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At least 109 records · Page 6Linked to original sources

PubMed2006

Passing it on: should health care professionals be permitted to disclose patients' genetic information to their reproductive partners?

This article considers whether Australian law should permit health care professionals to disclose patients' genetic information to their reproductive partners without the patients' consent. The issue is addressed with reference to four genetic disorders (Huntington Disease, Familial Adenomatous Polyposis, Multiple Endocrine Neoplasia Type 2A and Cystic Fibrosis) which illustrate differences in inheritance traits and availability of effective treatments. The article explores the familial nature of these disorders and the notion that genetic information has implications which extend beyond the individual patient to third parties such as reproductive partners. It addresses the opinions of legal academics and regulatory bodies regarding the potential amendment of Australian laws to permit such disclosure. Ultimately, it is submitted that the application of current laws regarding medical information to the needs of genetics is unlikely to generate adequate results. To allow for a more appropriate response to this debate, health care professionals' duties to patients should be qualified when it concerns reproductive partners.

Adenomatous Polyposis Coli↗

PubMed1996

Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector.

The in vivo administration of adenovirus vectors frequently elicits a neutralizing antibody response which eliminates or substantially reduces the efficacy of subsequent treatments. Methods to overcome this significant barrier to repeat delivery will be required for the application of adenovirus-based gene therapy in the treatment of chronic disease. We have evaluated the relationship between the initial vector dose and the effectiveness of a second vector administration. C57BL/6 mice injected intravenously with up to 10(7) p.f.u. of a lacZ adenovirus vector, Av1lacZ4, expressed significant levels of human factor IX when injected with 2 x 10(8) p.f.u. of the factor IX vector, Av1H9F, 5 weeks later. An initial dose of 10(8) p.f.u. of Av1lacZ4 completely prevented expression of factor IX following the second administration due to the generation of neutralizing antibody. However, transient immunosuppression with deoxyspergualin (DSG) or cyclophosphamide at the time of initial exposure to 10(8) p.f.u. of Av1lacZ4 prevented the formation of anti-adenovirus neutralizing antibody and permitted an effective second administration of a factor IX vector. Furthermore, transient immunosuppression with cyclophosphamide concomitant with delivery of the factor IX vector enabled an effective administration of a third vector encoding human factor VIII. This approach, together with strategies to prolong the persistence of adenoviral vector expression, should permit long-term therapy with adenovirus-based vectors.

Adenoviruses, Human↗

PubMed1997

Molecular mechanism of a mild phenotype in coagulation factor XIII (FXIII) deficiency: a splicing mutation permitting partial correct splicing of FXIII A-subunit mRNA.

Congenital factor XIII (FXIII) deficiency is potentially a severe bleeding disorder, but in some cases, the symptoms may be fairly mild. In this study, we have characterized the molecular mechanism of a mild phenotype of FXIII A-subunit deficiency in a Finnish family with two affected sisters, one of whom has even had two successful pregnancies without regular substitution therapy. In the screening tests for FXIII deficiency, no A-subunit could be detected, but by using more sensitive assays, a minute amount of functional A-subunit was seen. 3H-putrescine incorporation assay showed distinct FXIII activity at the level of 0.35% of controls, and also the fibrin cross-linking pattern in the patients clotted plasma showed partial gamma-gamma dimerization. In Western blot analysis, a faint band of full-length FXIII A-subunit was detected in the patients' platelets. The patients have previously been identified as heterozygotes for the Arg661 --> Stop mutation. Here we report a T --> C transition at position +6 of intron C in their other allele. The transition affected splicing of FXIII mRNA resulting in low steady state levels of several variant mRNA transcripts. One transcript contained sequences of intron C, whereas two transcripts resulted from skipping of one or two exons. Additionally, correctly spliced mRNA lacking the Arg661 --> Stop mutation of the maternal allele could be detected. These results demonstrate that a mutation in splice donor site of intron C can result in several variant mRNA transcripts and even permit partial correct splicing of FXIII mRNA. Further, even the minute amount of correctly processed mRNA is sufficient for producing protein capable of gamma-gamma dimerization of fibrin. This is a rare example of an inherited functional human disorder in which a mutation affecting splicing still permits some correct splicing to occur and this has a beneficial effect to the phenotype of the patients.

