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Biomedical subjects

N Young

Publications and source records attributed to N Young.

At least 19 recordsLinked to original sources
PubMed2001

Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition.

Glycogen synthase kinase 3 beta (GSK3 beta) plays a key role in insulin and Wnt signaling, phosphorylating downstream targets by default, and becoming inhibited following the extracellular signaling event. The crystal structure of human GSK3 beta shows a catalytically active conformation in the absence of activation-segment phosphorylation, with the sulphonate of a buffer molecule bridging the activation-segment and N-terminal domain in the same way as the phosphate group of the activation-segment phospho-Ser/Thr in other kinases. The location of this oxyanion binding site in the substrate binding cleft indicates direct coupling of P+4 phosphate-primed substrate binding and catalytic activation, explains the ability of GSK3 beta to processively hyperphosphorylate substrates with Ser/Thr pentad-repeats, and suggests a mechanism for autoinhibition in which the phosphorylated N terminus binds as a competitive pseudosubstrate with phospho-Ser 9 occupying the P+4 site.

Animals↗
PubMed2001

A mutation in the Gsk3-binding domain of zebrafish Masterblind/Axin1 leads to a fate transformation of telencephalon and eyes to diencephalon.

Zebrafish embryos homozygous for the masterblind (mbl) mutation exhibit a striking phenotype in which the eyes and telencephalon are reduced or absent and diencephalic fates expand to the front of the brain. Here we show that mbl(-/-) embryos carry an amino-acid change at a conserved site in the Wnt pathway scaffolding protein, Axin1. The amino-acid substitution present in the mbl allele abolishes the binding of Axin to Gsk3 and affects Tcf-dependent transcription. Therefore, Gsk3 activity may be decreased in mbl(-/-) embryos and in support of this possibility, overexpression of either wild-type Axin1 or Gsk3beta can restore eye and telencephalic fates to mbl(-/-) embryos. Our data reveal a crucial role for Axin1-dependent inhibition of the Wnt pathway in the early regional subdivision of the anterior neural plate into telencephalic, diencephalic, and eye-forming territories.

Animals↗
PubMed2001

HIV seroconversion during pregnancy and risk for mother-to-infant transmission.

Pregnant women infected with HIV-1 were enrolled in a prospective mother-to-infant transmission study from 1992 through 1994 in Bangkok. In participating hospitals, voluntary HIV testing was routinely offered at the beginning of antenatal care and again in the middle of the third trimester of pregnancy. Women who seroconverted to HIV during pregnancy were compared with women who had tested positive on their first antenatal test. Maternal HIV RNA levels were determined during pregnancy, at delivery, and postpartum using RNA polymerase chain reaction (PCR), and infection status in infants was determined by DNA PCR. No infants were breast-fed, but prophylactic antiretroviral therapy was not yet used in Thailand to prevent transmission from mother to infant. Among enrolled women, 16 who seroconverted during pregnancy and 279 who were HIV-1-seropositive at their first antenatal test gave birth. Median plasma RNA levels at delivery were similar for the two groups (17,505 and 20,845 copies/ml, respectively; p =.8). Two (13.3%) of 15 infants born to women who seroconverted and 66 (24.8%) of 266 infants born to previously HIV-seropositive women were infected with HIV (p =.5). There was no increased risk for mother-to-infant HIV transmission and no significant difference in viral load at delivery between HIV-infected women who seroconverted to HIV during pregnancy and those who were HIV-seropositive when first tested.

Adult↗
PubMed2001

Intracranial aneurysms: evaluation in 200 patients with spiral CT angiography.

The goal of this study was to assess the usefulness of spiral CT angiography (CTA) with three- dimensional reconstructions in defining intracranial aneurysms, particularly around the Circle of Willis. Two hundred consecutive patients with angiographic and/or surgical correlation were studied between 1993 and 1998, with CTA performed on a GE HiSpeed unit and Windows workstation. The following clinical situations were evaluated: conventional CT suspicion of an aneurysm; follow-up of treated aneurysm remnants or of untreated aneurysms; subarachnoid haemorrhage (SAH) and negative angiography; family or past aneurysm history; and for improved definition of aneurysm anatomy. Spiral CTA detected 140 of 144 aneurysms, and an overall sensitivity of 97%, including 30 of 32 aneurysms 3 mm or less in size. In 38 patients with SAH and negative angiography, CTA found six of the seven aneurysms finally diagnosed. There was no significant artefact in 17 of 23 patients (74%) with clips. The specificity of CTA was 86% with 8 false-positive cases. Spiral CTA is very useful in demonstrating intracranial aneurysms.

