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Biomedical subjects

S Young

Publications and source records attributed to S Young.

At least 91 records · Page 5Linked to original sources
PubMed1999

Combined NK(1)and NK(2)receptor antagonists on the bronchoconstrictor response to NKA in dogs.

The major pulmonary effects of tachykinins, including bronchoconstriction, are mediated by activation of both neurokinin-1 (NK(1)) and neurokinin-2 (NK(2)) receptors. In guinea-pigs NK(1)and NK(2)receptor antagonists interact synergistically to inhibit the bronchoconstriction induced by neurokinin-A (NKA). However, the effect of combined NK(1)and NK(2)receptor antagonists on tachykinin-induced bronchoconstriction in most other species has not been evaluated. In this study, the interactive effects of CP 99994, an NK(1)receptor antagonist and SR 48968, an NK(2)receptor antagonist, were evaluated against NKA-induced brochospasm in dogs. Pulmonary resistance (R(L)) and dynamic lung compliance (C(Dyn)) were measured in anesthetized, spontaneously breathing dogs to measure the bronchoconstrictor response to aerosolized NKA (1%). Mean arterial blood pressure (MAP) and minute volume (MV) were also measured to assess the NK(1)receptor mediated cardiorespiratory response to substance P (100 ng/kg, iv). Pretreatment with SR 48968 (0.3-3 mg/kg, po) in the presence of an NK(1)antagonist dose of CP 99994 (10 mg/kg, po) inhibited the NKA-induced bronchospasm. However, the inhibition produced by SR 48968 plus CP 99994 was no greater than that previously shown for SR 48968 alone. Therefore, dual NK(1)/NK(2)receptor antagonists do not interact synergistically against NKA-induced bronchospasm in dogs. This may relate to the fact that dogs, like humans, have the NK(2)receptor as the predominant receptor subtype producing bronchoconstriction.

Animals↗
PubMed1999

Mechanisms and impact of enteric infections.

The increased recognition of both old and new enteric pathogens and their potential impact requires an improved understanding of pathogenesis and effective interventions. While the overwhelming mortality (> 3 million children per year) due to diarrheal diseases is well-recognized, the potential long-term impacts of enteric infections and early childhood diarrhea morbidity are just beginning to be appreciated. Furthermore, several enteric infections are now being recognized as causes of growth shortfalls with or without diarrhea; i.e., malnutrition may be one of the greatest yet of the "emerging infectious diseases." The increased appreciation of this extended impact calls for further quantification and improved understanding of the deranged physiology. In particular, persistent diarrheal illnesses exhibit common themes of blunted villi, disruption of intestinal barrier function and varying degrees of sub-mucosal inflammation for which lactulose/mannitol permeability and fecal lactoferrin provide respective quantification. Finally, such improved understanding will allow targeted interventions among those most vulnerable, which will enable further documentation of cost effectiveness and the potential for improved human development which is critical to reducing the widening disparity and population overgrowth which increasingly threaten our global security.

Animals↗
PubMed1999

Correction of diabetic nod mice with insulinomas implanted within Baxter immunoisolation devices.

Insulin replacement by injection is clearly not a cure for Insulin Dependent Diabetes Mellitus (IDDM). Replacement of the destroyed islets by pancreas or islet allograft transplantation can achieve the good metabolic control required to prevent diabetic complications, but tissue supply is limited. The problem of islet supply to treat the 1 million IDDM patients in the USA could be overcome by using immortalized islet beta-cells as a donor source. However, before either allogeneic or xenogeneic immortalized beta-cells are used, some major problems have to be overcome: control of immortalized cell growth, allograft or xenograft rejection and recurrence of autoimmunity. To tackle these problems we have used a cell impermeable immunoisolation device containing mouse insulinoma cells. Transplantation of devices with insulinomas from NOD mice carrying the Rat-insulin promoter regulated SV40 T-Antigen transgene (RIP-TAg), normalized the blood glucose levels of diabetic NOD mice. Insulinomas from allogeneic CBA/NOD-RIP-TAg mice were also capable of normalizing diabetic NOD mice. Not only were non-fasting blood glucoses normalized but when given an intraperitoneal injection of glucose, the corrected mice had a near normal clearance of glucose from the blood. When the devices were removed from normalized mice they became diabetic again, demonstrating that the immunoisolation device was capable of protecting against both alloimmune and autoimmune destruction. The results with allogeneic mouse beta-cells suggest the possibility that immortalized human beta-cells could be an effective source of tissue to correct diabetes in IDDM patients without the use of immunosuppression.

