the patients but also psychological variables, which appeared to be a consequence of the functional handicap associated with asthma. Patients who assess the quality of their lives as poor would benefit from psychological evaluation and support.     

Correction to: Persistent major alopecia following adjuvant docetaxel for breast cancer: incidence,characteristics, and prevention with scalp cooling

Purpose

Dogs have been proposed as spontaneous animal models of human breast cancer, based on clinicopathologic similarities between canine and human mammary carcinomas. We hypothesized that a better knowledge of the natural history and prognostic factors of canine invasive mammary carcinomas would favor the design of preclinical trials using dogs as models of breast cancer.

Methods

The 2-year outcome of 350 female dogs with spontaneous invasive mammary carcinoma was studied. The investigated prognostic factors included age at diagnosis, pathologic tumor size, pathologic nodal stage, lymphovascular invasion, histological grade, and expression of Estrogen Receptor alpha (ERα), Progesterone Receptor, Ki-67, Human Epidermal Growth Factor Receptor 2, basal cytokeratins 5/6, and Epidermal Growth Factor Receptor. Multivariate survival analyses were performed using the Cox proportional hazards model.

Results

The overall survival after mastectomy was 11 months. Within 1 year post mastectomy, 41.5% of dogs (145/350) died from their mammary carcinoma. By multivariate analysis, the significant prognostic factors for overall survival included a pathologic tumor size larger than 20 mm [HR 1.47 (95% confidence interval 1.15–1.89)], a positive nodal stage [pN+, HR 1.89 (1.43–2.48)], a histological grade III [HR 1.32 (1.02–1.69)], ERα negativity [HR 1.39 (1.01–1.89)], a high Ki-67 proliferation index [HR 1.32 (1.04–1.67)], and EGFR absence [HR 1.33 (1.04–1.69)].

Conclusion

The short natural history of spontaneous canine invasive mammary carcinomas and high rate of cancer-related death allow for rapid termination of preclinical investigations. The prognostic factors of invasive mammary carcinomas are remarkably similar in dogs and humans, highlighting the similarities in cancer biology between both species.

     

Cantrell's pentalogy. Report of four cases and their management

Four neonates with the uncommon Cantrell's pentalogy seen in our hospital within a 6-month period without any apparent factor in common are described, with a review of the world literature. The first case was diagnosed prenatally at 15 weeks' gestation, the earliest intrauterine finding in the literature. The occurrence of imperforate anus with the syndrome, observed in one of the cases, has not been previously reported. Two were operated upon and only one of the four survived. This high mortality was confirmed by similar cases reported by other authors.     

Heparin in acute stroke with atrial fibrillation: clinical relevance of very early treatment.

BACKGROUND: The risk-benefit ratio of early vs late heparinization for acute stroke with nonvalvular atrial fibrillation remains unsettled. OBJECTIVE: To clarify the relationship between timing to heparinization and functional outcome in acute cardioembolic stroke. DESIGN: Consecutive case series. SETTING: Referral center. PATIENTS: In 231 patients with stroke and nonvalvular atrial fibrillation, intravenous or subcutaneous heparin administered with the goal of achieving an activated partial thromboplastin time (APTT) 1.5 to 2.0 times control values. Delay to the initiation of heparin therapy was less than 6 hours from the onset of symptoms in 74 patients and between 6 and 48 hours in 157 patients. Functional outcome (Rankin scale) was assessed 9 +/- 3 (mean +/- SD) days from stroke onset using multivariate analysis and including in the model treatment delay, risk factors (eg, age, hypertension, diabetes, hypercholesterolemia, previous stroke, and heart disease), initial neurological severity, and baseline computed tomographic findings (eg, early signs of infarction and white matter abnormalities). Clinical symptoms on admission (Mathew score) and baseline radiological findings were evaluated in all subjects. The bleeding rate was assessed on subsequent computed tomographic (CT) scans (obtained 7 +/- 2 days after stroke). The relationship between APTT ratios and stroke recurrence or hemorrhagic worsening was also tested. MAIN OUTCOME MEASURES: Functional outcome at hospital discharge and incidence of early recurrent strokes and bleeding complications. RESULTS: Mortality (9%), hemorrhagic worsening (3.4%), and early stroke recurrence (2.1%) occurred in the hospital. Complete recovery was associated with age younger than 70 years (odds ratio [OR], 0.21; 95% confidence interval [CI], 0.05-0.70), a baseline Mathew score higher than 74 (OR, 11.5; 95% CI, 4.95-26.70), normal baseline CT findings (OR, 8.86; CI, 3.99-19.60), and early heparinization (OR, 1.7; 95% CI, 1.10-2.50). Targeted APTT ratios were achieved at 24 hours in fewer than 50% of patients. Whereas stroke recurrence was associated with lower mean APTT ratios, higher mean APTT ratios were observed in patients with symptomatic bleeding, especially on the day of bleeding. Age, admission stroke severity, blood pressure, and baseline CT findings did not predict hemorrhagic worsening. CONCLUSIONS: Delaying anticoagulation in alert patients with stroke and nonvalvular atrial fibrillation is not endorsed by the initial severity of symptoms or the early signs of infarction on CT scan. Functional recovery is improved the sooner heparin is administered. These findings suggest that heparin also has therapeutic properties. However, close APTT monitoring is warranted to lessen the incidence of untoward complications.     

Accidental catheterization of the subdural space. Confirmation by radiological study

We report two cases of accidental subdural blockade after peridural anesthesia. The blockade was detected postoperatively in both cases, two hours after start of continuous perfusion in one patient and eight hours afterwards in the other. Subdural diffusion was confirmed after injection of a radiopaque contrast medium. Subdural blockade usually manifests as an extensive neural block that is disproportionate to the amount of anesthetic injected. We discuss the need for frequent monitoring of metameric, sensory and motor levels to detect possible catheter misplacement, in addition to routine monitoring of heart rate, arterial pressure and oxygen saturation. When subdural blockade is suspected, epidural perfusion should be discontinued in order to prevent extensive sensory and motor blocks. A firm diagnosis can only be made by X-ray. A simple radiograph may adequately demonstrate subdural placement in some cases, although computed axial tomography should be performed when doubt arises.