Adolescent↗
PubMed2001

EVT endovascular graft for abdominal aortic aneurysm.

BACKGROUND: A variety of prostheses are now available for the endovascular treatment of abdominal aortic aneurysm (AAA). Significant advantages of the EVT device are its unibody design, secure hook attachment system and graft fabric approximating that used in conventional surgery. METHODS: Implantation of the EVT device was attempted in 60 patients who were studied prospectively with an analysis of subsequent problems encountered. RESULTS: Conversion to open repair was required in four cases (6.7%). There were nine tube grafts inserted, 13 aorto-unilateral iliac with crossover grafts and 34 aorto-bi-iliac grafts. There was one death (mortality 1.7%). Endoleaks were identified in eight patients (14%), none of which were proximal; three sealed spontaneously, two were treated with coil embolization, two are being observed and one patient had an iliac attachment converted to an open anastomosis. Access vessel problems were seen in 21 patients (35%); two-thirds were corrected at the time of initial surgery. Seven patients (12%) had primary graft limb problems identified and treated before leaving the operating room. Nine patients (16%) developed secondary graft limb problems, which were diagnosed and treated after the initial surgery. Endovascular treatment was used in eight and was successful in six with surgical revision required in two. On review of these cases to assess if the problem could have been predicted at the time of initial surgery, it was felt that more aggressive treatment of intraoperatively diagnosed graft limb stenoses, even though considered mild, may have prevented 50% of subsequent secondary graft limb occlusions. CONCLUSION: Although the EVT device has significant advantages in the endovascular management of aortic aneurysm, potential graft limb problems need to be actively identified with the majority able to be successfully managed by supplementary endovascular techniques.

Aged↗
PubMed2001

Comparison of spiral CT angiography with conventional digital subtraction angiography in the evaluation of renal transplant donors: a pilot study.

Conventional digital subtraction renal arteriography (IA-DSA) has been traditionally used as the preoperative imaging modality for assessment of renal vascular anatomy for renal transplant donors. This study evaluates the potential use of spiral CT angiography in replacing IA-DSA in the preoperative assessment of this group of patients. Seven patients underwent both spiral CT angiography and IA-DSA between October 1997 and April 1998. It is concluded that spiral CT angiography can demonstrate the number, length and location of renal arteries and it is suggested that spiral CT angiography can potentially replace IA-DSA in the preoperative assessment of renal donors.

Adult↗
PubMed2001

Oral oseltamivir treatment of influenza in children.

BACKGROUND: Oral oseltamivir administration is effective treatment for influenza in adults. This study was conducted to determine the efficacy, safety and tolerability of oseltamivir in children with influenza. METHODS: In this randomized, double blind, placebo-controlled study, children 1 through 12 years with fever [> or =100 degrees F (> or =38 degrees C)] and a history of cough or coryza <48 h duration received oseltamivir 2 mg/kg/dose or placebo twice daily for 5 days. The primary efficacy endpoint was the time to resolution of illness including mild/absent cough and coryza mild/absent, return to normal activity and euthermia. RESULTS: Of 695 enrolled children 452 (65%) had influenza (placebo, n = 235; oseltamivir, n = 217). Among infected children the median duration of illness was reduced by 36 h (26%) in oseltamivir compared with placebo recipients (101 h; 95% confidence interval, 89 to 118 vs. 137 h; 95% confidence interval, 125 to 150; P < 0.0001). Oseltamivir treatment also reduced cough, coryza and duration of fever. New diagnoses of otitis media were reduced by 44% (12% vs. 21%). The incidence of physician-prescribed antibiotics was significantly lower in influenza-infected oseltamivir (68 of 217, 31%) than placebo (97 of 235, 41%; P = 0.03) recipients. Oseltamivir therapy was generally well-tolerated, although associated with an excess frequency of emesis (5.8%). Discontinuation because of adverse events was low in both groups (1.8% with oseltamivir vs. 1.1% with placebo). Oseltamivir treatment did not affect the influenza-specific antibody response. CONCLUSIONS: Oral oseltamivir administration is an efficacious and well-tolerated therapy for influenza in children when given within 48 h of onset of illness.

Acetamides↗
PubMed2001

Telomere length dynamics in normal individuals and in patients with hematopoietic stem cell-associated disorders.