DNA Mutational Analysis↗

PubMed1997

Development and evaluation of an endoscopic technique permitting rapid visualization of the cardiac region of the porcine stomach.

Our study was designed to ascertain whether a flexible videoscope could be used to efficiently monitor ulcers of the pars esophagea in a large group of grower-finisher swine. Gastroscopy was performed on 2 separate occasions in 32 pigs following anesthesia with intravenous pentobarbital, and ulcers of the pars esophagea were subjectively graded. The pigs were then necropsied. Grades from the second endoscopic examination were compared for agreement with grades derived from gross inspection of the pars esophagea at necropsy, and with grades derived from histopathologic examination of sections of the same region. The pars esophagea was adequately visualized in all endoscopic examinations. The average duration of each examination, from anesthetic induction, was approximately 8 min. Gastroscopy permitted appreciation of a wide range of focal and diffuse superficial and deep ulcerative lesions of the pars esophagea, but failed to unequivocally identify parakeratosis of the pars esophagea. Agreement between endoscopic and subsequent necroscopic and histopathologic gradings of ulcerations was poor. We concluded that the use of a flexible videoscope permitted rapid inspection of the pars esophagea, and was therefore a practical method of experimentally monitoring the progression of spontaneous gastric ulcers in pigs. We also postulated that the poor agreement between endoscopic and postmortem findings occurred because endoscopy was possibly more sensitive at detecting small and superficial ulcerations. However, further studies are needed to verify the accuracy of endoscopic diagnosis of gastric ulcers in the live pig.

Animals↗

PubMed1996

Problems in preparation of chromosomes for scanning electron microscopy to reveal morphology and to permit immunocytochemistry of sensitive antigens.

Although much information about chromosome structure and behaviour has been obtained using light microscopy, greater resolution is needed for a thorough understanding of chromosome organisation. Scanning electron microscopy (SEM) can provide valuable data about these three-dimensional organelles. The introduction of methods using osmium impregnation of methanol-acetic acid-fixed chromosome spreads revolutionised matters, producing life-like images of chromosomes. Nevertheless, it became clear that osmium impregnation introduced various artefacts, although the resulting images were still useful. Methanol-acetic acid-fixed chromosomes are, in fact, flattened on the glass substratum, and the 3-dimensional appearance obtained after osmium impregnation is the result of swelling during this process. At the same time, the fibrous substructure of the chromosomes becomes much coarser. More recently a number of alternative methods have become available for studying chromosomes by SEM. Isolated chromosomes, that have not been allowed to dry during preparation, retain a 3-dimensional appearance without osmium impregnation, and the same is true of methanol-acetic acid-fixed chromosomes that have been treated with 45% acetic acid and processed without drying; however, these methods do not permit the routine production of intact metaphase spreads. Use of cytocentrifuge preparations obviates the use of acetic acid fixation and osmium impregnation, produces intact metaphase spreads, and permits the immunocytochemical detection of antigens that are easily destroyed by routine fixation procedures.

Acetic Acid↗

PubMed1988

Grand Ducal Regulation authorizing the creation and use of a data bank on persons requesting work permits and their employers, 13 January 1987.

This Order authorizes the creation of a data bank with information about persons requesting work permits and their employers for the use of the Luxembourg Ministry of Labour and Employment Administration. The Order was issued in light of the Law of 28 March 1972, as amended, relative to the entry and residence of foreigners, the medical control of foreigners, and the employment of foreign labor.

Demography↗

PubMed1988

Reflex inhibition of urethral sphincters to permit voiding in paraplegia.