Animals↗
PubMed1999

Humanisation and characterisation of PR1A3, a monoclonal antibody specific for cell-bound carcinoembryonic antigen.

Carcinoembryonic antigen (CEA) is highly expressed by most tumours of gastrointestinal origin, but its use as a target for tumour therapy is complicated by the high levels of soluble CEA that are found circulating in the blood of cancer patients. A monoclonal antibody PR1A3 has been prepared, which binds preferentially to cell-surface rather than soluble CEA, this cell selectivity should make PR1A3 an ideal candidate for antibody-targeted tumour therapy. PR1A3 has been humanised and shown to retain its cell-surface specificity and affinity. Stable expression of the humanised antibody from chinese hamster ovary (CHO) cells has been achieved after transfection and amplification. Since PR1A3 binds preferentially to cell-associated CEA, a cell-free enzyme-linked immunosorbent assay (ELISA) has been developed to allow characterisation and routine assay of the antibody. This assay was developed using a recombinant chimeric protein constructed by cloning the domain of CEA that is bound by PR1A3 (the B3 domain) into a hybrid gene containing the Fc portion of IgG and three domains of biliary glycoprotein. Stable expression of this hybrid protein has been achieved from CHO cells. In ELISA both humanised and murine PR1A3 bound strongly to this antigen but only at a minimal level to soluble CEA. Two binding sites for the antibody were found on the gastric carcinoma cell line MKN45, one of higher affinity (1 nM) and the other at lower affinity (60 nM). Similar affinities were found for both murine and humanised antibodies. The data presented make it unlikely that the differential binding to cell-surface as distinct from soluble CEA can be accounted for by low affinity of PR1A3 for CEA, and provides further support for the hypothesis that some conformational change takes place on CEA release from cells and that it is this change that blocks PR1A3 binding to its epitope.

Amino Acid Sequence↗
PubMed1999

Examination of tumor and tumor-like conditions of bone.

Surgical pathology specimens composed of bone, ranging from core biopsy to limb amputation specimens, require special attention, processing, and often unique equipment. This readily translates into additional handling steps and time, especially when one factors in clinical correlation with the surgeon and radiologic review of all images with a knowledgeable musculoskeletal radiologist. When these factors are superimposed on the rarity of these lesions in routine practice, it is not surprising that most trainees, as well as seasoned pathologists, are wary of these lesions. In this report, we use a case of osteofibrous dysplasia (Campanacci's disease) to demonstrate the dissection of such a surgical specimen and complete the report with a brief discussion of the entity.

Adolescent↗
PubMed1999

Effect of long-term trimethoprim-sulfamethoxazole prophylaxis on ascites formation, bacterial translocation, spontaneous bacterial peritonitis, and survival in cirrhotic rats.

Selective intestinal decontamination with norfloxacin is useful in preventing spontaneous bacterial peritonitis in cirrhotic patients and also in cirrhotic rats. The emergence of norfloxacin-resistant infections in these patients warrants a search for alternative therapies. The aim of this study was to evaluate the effect of long-term trimethoprim-sulfamethoxazole administration on carbon tetrachloride (CCl4) -induced cirrhosis in rats with specific attention to intestinal flora, bacterial translocation, spontaneous bacterial peritonitis (SBP), and survival. Male Sprague-Dawley rats received CCl4 administered weekly by gavage. After eight weeks of CCl4 administration rats were randomly allocated into two groups. Group I received daily overnight trimethoprim-sulfamethoxazole diluted in phenobarbital water during follow-up and group II did not. The rats were killed when gravely ill, and a laparotomy was performed to culture samples of cecal stool, mesenteric lymph nodes, and portal and inferior vena caval blood. There was a trend toward a reduction in the incidence of bacterial translocation (8/17 vs 11/14, respectively) and SBP (5/17 vs 7/14, respectively) in treated rats that were killed just before death compared to untreated rats. A decrease in the incidence of bacterial translocation caused by gram-negative bacilli was observed in group I (17.6% vs 78.6%, P < 0.01). The development of ascites was delayed in group I (P < 0.05) and survival was prolonged in group I (P < 0.05), despite a higher CCl4 dose in this group (P < 0.05). In conclusion, long-term prophylactic trimethoprim-sulfamethoxazole administration in CCl4-induced cirrhosis in rats delayed the development of ascites, prolonged survival, and reduced the incidence of gram-negative bacterial translocation but not of SBP, without increasing gram-positive episodes. These data suggest that trimethoprim-sulfamethoxazole might be a good alternative to norfloxacin for preventing gram-negative bacterial translocation.

