The ecological cause of the higher accumulation of 90Sr and 137Cs in the food of northern inhabitants

PURPOSE: To quantify S-antigen-specific (S-Ag) T cells in the retina after adoptive transfer, and to evaluate their role in the initiation and progress of destructive ocular inflammation in experimental autoimmune uveoretinitis (EAU). METHODS: Lewis rats were administered 10 x 10(6) S-Ag-specific T cells from the SP35 cell line or 10 x 10(6) concanavalin A-stimulated syngeneic spleen cell lymphoblasts labeled with lipophilic PKH26 fluorescent dye immediately before intravenous inoculation. Labeled cells in each retina were counted at various times from 4 to 120 hours after cell transfer by fluorescence microscopic analysis of each dissociated retina. Recipient eyes were examined within the same period by light and confocal microscope. RESULTS: SP35 T cells showed a biphasic distribution in the retina. The first peak of 160 cells/retina was noted at 24 hours. A steady decline of labeled cells at 48 and 72 hours was followed by a rapid increase at 96 and 120 hours. Concanavalin A-stimulated, control-labeled cell populations showed an identical peak at 24 hours but a persistent decline thereafter; only two or three T cells were present in each retina at 120 hours. Concurrent inoculation of SP35 cells and nonspecific T cell blasts did not produce more SP35 cells than control cells in the retina at any time. Microscopic analysis showed mononuclear cell infiltration of the iris, ciliary body, and aqueous humor at 48 hours, which intensified rapidly and persisted through 120 hours. Retinal inflammation did not begin until 80 hours. Mononuclear cell adherence to vascular endothelium and perivascular macrophage infiltration of the innermost layers progressed to edema, and profound destructive inflammation and loss of retinal stratification were observed at 120 hours. CONCLUSIONS: There is no evidence of a blood-ocular or blood-retinal barrier to activated T cell blasts. Autologous S-Ag does not provoke a more rapid entry of specific T cells at that site. The data confirm that anterior segment inflammation precedes retinal inflammation, even though S-Ag-specific T cells were present in the retina within a few hours after cell transfer. Because S-Ag is clearly present in the retina, delay in antigen presentation at that site may account for the temporal difference between retinal and anterior segment inflammation.     

Functional characterization of transforming growth factor beta type II receptor mutants in human cancer

We recently identified missense mutations at amino acid residues 526 and 537 located within the highly conserved subdomain XI of the transforming growth factor beta type II receptor (TbetaR-II) serine-threonine kinase in two human squamous carcinoma cell lines. These cell lines are resistant to transforming growth factor beta-mediated inhibition of growth. Moreover, treatment with transforming growth factor beta fails to increase the levels of type 1 plasminogen activator inhibitor and fibronectin synthesis. To test the effects of the mutations on receptor function, mutant TbetaR-II cDNAs were expressed in TbetaR-II-deficient T47D cells. Cyclin A promoter activity was reduced by 50% in cells expressing wild-type TbetaR-II but increased 2-fold in cells transfected with either of the two mutant receptors. Conversely, plasminogen activator inhibitor type 1 promoter activity was increased 6-fold in cells transfected with wild-type receptor but not with either of the two mutant receptors. Moreover, the activity of both mutant serine-threonine kinases was strongly reduced compared to that of the wild-type receptor. Thus, the amino acid residues at positions 526 and 537 seem to be essential for kinase function and signaling activity of the TbetaR-II.     

Mutational analysis of N-RAS and GAP-related domain of the neurofibromatosis type 1 gene in chronic myelogenous leukemia