When the spinal motoneurons innervating the external sphincter of the urethra cannot be inhibited voluntarily due to lesions of the spinal cord, the normal capacity to relax this physiologic valve during micturition is lost. Even if contractions of the bladder occur, urinary outflow may be completely blocked at the sphincter, leading to distention of the bladder and the risk of urinary infection. A method is described for controllably relaxing the sphincter, which permits free outflow of urine in paraplegic cats. One pudendal nerve is sectioned, paralyzing half of the sphincter, but leaving the experimental animals entirely continent. The motoneurons supplying the other half of the sphincter are inhibited by means of spinal reflexes, eliminating active resistance to urethral flow. The simplicity of this approach suggests that it may prove equally effective in human paraplegia.

Animals↗

PubMed2000

The contralateral bilobed trapezius myocutaneous flap for closure of large defects of the dorsal neck permitting primary donor site closure.

BACKGROUND: Various reliable local flaps can be used to cover soft tissue defects of the posterior neck. Among others, the (either vertical or transverse) trapezius myocutaneous flap is a reliable option in this context. However, for defects with a diameter larger than 15 cm, these flaps require skin grafting of the donor site. METHODS: To prevent this additional morbidity we describe a contralaterally based bilobed trapezius musculocutaneous flap successfully applied in two elderly patients with large tumors of the posterior neck in palliative situations. RESULTS: This novel approach makes use of a standard vertical skin paddle to cover the neck, together with a transverse cervical flap in a bilobed design to primarily close the paravertebral donor site. CONCLUSIONS: The bilobed technique allows the primary closure of massive soft tissue neck wounds. Preservation of the accessory nerve to the superior fibers of the trapezius muscle permitted normal arm elevation in our patients.

Accessory Nerve↗

PubMed2001

Development of high-performance stent: gelatinous photogel-coated stent that permits drug delivery and gene transfer.

Hydrogel-coated metallic stents may provide supplementary functions such as local drug delivery and gene transfer in addition to mechanical dilation function. To this end, we used a photoreactive material consisting of gelatin macromer (multiple styrene-derivatized gelatin) and carboxylated camphorquinone (photo-initiator). A few minutes of visible light irradiation of a stent after dip-coating of an aqueous solution of the photoreactive material resulted in the formation of a homogeneously crosslinked gelatinous layer on the entire exterior surface of the stent. As the metal stent, gold stents under development were used. Rhodamine-conjugated albumin as a model drug or adenoviral vector expressing bacterial beta-galactosidase (AdLacZ) as a model gene were photo-immobilized in the gelatinous gel layer. In vitro experiments using hybrid tubular tissue, which is a self-shrinkaged, vascular smooth muscle cell-incorporated type-I collagen gel, as a vascular model, showed that the immobilized dye-derivatized albumin was released on and permeated into tissues, as observed by confocal laser microscopy, and that the cells transfected with immobilized AdLacZ produced beta-galactosidase up to almost 3 weeks, as observed by x-gal staining. In preliminary in vivo experiments these drug- or adenovirus-immobilized stents were implanted in rabbit common carotid arteries. Within 3 weeks of implantation, drug permeation and gene expression in the vascular tissues were observed, indicating that the gelatinous photogel effectively serves as a matrix or coating for a bioactive stent,which permits drug release as well as gene transfer. This intraluminal approach has the potential to realize drug and gene therapy in atherosclerotic plaque.

Albumins↗

PubMed1987

Dysfunctional alpha-globin genes in hemoglobin H disease in blacks: variation in restriction fragment size permits the detection of the -alpha/-alpha T genotype.

Hemoglobin H (HbH) disease is most often due to deletion of three of the four alpha-globin genes (genotype --/--alpha). In black subjects although the -alpha/chromosome is common, the --/haplotype is very rare and few examples of HbH disease have been detected. We have studied three black siblings with HbH by restriction endonuclease mapping of the alpha-like gene complex (5'-zeta-psi zeta-psi alpha 2-psi alpha 1-alpha 2-alpha 1-3') using zeta- and alpha- specific probes. The presence of size differences in the previously described hypervariable region between the zeta and psi zeta genes results in a restriction fragment length polymorphism which permitted the detection of single alpha genes on both number 16 chromosomes in these subjects. Quantitative DNA hybridization by a slot-blot technique confirmed that their genomes contained two alpha-globin genes. The results establish that in these black subjects HbH disease is associated with dysfunctional alpha-globin genes (genotype: -alpha/-alpha T).