Animals↗
PubMed1999

A randomized phase II trial of interferon-alpha2b versus 5-fluorouracil after trabeculectomy.

PURPOSE: The aim of the present study was to investigate the safety and potential efficacy of subconjunctival interferon-alpha2b (IFN-alpha), either alone or in combination with 5-fluorouracil (5-FU), in reducing the risk of failure of glaucoma surgery METHODS: A prospective, masked randomized phase II study was undertaken in which patients received three subconjunctival injections per week for 3-4 weeks postoperatively. Three treatments were compared: (i) IFN-alpha (1 x 10(6)IU per dose); (ii) 5-FU (5 mg per dose); and (iii) alternating IFN-alpha and 5-FU (BOTH). The primary outcome measures were: (i) rate of successful control of intra-ocular pressure without further surgery; and (ii) the incidence of side effects. RESULTS: Fifty-seven patients undergoing glaucoma surgery with an increased risk of failure were evaluated, including 23 patients (40%) undergoing trabeculectomy combined with extracapsular cataract extraction as well as other conventional high-risk groups. With 53 patients (93%) completing 2 years follow up,there was no significant difference in success rates among the three groups. Intra-ocular pressure was controlled without further surgery in 79% of patients (95% confidence interval (CI): 61, 97%) receiving IFN-alpha, in 89% of patients (76, 100%) receiving 5-FU and in 89% of patients (76, 100% receiving BOTH. Side effects were similar among the three groups. CONCLUSIONS: These results are consistent with a beneficial effect of IFN-alpha2b given either alone or in combination with 5-FU after glaucoma filtering surgery. However, the lack of a clear and substantial benefit over conventional anti-fibrotic therapy does not support the further clinical evaluation of these treatments.

Adult↗
PubMed1999

Control of vancomycin-resistant enterococci at a community hospital: efficacy of patient and staff cohorting.

OBJECTIVE: To evaluate the efficacy of patient and staff cohorting to control vancomycin-resistant enterococci (VRE) at an Indianapolis community hospital. DESIGN: To interrupt transmission of VRE, a VRE point-prevalence survey of hospital inpatients was conducted, and VRE-infected or -colonized patients were cohorted on a single ward with dedicated nursing staff and patient-care equipment. To assess the impact of the intervention, staff compliance with contact isolation procedures was observed, and the VRE point-prevalence survey was repeated 2 months after the cohort ward was established. RESULTS: Following the establishment of the cohort ward, VRE prevalence among all hospitalized inpatients decreased from 8.1% to 4.7% (25 positive cultures among 310 patients compared to 13 positive cultures among 276 patients, P=.14); VRE prevalence among patients whose VRE status was unknown before cultures were obtained decreased from 5.9% to 0.8% (18 positive cultures among 303 patients compared to 2 positive cultures among 262 patients, P=.002); and observed staff-patient interactions compliant with published isolation recommendations increased (5 [22%] of 23 interactions compared to 36 [88%] of 41 interactions, P<.0001). CONCLUSIONS: Our data suggest that, in hospitals with endemic VRE or continued VRE transmission despite implementation of contact isolation measures, establishing a VRE cohort ward may be a practical and effective method to improve compliance with infection control measures and thereby to control epidemic or endemic VRE transmission.

Adult↗
PubMed1999

Effects of age on balance assessment using voluntary and involuntary step tasks.