The telomere length in nucleated peripheral blood (PB) cells indirectly reflects the mitotic history of their precursors: the hematopoietic stem cells (HSCs). The average length of telomeres in PB leukocytes can be measured using fluorescence in situ hybridization and flow cytometry (flow FISH). We previously used flow FISH to characterize the age-related turnover of HSCs in healthy individuals. In this review, we describe results of recent flow FISH studies in patients with selected hematopoietic stem cell-associated disorders: chronic myelogenous leukemia (CML) and several bone marrow failure syndromes. CML is characterized by a marked expansion of myeloid Philadelphia chromosome positive (Ph+) cells. Nevertheless, nonmalignant (Ph-) HSCs typically coexist in the bone marrow of CML patients. We analyzed the telomere length in > 150 peripheral blood leukocytes (PBLs) and bone marrow samples of patients with CML as well as samples of Ph- T-lymphocytes. Compared to normal controls, the overall telomere fluorescence in PBLs of patients with CML was significantly reduced. However, no telomere shortening was observed in Ph- T-lymphocytes. Patients in late chronic phase (CP) had significantly shorter telomeres than those assessed earlier in CP. Our data suggest that progressive telomere shortening is correlated with disease progression in CML. Within the group of patients with bone marrow failure syndromes, we only found significantly shortened telomeres (compared to age-adjusted controls) in granulocytes from patients with aplastic anemia (AA). Strikingly, the telomere length in granulocytes from AA patients who had recovered after immunosuppressive therapy (recAA) did not differ significantly from controls, whereas untreated patients and nonresponders with persistent severe pancytopenia (sAANR) showed marked and significant telomere shortening compared to healthy donors and patients with recAA. Furthermore, an inverse correlation between age-adjusted telomere length and peripheral blood counts was found in support of a model in which the degree of cytopenia and the amount of telomere shortening are correlated. These results support the concept of extensive proliferation of HSCs in subgroups of AA patients and suggest a potential use of telomere-length measurements as a prognostic tool in this group of disorders as well.

Anemia, Aplastic↗
PubMed2001

Safety of late in utero exposure to zidovudine in infants born to human immunodeficiency virus-infected mothers: Bangkok. Bangkok Collaborative Perinatal HIV Transmission Study Group.

BACKGROUND: Short-course zidovudine (ZDV) given in the late antenatal period can reduce mother-infant human immunodeficiency virus (HIV) transmission by one half. Because this intervention is being implemented in developing countries, evidence of its safety is needed. METHODS: In a randomized, double-blinded, placebo-controlled trial in Bangkok, HIV-infected pregnant women received either ZDV (300 mg twice daily from 36 weeks' gestation until labor, then every 3 hours until delivery) or an identical placebo regimen. Infants were evaluated at birth and at 1, 2, 4, 6, 9, 12, 15, and 18 months of age. Growth, clinical events, and hematologic and immunologic measurements were compared between treatment groups. RESULTS: Of the 395 children born (196 in ZDV group and 199 in placebo group), 330 were uninfected, 55 were infected, and 10 had indeterminate infection status. Overall, 319 children (81%) completed 18 months of follow-up, and 14 (4%) died before 18 months of age. Among uninfected children, the mean hematocrit was lower in the ZDV group at birth (49.1% vs 51.5%) but not at later ages; mean weight, height, head circumference, and CD4(+) and CD8(+) T lymphocyte counts were similar in both groups at all ages. Five uninfected children in the ZDV group but only one in the placebo group had a febrile convulsion. No other signs suggestive of mitochondrial dysfunction and no tumors were observed. Among infected children, an estimated 62% in the ZDV group and 77% in the placebo group survived free of Centers for Disease Control and Prevention class C disease during the 18-month follow-up. CONCLUSIONS: No significant adverse events were associated with short-course ZDV during 18 months of follow-up in this population.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Protease inhibitors stimulate hematopoiesis and decrease apoptosis and ICE expression in CD34(+) cells.