Black People↗

PubMed1980

Intraoperative irrigation of the colon to permit primary anastomosis.

A technique is described which permits intraoperative application of antegrade bowel irrigation to clear the obstructed or loaded colon of faeces with minimal risk of contamination. The procedure extends the indications for safe primary anastomosis in surgery of the left colon.

Aged↗

PubMed1994

Gene transfer of the interleukin (IL)-2 receptor beta chain into an IL-7-dependent pre-B cell line permits IL-2-driven proliferation: tyrosine phosphorylation of Shc is induced by IL-2 but not IL-7.

Expression of the interleukin (IL)-2 receptor beta chain in the IL-7-dependent pre-B cell line IxN/2B permitted growth in presence of either IL-2 or IL-7, allowing for a direct comparison of intracellular signaling events. Protein tyrosine phosphorylation was essential for IL-2 and IL-7-induced signal transduction since the tyrosine kinase inhibitor herbimycin A blocked proliferation in response to both factors. Western blot analysis of tyrosine-phosphorylated proteins revealed that both IL-2 and IL-7 stimulation led to enhanced phosphorylation of proteins of 170-, 145-, 115- and 99-kDa, as well as induction of phosphorylation of a 96-kDa protein. However, a 55- and a 155-kDa protein were only phosphorylated after IL-2 stimulation. The 55-kDa protein specifically phosphorylated by IL-2 could be identified as p52shc which has recently been shown to be critically involved in Ras activation. Shc tyrosine phosphorylation as a result of IL-2 stimulation was consistently found in CTLL-2 cells and human T lymphoblasts. Taken together our results indicate that the IL-2- and IL-7-stimulated intracellular pathways are partially different and that Shc is a target of IL-2-, but not IL-7-, stimulated tyrosine phosphorylation.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat.

The host immune response limits the duration of expression of adenovirally transduced genes and precludes long-term gene expression upon re-administration of the virus. In this study we wished to evaluate whether short-term immunosuppression of the host, at the time of recombinant virus administration, would allow expression of the therapeutic gene product upon virus reinjection. Gunn rats were used as recipients of recombinant adenoviruses expressing human BUGT (Ad-hBUGT) or E. coli beta-galactosidase (Ad-LacZ). Rats were treated with FK506 (1-1.5 mg/kg, per OS daily) for three days beginning 24 hours before each virus injection. Control groups did not receive any immunosuppressant. The serum bilirubin level was reduced from 7.1 +/- 0.75 mg/dL to 2.0 +/- 0.7 mg/dL within two days of viral injection in both FK506 treated and control groups, and then gradually increased in 6 weeks. FK506-treated rats had low or undetectable antibody titers against the recombinant adenovirus and minimal or no cytotoxic T lymphocyte (CTL) response against adenovirus-infected cells. The tolerized rats received two subsequent injections 42 and 98 days after the first injection, which reduced the bilirubin levels again to 2.0 +/- 0.56 and 2.2 +/- 0.61 mg/dL, respectively. In contrast, control rats developed high titer neutralizing antibodies and a CTL response, and their serum bilirubin levels were not reduced following subsequent injections. We conclude that short-term FK506 treatment around the time of virus administration prevents the host immune response, permitting long-term gene therapy by repeated administration of the recombinant virus.

Adenoviridae↗

PubMed1998

Oral tolerization to adenoviral proteins permits repeated adenovirus-mediated gene therapy in rats with pre-existing immunity to adenoviruses.

