The orphan granzymes of humans and mice

The granzyme/perforin pathway is a central pathway for lymphocyte-mediated killing in both the innate and adaptive immune systems. This pathway is important in a variety of host defenses, including viral clearance and tumor cell killing, and its dysregulation results in several human and rodent diseases. To date, the majority of reports in this field have concentrated on the functions of granzymes A and B. Recent reports, however, suggest that the non-A/non-B 'orphan' granzymes found in both humans and mice are potentially significant. Although the functions of these orphan granzymes have yet to be fully established, initial data suggests their importance in both immune and nonimmune cells.     

Rupture recurrence after surgical repair of postinfarction ventricular septal rupture. Influence of early thrombolysis

OBJECTIVES: The aim of this study was to identify factors causing rupture recurrence after surgical repair of postinfarction ventricular septal rupture and to evaluate the indication for reoperation. PATIENTS: Recurrence of rupture was analysed in 25 out of a series of 109 patients who underwent surgical repair for postinfarction ventricular septal rupture between 1980 and 1992 in our institution. RESULTS: The mean interval between initial operation and recurrence was 3.6 days with a median of 2 days. Multivariate logistic regression analysis identified early thrombolysis after infarction (P = 0.0085) as a risk factor for recurrence of the rupture. Rupture recurrence occurred more in the anterior then in the posterior infarction site, although non-significant. Reoperation was indicated in 15 patients, in 13 for postrecurrent cardiac failure. The main determinant of cardiac failure was a large postrecurrent shunt (P = 0.05). The mean interval between initial operation and reoperation was 136 days with a median of 101 days. In 6 patients a combined apical ventricular septal rupture recurrence and anterior ventricular aneurysm was found, in 9 patients the recurrent rupture was proximally located, without concomitant aneurysm formation. Of 15 patients who were reoperated, one died in hospital and three after the in-hospital period. Of 10 patients treated conservatively, one died in hospital and two after the in-hospital period. One residual ventricular septal rupture closed spontaneously. CONCLUSIONS: Rupture recurrence is mainly determined by early thrombolysis. Postrecurrent cardiac failure, as the main indication for reoperation, is dependent on postrecurrent shunt size.     

Dissection of the carotid artery and vertebral artery--diagnosis and therapy

Carotid and vertebral artery dissections typically occur in young adults after major trauma, although they can arise spontaneously or after trivial injury. Many patients with carotid dissections have minor symptoms such as a subject bruit or Horner's syndrome. Cephalic pain is also frequent and often inaugural in carotid dissection. However, extracranial dissection is a well recognised cause of ischaemic stroke. The diagnosis of dissection was based on angiographic findings. Noninvasive imaging also allows prompt and reliable diagnosis. Our goal was to demonstrate the spectrum of neuroradiologic (CT, MR and angiographic) findings in craniocervical arterial dissection and compare the diagnostic utility of CT, MR, MR angiography. Clinical data imaging studies, and outcome were reviewed and compared with the results in four patients with carotid artery dissection.     

Developmental and behavioral effects of prenatal primidone exposure in the rat

Pregnant Sprague-Dawley rats were administered primidone (PRM) by oral gavage on gestation days 8-17 in doses of 0.40, and 80 mg/kg. Although these doses of PRM did not produce significant differences in litter size, birth weight, mortality, date of attainment of developmental landmarks or measures of preweaning reflex and motor development, there were a number of significant differences that developed as the animals approached and entered adulthood. When tested as adults, the 80 mg/kg male rats showed a deficit in the performance of an eight-arm radial maze task. These same animals showed a significant reduction in open field activity when tested as adults. In addition, both male and female PRM-treated animals showed reduced body weights at different periods corresponding to onset of sexual maturation during development. These findings are consistent with the larger body of literature reporting on the neurobehavioral teratology of phenobarbital, including its ability to produce lesions in the hippocampus and endocrine dysfunction resulting in reproductive deficits. These results suggest that PRM produces its adverse effects as a result of its metabolism to phenobarbital, which in turn affects the limbic system.     