Highly active retroviral therapy has been associated with a decline in the frequency of cytopenia in patients with human immunodeficiency virus (HIV) infection. This may result from lower hematologic toxicity of newer antiviral drugs and their increased efficacy against HIV-1. Protease inhibitors, in addition to their effects on HIV replication, appear to affect various cellular functions. Recently, it was reported that ritonavir inhibited caspase-1 expression in normal CD4(+) cells. It was hypothesized that protease inhibitors may improve hematopoietic function owing to their direct effects on the bone marrow progenitor cells. When ritonavir was added to methylcellulose cultures of bone marrow cells from HIV-infected patients and normal controls, colony formation increased 2.4-fold (n = 5) in control cultures and 4-fold (n = 5) in cultures of cells from HIV-infected patients. In the presence of ritonavir, cultures of CD34(+) cells showed markedly decreased apoptosis in comparison with untreated cultures (45% decrease in apoptotic cell number; n = 6). A synthetic inhibitor of caspase 1 (Ac-Tyr-Val-Ala-Asp-aldehyde [single-letter amino acid codes]), which inhibits activation of several caspases including CPP32 and interleukin 1beta-converting enzyme (ICE or caspase 1), also decreased the rate of apoptosis and enhanced colony formation by progenitor cells derived from HIV-infected patients (3-fold; n = 5). In ritonavir-treated samples derived from HIV-infected individuals, the number of cells expressing ICE also decreased. In conclusion, HIV protease inhibitors may, by blocking the caspase-dependent apoptotic pathway, overcome inhibition of hematopoiesis seen in patients with HIV infection, an effect unrelated to their antiviral activity. (Blood. 2000;96:2735-2739)

Antiretroviral Therapy, Highly Active↗
PubMed2000

A comparison of full-length glycoprotein 120 from incident HIV type 1 subtype E and B infections in Bangkok injecting drug users with prototype E and B strains that are components of a candidate vaccine.

Complete gp120 sequence information was obtained from eight persons with incident HIV-1 infections (four subtype E and four subtype B) who were part of a prospective injecting drug user (IDU) cohort in Bangkok, Thailand, during 1996-1998. The incident subtype E strains were similar to the prototype subtype E strain CM244 isolated in 1992 in northern Thailand. The incident subtype B strains displayed divergence, in both overall genetic distance and other significant gp120 characteristics, from the prototype North American subtype B strain HIV-MN. Recombinant gp120s derived from CM244 and HIV-MN strains are components of a vaccine that is undergoing phase III efficacy testing, begun in March 1999, among Bangkok area IDUs. The information presented here will be important in the evaluation of any breakthrough HIV-1 infections occurring among vaccinees during the vaccine trial and in ongoing vaccine development efforts in Thailand.

AIDS Vaccines↗
PubMed2000

Early experience in the use of Levovist ultrasound contrast in the evaluation of liver masses.

The aim of the present paper was to assess the utility of Levovist in defining the pathology of liver masses. Levovist is a new ultrasound contrast agent consisting of galactose microparticles, air bubbles and palmitic acid. Prospective studies were performed in patients referred for further evaluation of known liver masses. Levovist was peripherally injected and colour Doppler ultrasound studies were performed. Findings were correlated with clinicopathology and three other imaging modalities: biphasic spiral CT, CT arterial portography and contrast MRI. Twenty-five patients were studied (15 male and 10 female) in the age range 25-74 years. Liver masses ranged from 0.5 to 7 cm in maximum diameter. Thirteen lesions were benign and 12 were malignant (four hepatomas (HCC) and eight metastases). Levovist enhancement occurred in 18 lesions. Of these, six were benign (four focal nodular hyperplasias (FNH) and two haemangiomas). All 12 malignant lesions demonstrated enhancement. The HCC showed a mosaic pattern of central and peripheral enhancement, and the FNH demonstrated a spoke-wheel pattern. It was not possible to distinguish between haemangiomas and malignant lesions. Non-enhancing lesions may well be benign, with all malignancies showing some enhancement. Characteristic enhancement patterns were found for HCC (mosaic) and FNH (spoke-wheel). It was not possible to distinguish between metastases and benign lesions (haemangiomas) when the pattern of enhancement was peripheral.

Adult↗
PubMed2000

Disability evaluation in children with hemidecorticectomy: use of the activity scales for kids and the pediatric evaluation disability inventory.

The purpose of this study is to investigate the level of disability of children who are either candidates for or have undergone a hemidecorticectomy. The Activity Scales for Kids and the Pediatric Evaluation Disability Inventory were demonstrated to be useful measurement tools yielding comparative results between subgroups. Overall, children with congenital disease seemed less autonomous postoperatively than were preoperative patients or children with acquired disease. Age at surgery and the interval between seizure onset and surgery are potentially important predictors of disability. This could reflect the importance of timing of surgery, development, environment, and possibly brain plasticity processes in this population.