Exposure to wild-type adenoviruses is common in humans and results in immune response against adenoviruses. The pre-existing antibodies and a strong secondary humoral and cellular immune response would interfere with gene transfer using recombinant adenoviral vectors. To test whether the secondary immune response can be abrogated by oral tolerization to adenoviral antigens, we immunized bilirubin-UDP-glucuronosyltransferase (BUGT)-deficient jaundiced Gunn rats with a recombinant adenovirus (5 x 10(9) pfu/rat) expressing the human UDP-glucouronosyltransferase (BUGT1) gene (Ad-hBUGT). Transgene expression was shown by reduction of mean serum bilirubin levels from 7.0 mg/dL to 2.3 mg/dL in 14 days, which then increased gradually to pretreatment levels in 6 weeks. All recipients developed antibodies (1:2[10]) and cytotoxic lymphocytes against the adenovirus. For oral tolerization, we administered to the immunized rats protein extracts of a recombinant adenovirus type 5 (1-1.5 mg/day) via duodenostomy tubes 10 to 40 days after the initial virus injection; control rats received bovine serum albumin. In rats fed adenoviral proteins and the BSA-fed controls, the antibody titers decreased to 1:2(7) and 1:2(9), respectively, in 70 days. Lymphocytes from the tolerized rats expressed TGF-beta1 upon exposure to antigen-presenting cells primed with adenoviral antigens, whereas IFN-gamma expression was undetectable. In contrast, lymphocytes from the BSA-treated control rats expressed IFN-gamma but not transforming growth factor beta1 (TGF-beta1). Seventy days after the first injection in the orally tolerized rats, but not in the controls, a second Ad-hBUGT injection caused human BUGT1 expression again, reducing serum bilirubin levels to those observed after the first injection. In the tolerized rats, serum antibody titers and anti-adenoviral cytotoxic lymphocyte activities continued to decline despite the second injection, whereas the antibody levels were boosted in the non-tolerized group. This results show that by preventing the secondary booster response, oral tolerization permits repeated adenovirus-directed gene transfer despite the presence of a residual antibody titer from a previous adenoviral exposure.

Adenoviridae↗

PubMed1993

Level of preadipocyte growth factor in rat adipose tissue which specifically permits the proliferation of preadipocytes is affected by restricted energy intake.

We previously reported the presence of a protein growth factor in rat adipose tissue which specifically permits the proliferation of 3T3-L1 and Ob1771 preadipocytes [Biochem. Biophys. Res. Commun. 1990;171:905-912, ref. 1] and which is hereinafter referred to as PAGF (preadipocyte growth factor). In this study, the effects of long-term restricted energy intake on the PAGF activity in rat epididymal and perirenal adipose tissue toward 3T3-L1 preadipocytes were investigated. When rats were subjected to restricted energy intake for three weeks, PAGF activity increased with energy intake. The body weight, epididymal and perirenal fat depot weights and glycerol 3-phosphate dehydrogenase activity also increased with the energy intake, whereas the lactate dehydrogenase activity remained almost constant in all energy intake groups. These results suggest that the PAGF in fat depots functions in response to energy intake and contributes to the de novo formation of adipocytes and the growth of adipose tissue. This factor may provide a useful tool for further elucidation of the relationship between energy storage in adipose tissue and adipose tissue development.

3T3-L1 Cells↗

PubMed1994

Autoprotection: stimulated tissue repair permits recovery from injury.

Autoprotection is a phenomenon whereby prior exposure to a small dose of a chemical results in protection against a subsequently administered lethal dose of the same compound. While CCl4 autoprotection has been studied the most, it has also been demonstrated for other chemicals. Recent studies indicate that the prevailing concept of decreased bioactivation of the normally lethal dose of CCl4 owing to decreased hepatic microsomal cytochrome P-450 content cannot be supported by direct end points of liver injury such as necrosis. These findings suggest a pivotal role for hepatocellular division and tissue healing processes stimulated by the protective dose in the mechanism of autoprotection. Augmentation of hepatocellular regeneration and tissue repair, stimulated by the protective dose, appears to permit timely recovery and restoration of hepatic structure and function. In the absence of the protective dose, hepatocellular division is substantially deficient and it occurs too late to tip the delicate balance between recovery from injury and progression of massive injury in favor of recovery. Abolition of autoprotection by colchicine antimitosis, under conditions where metabolism and disposition of CCl4 are not altered, is supportive of this concept. Selective colchicine antimitotic suppression of the early phase of hepatocellular division and tissue repair induced by a low dose of CCl4 results in progression of toxic liver injury, leading to hepatic failure and mortality. Studies have shown that pretreatment with phenobarbital results in postponed low-dose CCl4-stimulated cell division by 24 hours, which accordingly postpones the optimal autoprotection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1980

Learning, using natural reinforcements, in insect preparations that permit cellular neuronal analysis.