BACKGROUND: Taking a step while standing and modifying a step while walking are two strategies often used to maintain balance when balance disturbances are encountered during activities of daily living. This study investigated whether performance on an involuntary step task, which is assumed to be a surrogate for fall recovery abilities, was comparable to performance on a voluntary step task. METHODS: The performance of a voluntary and an involuntary step task was measured in healthy young adult (mean age 21 years) and healthy elderly adult (mean age 68 years) female subjects. Subjects stepped as fast as possible in the direction of a minimally destabilizing lateral waist pull (voluntary step task), or they responded naturally to a large destabilizing lateral waist pull (involuntary step task). The effects of age, task, and their interaction on the primary outcome variables of step foot liftoff time, landing time, step length, and step height were examined. RESULTS: In the voluntary step task, the older adults, compared to the young, required significantly more time to lift their foot (Young: 307 msec; Elderly: 424 msec). In the involuntary step task, the elderly were as quick as the young in lifting their foot (Young: 322 msec; Elderly: 335 msec). The young lifted their foot at about the same time for the two tasks. The elders, on the other hand, lifted their foot significantly earlier in the involuntary step task, compared to the voluntary step task (Vol: 424 msec; Invol: 335 msec). CONCLUSIONS: A voluntary step task underestimates the ability of healthy elderly adults to respond quickly when large destabilizing balance disturbances are encountered.

Accidental Falls↗
PubMed1999

Dialysis-associated renal cystic disease resembling autosomal dominant polycystic kidney disease: a report of two cases.

Acquired renal cystic disease is common in patients receiving dialysis. Characteristically, the kidneys are small or, less often, normal in size, and the cysts are usually less than 0.6 cm in diameter. We present here 2 patients who, after 5 and 7 years on hemodialysis, developed marked renal enlargement, with large cysts in the kidneys and, in 1 patient, in the liver as well; the appearance on ultrasonography and computed tomography was indistinguishable from autosomal dominant polycystic kidney disease. Before starting dialysis the first patient was a 19-year-old man who developed renal shutdown from crescentic glomerulonephritis, and the second patient was a 33-year-old man who developed end-stage renal failure from malignant hypertension. Neither patient had renal cysts at the onset of end-stage renal failure.

Adult↗
PubMed1999

Functional alterations of alveolar macrophages subjected to smoke exposure and antioxidant lazaroids.

Acute inhalation of diesel fuel-polycarbonate plastic (DFPP) smoke causes severe lung injury, leading to acute respiratory distress syndrome (ARDS) and death. It has been reported that the initiation of acute lung injury is associated with the activation of pulmonary alveolar macrophages (PAM). To further explore the pathogenesis, alveolar macrophages (AM) of New Zealand rabbits ventilated and exposed to a 60 tidal volume of DFPP smoke in vivo were recovered at 1 h post-smoke. Smoke exposure induced significant increases in both mRNA and protein levels for PAM tumor necrosis factor-alpha (TNF-alpha), when compared to smoke control. Smoke also induced a biphasic response (inhibited at 2 h, enhanced at 24 h after cell isolation) in the production of superoxide (O2-) by PAM. However, aerosolized lazaroid, U75412E (1.6 mg/kg body weight), significantly attenuated smoke-induced expression in AM TNF-alpha at the protein level but not at the mRNA level, and smoke-induced changes in AM production of O2-. This study suggests that highly expressing AM TNF-alpha following smoke may be a key contributor to the cascade that establishes an acute injury process and exacerbates oxidant-derived cell injury. Whereas, the lazaroid may ameliorate smoke-induced lung injury by attenuating AM TNF-alpha release, in addition to its primary antioxidative mechanism.

Aerosols↗
PubMed1999

A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging.