Adolescent↗
PubMed2000

Sequence variants of the axin gene in breast, colon, and other cancers: an analysis of mutations that interfere with GSK3 binding.

Axin is a recently discovered component of a multiprotein complex containing APC, beta-catenin, GSK3, and PP2A, which functions in the degradation of the beta-catenin protein. As part of WNT signal transduction, the function of the Axin complex is inhibited, leading to the accumulation of beta-catenin. The inappropriate stabilization of beta-catenin has been implicated in a range of human tumors. Two oncogenic mechanisms leading to beta-catenin stabilization are the loss of the APC tumor suppressor protein and the mutational activation of beta-catenin, such that the Axin/APC complex can no longer regulate it. Studies in Drosophila and mammalian tissue culture showed loss of Axin function interfered with beta-catenin turnover and activated beta-catenin/TCF-dependent transcription. Based on these observations, Axin was screened for mutations in a range of human tumor cell lines and primary breast tumor samples. We identified two sequence variants causing amino acid substitutions in four colon cancer cell lines, a Ser-to-Leu at residue 215 in LS513 and a Leu-to-Met at residue 396 in HCT-8, HCT-15, and DLD-1. The Axin L396M mutation was selected for further study since it lay within a region that was shown to interact with glycogen synthase kinase-3. Biochemical and functional studies showed that the L396M change interfered with Axin's ability to bind GSK3. Interestingly, this mutation and a neighboring L392M change differentially altered Axin's ability to interfere with two upstream activators of TCF-dependent transcription, Frat1 and Disheveled.

Amino Acid Sequence↗
PubMed1999

Clinical disease associated with HIV-1 subtype B' and E infection among 2104 patients in Thailand.

BACKGROUND: Two HIV-1 envelope subtypes have accounted for virtually all infections in Thailand: subtype B' (Thai B), found mainly in injection drug users (IDU), and subtype E, found in over 90% of sexually infected persons and an increasing proportion of IDU in recent years. It remains unclear whether there are differences in pathogenesis associated with these HIV-1 subtypes. METHODS: From November 1993 to June 1996, demographic, risk, clinical, and laboratory data were collected by enhanced surveillance from HIV-infected inpatients (> or =14 years) at an infectious disease hospital near Bangkok. HIV-1 subtype was determined by V3-loop peptide enzyme immunoassay (EIA). Because of confounding, multivariate analyses were stratified by risk category and controlled for sex and age. RESULTS: The infecting HIV-1 subtype was determined for 2104 (94.9%) of 2217 HIV-infected patients with complete data: 284 (13.5%) were subtype B', 1820 (86.5%) were E. Specimens from 113 (5.1%) patients were non-reactive or dually reactive on peptide EIA and were excluded. Among IDU, 199 (67.2%) had subtype B', and 97 (32.7%) had E. IDU accounted for 70.1% (199/284) of patients with subtype B' and 5.3% (97/1820) of those with E. Patients infected with HIV-1 subtypes B' or E had similar spectrums of opportunistic infections (OI), levels of immunosuppression, and in-hospital mortality rates. Of patients who did not inject drugs, more patients infected with subtype E had extrapulmonary cryptococcosis than those with subtype B' (adjusted odds ratio, 2.6; 95% confidence interval, 1.28-5.37). CONCLUSION: HIV-1 subtypes B' and E seem to be associated with similar degrees of immunosuppression and, with one exception, with similar OI patterns. These data do not suggest an association between HIV-1 subtype and differences in pathogenicity.

Adolescent↗
PubMed1999

Pitfalls in the use of spiral CT for identification of intracranial aneurysms.

We describe problems encountered in our first 136 patients, with 95 aneurysms, who underwent spiral CT for investigation of possible aneurysms involving the circle of Willis and adjacent major vessels, and who had surgical and/or angiographic confirmation. There were seven false-positive cases, of which the first three could be explained by operator inexperience. There were four false negatives, all small aneurysms; two were not seen because of operator error and two were hidden by an adjacent larger aneurysm. Clip artefacts prevented diagnostic studies in six of 21 postoperative studies. One aneurysm was outside the CT field of view, being on a pericallosal artery. One basilar artery tip aneurysm was excluded from the field of the CT study because of a planning error. Inspection of the axial source images is critical if the diagnosis of small or thrombosed aneurysms is to be made. Close attention to image acquisition and computer modelling is required to reduce errors in spiral CT angiography of intracranial aneurysms.

Adolescent↗