RAS mutations can be detected in a variable number of patients with myeloproliferative disorders such as myelodysplastic syndromes and acute myeloid leukemia, but are rare events in chronic myelogenous leukemia in chronic phase. However, there is good evidence supporting the involvement of RAS signalling pathway in CML and this could be due to alterations in RAS activity regulatory proteins. The neurofibromatosis (NF1) gene down-regulates the RAS signal transduction pathway through the inhibitory function of its GAP-related domain (GRD) on RAS protein. The loss or alteration of neurofibromin (the NF1 protein) may produce a disfunction similar to point mutations in the RAS gene resulting in the permanent stimulation of the RAS signal transduction pathway. Mutations involving the GRD region of the NF1 gene (GRD-NF1) have been described in a variety of tumors such as colon carcinoma and astrocytoma. Germline mutations and deletions in the NF1 gene, as seen in neurofibromatosis type 1, are also associated with certain myeloid disorders. In the present work, we sought to identify mutations in the codons 12/13 and 61 of RAS gene and in the Lys-1423 codon of GRD-NF1, which are well known hot spots in these genes, in a group of 36 adults and ten children with chronic myelogenous leukemia in chronic phase and blast crisis. Using the PCR-SSCP and the allele-specific restriction assay (ASRA) techniques, we were not able to observe any RAS or NF1 detectable mutation. These findings suggest that RAS and GRD-NF1 mutations are not involved either in chronic phase or in the progression to blast crisis in chronic myelogenous leukemia in adults and children.     

Long-term results after reoperation for failed antireflux procedures

From January 1960 to June 1995, 185 patients underwent reoperation without esophageal resection for symptoms of recurrent gastroesophageal reflux disease. There were 102 men and 83 women. Median age was 58 years (range 20 to 84 years). A single previous antireflux operation had been performed in 147 patients, two in 33, and three in 5. The median interval between the reoperation and the previous operation was 36 months (range 1 to 291 months). Indications for reoperation were symptoms in 184 patients and a large paraesophageal hernia in one patients. The surgical approach was by means of a thoracotomy in 133 patients (71.9%), laparotomy in 27 (14.6%), and a thoracoabdominal incision in 25 (13.5%). A Nissen fundoplication was performed in 107 patients (57.8%), Belsey fundoplication in 47 (25.4%), truncal vagotomy and antrectomy with Roux-en-Y reconstruction in 17 (9.2%), anatomic hernia repair in 12 (6.5%), and Hill gastropexy in 2 (1.1%). A Collis gastroplasty was added to the fundoplication in 116 patients (62.7%), and a pyloroplasty was performed in 17 (9.2%). There was one operative death (0.5%). Complications occurred in 47 patients (25.4%). Median postoperative hospitalization was 9 days (range 5 to 58 days). Follow-up was complete in 156 patients (84.3%) and ranged from 3 to 283 months (median 44 months). Improvement occurred in 137 patients (87.8%). Functional results were classified as excellent in 65 patients (41.6%), good in 29 (18.6%), fair in 43 (27.6%), and poor in 19 (12.2%). No single operative approach or procedure proved to be functionally superior. We conclude that reoperation with esophageal preservation after a failed antireflux procedure will result in significant functional benefit and can be performed with low mortality and acceptable morbidity. The type of repair should be tailored to the individual patient.     

The relationship between myenteric neuronal denervation, smooth muscle thickening and epithelial cell proliferation in the rat colon

The aim of the present experiment was to (i) study the healing after 3 and 7 months of bone defects filled with cancellous bovine bone mineral and (ii) compare the healing around implants placed in normal bone and in defects filled with bovine bone mineral. 5 beagle dogs, about 1-year-old, were used. At baseline, extractions of all mandibular left and right premolars were performed. Bone defects were prepared in the left mandibular quadrant. The defect was immediately filled with natural bovine cancellous bone mineral particles (Bio-Oss, Geistlich Sons Ltd. Wolhusen, Switzerland). No resective surgery was performed in the right jaw quadrant. In both quadrants the flaps were adjusted to allow full coverage of the edentulous ridge and sutured. 3 months later, 2 dogs (group I) were euthanized and biopsies from the premolar regions obtained and prepared for histologic analysis. The 3 remaining dogs (group II) were at this time interval (3 months) subjected to implant installation in the premolar region of both the right and left mandibular jaw quadrants. 2 fixtures of the ITI Dental Implant System (Straumann, Waldenburg, Switzerland; solid-screw; 8 x 3.3 mm) were installed in each side. The fixtures in the test side were placed within the previously grafted defect area, while the fixtures in the control side were placed in normally healed extraction sites. A 4 month period of plaque control was initiated. At the end of this period, a clinical examination including assessment of plaque and soft tissue inflammation was performed and radiographs obtained from the implant sites. Biopsies were harvested and 4 tissue samples were yielded per dog, each including the implant and the surrounding soft and hard peri-implant tissues. The biopsies were processed for ground sectioning or "fracture technique" and the sections produced were subjected to histological examination. The volume of the hard tissue that was occupied by clearly identified Bio-Oss particles was reduced between the 3- and 7-month intervals. This indicates that with time, Bio-Oss becomes integrated and subsequently replaced by newly formed bone. In other words, this xenograft fulfils the criteria of an osteoconductive material. It was also observed that 4 months after implant installation, the titanium/hard tissue interface at test and control sites exhibited, from both a quantitative and qualitative aspect, a similar degree of "osseointegration".     