Gadolinium Texaphyrin (Gd-Tex) is a radiation sensitizer with a novel mechanism of action that sensitizes both oxic and hypoxic cells, localizes selectively in tumors, and is detectable by magnetic resonance imaging (MRI). This Phase I single-dose trial of Gd-Tex administered concurrently with radiation therapy was carried out to determine the maximally tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, and biolocalization of Gd-Tex as determined by MRI. Adults with incurable cancers of any histology requiring radiation therapy were eligible. A single i.v. dose of Gd-Tex was followed at least 2 h later by radiation therapy. The Gd-Tex dose was escalated in cohorts of 3 to 5 patients. Thirty-eight patients (median age, 58 years; range, 35-77 years) with incurable cancers of the lung (26), cervix (3), or other solid tumors (9) received a total of 41 single administrations of Gd-Tex. The Gd-Tex dose was escalated from 0.6 to 29.6 mg/kg. Irradiated sites included the thorax, brain, pelvis, bone, soft tissue, and sites of nodal metastases. The MTD was 22.3 mg/kg, determined by reversible acute tubular necrosis as the dose-limiting toxicities. Gd-Tex selectively accumulated in primary and metastatic tumors as demonstrated by MRI. No increase in radiation toxicity to normal tissues was seen. The median half-life of Gd-Tex after single-dose administration is 7.4 h. This study demonstrates that Gd-Tex is well tolerated in doses below the MTD, and that there is selective biolocalization in tumors. The maximum recommended dose for single administrations is 16.7 mg/kg.

Adult↗
PubMed1999

Penetrating cardiac injuries.

Our objective was to determine the influence of several clinical factors on the survival of patients with penetrating wounds to the heart. A retrospective review of 80 consecutive penetrating cardiac injuries treated in a Level II urban trauma center from 1980 through 1994 were examined. Thirty-six patients (45%) had gunshot wounds (including 1 shotgun wound), and 44 (55%) had stab wounds. Intervention consisted of emergency room (ER) or operating room thoracotomy. We measured the effect of several clinical factors on morbidity and patient survival. Survival rate was 17 of 36 (47%) in gunshot injuries and 35 of 44 (80%) in stab injuries, with an overall survival rate of 52 of 80 patients (65%). The average age was 24 years (range, 9-53), and there were 3 female patients. Twelve patients (15%) had multiple cardiac injuries, and 63 (79%) had other associated injuries. Fourteen patients (17%) presented with no blood pressure, and 55 (69%) were hypotensive on admission. ER thoracotomy was performed on 7 of 52 survivors (13%) and 24 of 28 nonsurvivors (86%). Survival after ER thoracotomy was 7 of 31 patients (22%). A selective approach is recommended, because ER thoracotomy has a limited role in penetrating cardiac injury. A high index of suspicion, prompt resuscitation, and immediate definitive surgical management resulted in a high survival rate for these frequently lethal injuries.

Adolescent↗
PubMed1998

Prevention of mammalian DNA reduplication, following the release from the mitotic spindle checkpoint, requires p53 protein, but not p53-mediated transcriptional activity.

The tumor suppressor p53 has been identified as a component of a mitotic spindle checkpoint. When exposed to a spindle-disrupting drug such as nocodazole, fibroblasts derived from mice having wild-type p53 are blocked with a 4N content of DNA. Conversely, fibroblasts from p53-deficient mice become polyploid. To learn if transcriptional activation of downstream genes by p53 plays a role in this putative checkpoint, three cell lines were exposed to nocodazole. In one line, p53 protein is not expressed, while the other two cell lines over-express p53. In one of these two lines, the N-terminal transactivation domain is wild-type and in the second, this region contains a mutation that eliminates the ability of the protein to act as a transcription factor. Incubation with nocodazole of cells containing wild-type p53 results in accumulation of both 2N and 4N populations of cells. Under the same conditions, cells containing a transactivation-deficient mutant of p53 accumulate a 4N population of cells, but not a 2N population of cells. Cells entirely deficient in p53 protein become hyperdiploid, and display 8N to 16N DNA content. In all three cell lines, nocodazole elicited an initial increase in mitotic cells, but within 24 h the mitotic index returned to baseline. Expression patterns of cyclins B and D indicated that following entry into mitosis, the cells returned to a G1 state but with 4N DNA content. Subsequent re-duplication of DNA beyond 4N is prevented in cells containing either wild-type or transcriptionally inactive p53 protein. In cells entirely lacking p53 protein, DNA is re-duplicated (without an intervening mitosis) and the cells become hyperdiploid. These experiments indicate that p53 does not participate in the transient mitotic arrest that follows spindle disruption, but is essential to prevent subsequent reduplication of DNA and the resulting hyperdiploid state. This function is intact in a mutant that is transcriptionally inactive.

Amino Acid Substitution↗