A general paradigm is described that permits testing the ability of an arthropod to learn (by operant conditioning) to alter the position of a single leg segment in order to relate to behaviorally appropriate reinforcement. The paradigm was designed so that intracellular recording from identified neurons involved would be possible during the training of a locust or grasshopper, for which extensive neuron maps are available. As a prelude to such studies, electromyograms were made from the antagonistic muscles that move the conditioned limb, which in the present experiments was the tibia of the metathoracic leg. Negative (aversive) reinforcement was provided by a loud sound/vibration and positive (reward) reinforcement by food in the form of sugar-water or fresh-growing grass. In the aversive reinforcement experiments the sound, which reflexly caused flexion, was on continually except when the tibia of one hind leg was voluntarily placed in an electronically set position "window" displaced, in extension, away from the preferred position. In feeding experiments, food was brought automatically to the mouth by a motor-driven arm when the tibia was held within a position window set away from the preferred position in either extension or flexion. Whole or headless insects learned to turn off the sound permanently, except for sporadic brief interruptions, by tonic shifting of tibial position. Insects learned to bring food to the mouth by modifying the plateau phase of a position displacement lasting for a few minutes, that was found to occur from time to time also in controls. In aversive learning, minimum times to turn off the sound were 22 sec for the easiest position and 4 min for the most difficult. The longest time in the easiest position was 1 min 40 sec and in the most difficult 39 min; excluding measurement for individuals that did not learn. In reward learning, the minimum time in the easiest position was just under 1 min, and 12 min in the most difficult position. The longest times were about 8 hr regardless of difficulty.

Animals↗

PubMed1993

5-fluorouracil permits access to a primitive subpopulation of peripheral blood stem cells.

Peripheral blood stem cells (PBSC) contain a mixture of mature and immature hematopoietic progenitors. Resistance to 5-Fluorouracil (5-FU) has been used to identify and characterize primitive quiescent stem cells among bone marrow (BM) cells. To see if the same technique could be used to isolate a similar population of cells among PBSC, low-density peripheral blood mononuclear cells (PBMNC) were collected by cytapheresis in the regenerative phase after high-dose chemotherapy from patients with hematological malignancies. These PBMNC were incubated with increasing concentrations of 5-FU for 24 h. The viable 5-FU resistant cells were then cultured in semi-solid media in the presence of either single cytokines: TCM 5637, Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), or a combination of cytokines: interleukin 1 (IL-1) IL-1 + IL-3 + 5637, IL-1 + IL-3 + Stem Cell Factor (SCF). Low concentrations (5-10 micrograms/ml 5-FU) eliminated mature day 7 Colony Forming Units-Granulocyte Macrophage (CFU-GM) and spared day 7 clusters while enriching for day 14 CFU-GM, irrespective of the growth factors used. Higher concentrations of 5-FU (15, 20, 25 micrograms/ml) selected for later forming clonogenic elements. A combination of synergistic growth factors was required for the development of morphologically identifiable clonogenic elements resistant to 25 micrograms/ml 5-FU at day 21 of culture. Further experimentation demonstrated that SCF could effectively replace TCM 5637 in the cytokine combination for the detection of primitive late forming clonogenic elements. The presence of SCF potentiated colony formation by 5-FU resistant PBMNC. It was confirmed that GM-CSF alone was unable to support colony formation by PBMNC resistant to 25 micrograms/ml. These observations demonstrate that PBSC contain a heterogenous mixture of hematopoietic progenitors and that incubation with 25 micrograms/ml 5-FU permits access to a quiescent primitive stem cell population that requires a combination of synergistic growth factors for the development of morphologically identifiable clonogenic elements at day 21. Taken together, these results suggest that PBSC have similar characteristics to BM derived stem cells.

Antineoplastic Agents↗