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T Hatch

Publications and source records attributed to T Hatch.

13 recordsLinked to original sources
PubMed2006

Radiation-induced transgenerational alterations in genome stability and DNA damage.

Mutation induction in directly exposed cells is currently regarded as the main component of the genetic risk of ionizing radiation for humans. However, recent data on the transgenerational increases in mutation rates in the offspring of irradiated parents indicate that the genetic risk could be greater than predicted previously. Here, we have analysed transgenerational changes in mutation rates and DNA damage in the germline and somatic tissues of non-exposed first-generation offspring of irradiated inbred male CBA/Ca and BALB/c mice. Mutation rates at an expanded simple tandem repeat DNA locus and a protein-coding gene (hprt) were significantly elevated in both the germline (sperm) and somatic tissues of all the offspring of irradiated males. The transgenerational changes in mutation rates were attributed to the presence of a persistent subset of endogenous DNA lesions (double- and single-strand breaks), measured by the phosphorylated form of histone H2AX (gamma-H2AX) and alkaline Comet assays. Such remarkable transgenerational destabilization of the F(1) genome may have important implications for cancer aetiology and genetic risk estimates. Our data also provide important clues on the still unknown mechanisms of radiation-induced genomic instability.

Animals↗
PubMed1999

Transfer of swine major histocompatibility complex class II genes into autologous bone marrow cells of baboons for the induction of tolerance across xenogeneic barriers.

BACKGROUND: The present study examined the potential role of gene therapy in the induction of tolerance to anti-porcine major histocompatibility complex (SLA) class II-mediated responses after porcine renal or skin xenografts. METHODS: Baboons were treated with a non-myeloablative or a myeloablative preparative regimen before bone marrow transplantation with autologous bone marrow cells retrovirally transduced to express both SLA class II DR and neomycin phosphotransferase (NeoR) genes, or the NeoR gene alone. Four months or more after bone marrow transplantation, the immunological response to a porcine kidney or skin xenograft was examined. Both the renal and skin xenografts were SLA DR-matched to the transgene, and recipients were conditioned by combinations of complement inhibitors, adsorption of natural antibodies, immunosuppressive therapy, and splenectomy. RESULTS: Although the long-term presence of the SLA transgene was detected in the peripheral blood and/or bone marrow cells of all baboons, the transcription of the transgene was transient. Autopsy tissues were available from one animal and demonstrated expression of the SLA DR transgene in lymphohematopoietic tissues. After kidney and skin transplantation, xenografts were rejected after 8-22 days. Long-term follow-up of control animals demonstrated that high levels of induced IgG antibodies to new non-alphaGal epitopes developed after organ rejection. In contrast, induced non-alphaGal IgG antibody responses were minimal in the SLA DR-transduced baboons. CONCLUSIONS: Transfer and expression of xenogeneic class II DR transgenes can be achieved in baboons. This therapy may prevent late T cell-dependent responses to porcine xenografts, which include induced non-alphaGal IgG antibody responses.

Animals↗
PubMed1999

Peripheral tolerance to class I mismatched renal allografts in miniature swine: donor antigen-activated peripheral blood lymphocytes from tolerant swine inhibit antidonor CTL reactivity.

Studies utilizing partially inbred miniature swine have demonstrated that a short course of cyclosporin A leads to indefinite survival of two haplotype class I mismatched renal allografts. In the present study, we have examined peripheral regulatory mechanisms that may be involved in maintenance of tolerance by coculturing PBL from long-term tolerant animals with naive recipient-matched PBL in cell-mediated lympholysis assays. We show that PBL from tolerant animals, primed in vitro with donor Ag, suppress antidonor CTL reactivity by naive recipient-matched PBL. Suppression was not observed when PBL from naive animals, primed with donor-matched PBL, were cocultured with PBL from a second naive animal, nor did PBL from either tolerant or naive recipient-matched control animals, primed with third-party Ag, suppress the generation of anti-third-party CTL by a second naive animal. The suppression was cell dose-dependent, radiation-sensitive, required cell-to-cell contact not reversed by the provision of exogenous IL-2, and associated with lower levels of IL-2R expression on the suppressive effector group (particularly the CD8 single positive cells) when compared with the control effector group. These data indicate an association between the presence of peripheral regulatory cells demonstrable in vitro and the maintenance of tolerance to renal allografts.

Animals↗
PubMed1997

Pig to monkey bone marrow and kidney xenotransplantation.