Blood flow dynamics in different layers of the somatosensory region of the cerebral cortex on the rat during mechanical stimulation of the vibrissae

Since the creation of the Office of Alternative Medicine (OAM) at the National Institutes of Health (NIH), progress has been made in the evaluation and, where appropriate, the clinical and scientific acceptance of "complementary and alternative" medicine (CAM). This progress is due in part to initiatives jointly conducted by the NIH and the U.S. Food and Drug Administration (FDA). In particular, advances in the evaluation and acceptance of two CAM practices, acupuncture and botanical medicine, have resulted from ongoing cooperation between the two agencies. The legalization of the use of acupuncture needles in 1996 came as a result of a workshop sponsored by the OAM with the participation of the FDA, which explored key regulatory issues. Prompted by similar regulatory issues, as well as by the initiation of NIH-funded research projects, the OAM sponsored an international symposium to examine the evidence for and the role of botanical medicine in the United States. This conference generated a series of workshops sponsored by the Drug Information Association in conjunction with NIH and FDA, which explored the scientific, regulatory, and policy issues of heterogeneous botanical products. These efforts resulted in the initiation of a large randomized multicenter clinical trial (sponsored by the National Institute of Mental Health) of the botanical, St. John's wort, for the treatment of depression, and the formation of internal working groups within the FDA that are drafting a guidance policy for the development of botanicals as drugs in the United States. This document is expected to be available in the near future.     

The protective reaction of the myocardium to ischemic damage

The morphological and functional consequences of epinephrine-induced myocardial infarction were studied in normo- (Wistar) and hypertensive (ISIAH) rats. After experimental myocardial infarction there was an irreversible transition to the "worn-out" stage or "plastic damage" to the myocardium. Thus, myocardial hibernation in ISIAH rats anticipates and determines the development of myocardial stunning, i.e., irreversible myocardial damage, whereas in the normotensive animals, the protective effect of hibernation is fully shown. The ontogenetic features of myocardial response of ISIAH rats to hypoxia promote transformation of adaptive hibernation and stunning to maladaptive pathological changes causing hypoxic alterations.     

Retinoic acid disrupts anterior ectodermal and endodermal development in ascidian larvae and postlarvae

In vertebrates, excess all-trans retinoic acid (RA) applied during axis formation leads to the apparent truncation of anterior structures. In this study we sought to determine the type of defects caused by ectopic RA on the development of the ascidian Herdmania curvata. We demonstrate that H. curvata embryos cultured in the presence of RA develop into larvae whose trunks are shortened and superficially resemble those of early metamorphosing postlarvae. Despite RA-treated larvae lacking papillar structures they respond normally to natural cues that induce metamorphosis, indicating that chemosensory functionality previously mapped to the most anterior region of normal larvae is unaffected by RA. Excess RA applied during postlarval development leads to a graded loss of the juvenile pharynx, apparently by respecifying anterior endoderm to a more posterior fate. This structure is considered homologous to the gill slits of amphioxus, which are also lost upon RA treatment. This suggests that RA may have had a role in the development of the pharynx of the ancestral chordate and that this function has been maintained in ascidians and cephalochordates and lost in vertebrates.