A novel method for replacement of the dislodged tracheostomy tube: the nasogastric tube "guidewire" technique

The ready access to blood (plasma and formed cellular elements) makes it unusually susceptible to the deleterious effects of pollutants whose origins may be in the air. The red blood cells' hemoglobin may be rendered useless for oxygen transport by combination with carbon monoxide or conversion to methemoglobin or sulfhemoglobin. Lead and arsine can damage the erythrocytes' membranes, resulting in anemia. Metabolites of benzene and other volatile polycyclic hydrocarbons are implicated in the causation of leukemias. The extensive use of pesticides and herbicides may be associated with the development of Hodgkin's disease, non-Hodgkin's lymphoma, and aplastic anemia. The carcinogenic risks from ionizing radiation, especially for leukemia, are well known. More information is needed concerning the epidemiology of environmental factors responsible for damage to blood. Enhanced knowledge about the molecular biology of toxins' effects on the hematopoietic system and improved detection and prevention technologies are needed to answer environmentally related health questions.     

Parathyroid hormone-related protein in patients with primary breast cancer and eucalcemia

Parathyroid hormone-related protein (PTHrP) is a causative factor of humoral hypercalcemia in breast cancer and other malignancies. We studied circulating PTHrP levels with three different immunoassays directed against different parts of the PTHrP molecule in 48 patients with breast cancer and eucalcemia. The methods used were: (a) a RIA with antibodies directed toward the midregion (63-78); (b) an immunofluorometric assay with two antibodies against 1-34 and 38-67; and (c) an immunoradiometric assay with antibodies against 1-40 and 1-72. Although most patients had PTHrP levels indistinguishable from normal when measured by all three methods, four patients had increased serum levels in the IFMA. PTHrP was detected by immunohistochemistry in tumors from nearly all patients. One patient with elevated PTHrP in plasma measured by IFMA showed intense staining of tumor by immunohistochemistry; the tumor was histologically graded as III (severe) and was the largest of all tumors in this patient group. The IFMA can identify increased serum PTHrP in some patients with breast cancer who are not hypercalcemic. This assay may be especially useful in screening patients for this tumor during a relative early phase of the disease.     

Orthopaedic surgery in hemophilic patients with human immunodeficiency virus

Patients registered at the author's hemophilia center between 1982 and 1994 were studied to establish whether major orthopaedic surgical procedures accelerate the fall of CD4 lymphocyte counts of patients with hemophilia who are infected with the human immunodeficiency virus, and whether patients who had surgery had different rates of development of acquired immune deficiency syndrome or death when compared with patients who did not have surgery. The patients were divided into four groups: Group 1, 22 patients who were human immunodeficiency virus positive undergoing orthopaedic surgery; Group 2, 89 patients who were human immunodeficiency virus positive not undergoing orthopaedic surgery; Group 3, 18 patients who were human immunodeficiency virus negative undergoing orthopaedic surgery; and Group 4, 135 patients who were human immunodeficiency virus negative not undergoing orthopaedic surgery. There was no significant difference between the rates of decline of CD4 lymphocyte counts for patients who were human immunodeficiency virus positive who underwent surgery when compared with human immunodeficiency virus positive patients who did not undergo surgery, nor was there any significant difference between the two human immunodeficiency virus negative groups. There were no significant differences in the rate of development of acquired immune deficiency syndrome or mortality rates between patients who had surgery and those who did not.     

Pigmented epithelium sustains cell proliferation and decreases expression of opsins and acetylcholinesterase in reaggregated chicken retinospheroids

We investigated the effect of the retinal pigmented epithelium on cell proliferation and differentiation in rosetted retinospheroids, which are retina-like spheres reaggregated in the complete absence of retinal pigmented epithelium from dissociated retinal cells of 6-day-old chick embryos in a rotation culture system. In spheroids raised in the absence of retinal pigmented epithelium (controls), acetylcholinesterase was expressed in cells of an inner nuclear-like layer and their neuropil matrices. Moreover, the ratio between rods and cones was found to be approximately normal throughout the spheroid. When spheroids were cultured in the presence of retinal pigmented epithelium monolayers, cell proliferation in spheroids as determined by BrdU labelling was significantly increased and extended for 1 week, while acetylcholinesterase protein levels and specific activities in homogenates were decreased to approximately 30%. At the same time, opsin immunoreactivity was completely suppressed within the spheroid and appeared slowly in cells around its periphery; i.e. the proportion of rhodopsin-positive cells decreased from 14 to 3%. This study reveals that the retinal pigmented epithelium in vitro sustains cell proliferation but inhibits the differentiation of acetylcholinesterase-positive cells and of photoreceptors.