BACKGROUND: The intensity of discordant xenograft cellular rejection makes it unlikely that safe doses of immunosuppressive drugs will alone be sufficient to permit long-term survival. We have therefore concentrated our efforts on establishing tolerance to xenogeneic organs through lymphohematopoietic chimerism and the elimination of preformed natural antibodies (nAbs). METHODS: Here we report the most recent series of 11 technically successful porcine to nonhuman primate transplantation procedures. In eight experimental animals induction therapy consisted of (1) 3 x 100 cGy nonlethal whole body irradiation (day -6 and day -5) to all animals, (2) horse anti-human thymocyte globulin (day -2, day -1, and day 0) to seven of the animals, (3) 700 cGy thymic irradiation (day -1) to five of the animals, and (4) pig bone marrow infused on day 0 (2-9 x 10(8)/cells/kg). On day 0, just before the renal xenograft, the recipient was splenectomized, and antipig nAbs were removed by means of perfusion of the monkey's blood through either a pig liver (n = 6) or a Gal-alpha (1,3)-Gal adsorption column (n = 5). There control animals did not receive this pretransplantation induction therapy but did undergo hemoperfusion and posttransplantation immunosuppression identical to the experimental animals. All 11 recipients were treated after transplantation with cyclosporin A and 15-deoxyspergualin. Recombinant pig-specific growth factors (interleukin-3 and stem cell factor) were given to six experimental animals from day 0 until the termination of the experiment. RESULTS: Analysis of recipients' sera by means of flow cytometry indicated the effective removal of immunoglobulin M and immunoglobulin G nAbs by either liver perfusion or column adsorption. In the eight experimental animals, nAb titers remained low until death (up to 15 days), but in the three control animals nAb titers increased substantially with time. The longest surviving recipient maintained excellent kidney function with creatinine levels at 0.8 to 1.3 mg/dl throughout its course. Death occurred at day 15 from complications caused by a urinary leak and pancytopenia. Histologic examination of the xenograft revealed only focal tubular necrosis and cytoplasmic vacuolization, with trace amounts of fibrin and C3 in peritubular capillaries. In this animal a fraction of the peripheral blood cells (3%) at day 7 were of pig origin as detected by pig-specific monoclonal antibodies. In addition, colony-forming assays performed on a bone marrow biopsy specimen taken at day 14 indicated that approximately 30% of the relatively few myeloid progenitors detected were of swine origin. CONCLUSIONS: We have demonstrated that our protocol is effective in the prevention of hyperacute rejection and in the maintenance of excellent function of the renal xenograft for up to 15 days. These results also indicate that at least short-term engraftment of the xenogeneic donor bone marrow cells is possible to achieve in this discordant large animal combination. Longer survivals will be required to assess the possible effect of this engraftment on induction of tolerance.

Animals↗
PubMed1992

Beyond the basics: preschool children label objects flexibly at multiple hierarchical levels.

Although preschoolers typically accept the basic level label for an object (e.g. dog) and tend to resist all others (e.g. collie, animal), this tendency is not inviolable. Under certain circumstances, children accept more than one label per object. In this experiment, with 20 three- and 20 four-year-old children, we extended this body of research in three ways. We examined (I) children's production of multiple, hierarchically related labels; (2) the pragmatic consequences of the inherent asymmetry of inclusion relations; and (3) the influence of morphology (modifier+noun constructions vs. simple lexemes) at the subordinate level. Children labelled objects most frequently at the basic level, but also readily produced many non-basic level terms. Children, like adults, may prefer to label objects at the basic level, but they exhibit no general prohibition against also labelling at other, non-basic levels. Their performance challenges the notion that the ability to label objects flexibly at multiple levels is beyond the young child's capacity.

Child Language↗
PubMed1989

Renal adenocarcinoma with solitary metastasis to the contralateral adrenal gland: report of 2 cases and review of the literature.

We report 2 rare cases of renal adenocarcinoma with solitary metastasis to the contralateral adrenal gland, 1 recognized synchronously with the primary neoplasm and 1 found 15 years after nephrectomy. The latter case represents the longest reported interval between nephrectomy and treatment of a solitary contralateral adrenal metastasis of renal adenocarcinoma. Distinction of these metastatic tumors from primary adrenocortical carcinoma was facilitated by immunohistochemical markers. Twelve other reported cases of renal adenocarcinoma with solitary contralateral adrenal metastasis support aggressive surgical management of this lesion.

Adrenal Gland Neoplasms↗
PubMed1987

Extragonadal germ cell tumor: the preoperative urological evaluation.

Primary extragonadal germ cell tumors were diagnosed in 4 patients in whom surgical or postmortem examination of the testis failed to reveal germ cell tumor. A fifth patient underwent serial examination with testicular ultrasound without evidence of any abnormalities and he remains free of disease following chemotherapy. Based on our experience and a literature review, it is our opinion that orchiectomy is not indicated unless there is a palpable testicular abnormality, recent change in testicular size or consistency, abnormal testicular ultrasound or history of cryptorchidism, or if the primary tumor is choriocarcinoma.

Adult↗
PubMed1982

Dissolution of cystine calculi by pelviocaliceal irrigation with tromethamine-E.

We report 3 cases of cystine calculi. The stones were dissolved by pelviocaliceal irrigation with tromethamine-E, performed either through a percutaneous nephrostomy tube or ureteral catheters. The 25, 27 and 37-day courses of irrigation were well tolerated by all patients. Complications included a single asymptomatic urinary tract infection that required antibiotic therapy and transient hematuria due to catheter irritation. Our experience demonstrates that cystine calculi, including staghorn, can be dissolved by tromethamine-E irrigation, thereby obviating the need for surgical intervention.

Adolescent↗
PubMedDate not supplied

Regulation of insulin-like growth factor-1 expression in vascular endothelial cells by the inflammatory cytokine interleukin-1.

Insulin-like growth factor-1 (IGF-1) has important roles in vascular physiology and pathologies such as atherosclerosis. However, the factors that control expression of this growth factor in human vascular cells are largely unknown. In this study the effects of the inflammatory cytokine interleukin-1 (IL-1) on IGF-1 mRNA and peptide synthesis was examined in human endothelial cells. Cultured human umbilical vein endothelial (HUVE) cells were challenged with interleukin-1 and IGF-1 Ea and Eb mRNA levels were determined by nuclease protection assays and reverse transcription/polymerase chain reaction. IL-1 caused a dramatic increase in IGF-1 Ea mRNA in HUVE cells. Transcript levels peaked between 2 and 4 h of IL-1 treatment and declined over the subsequent 4 h. Consistent with its effect on mRNA, the inflammatory cytokine causes a 3-fold stimulation in production of IGF-1 peptide from endothelial cells. These results demonstrate increased IGF-1 mRNA and peptide in vascular endothelial cells stimulated with IL-1. This suggests that under conditions of local inflammation at the vessel wall the direct action of IL-1 on endothelium can lead to induction of IGF-1 which could promote the intimal hyperplasia often seen in these circumstances.

Cells, Cultured↗