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Biomedical subjects

P Liu

Publications and source records attributed to P Liu.

At least 19 recordsLinked to original sources
PubMed1995

Chromosome engineering in mice.

Chromosomal rearrangements are the major cause of inherited human disease and fetal loss. Translocations and loss of heterozygosity are important genetic changes causally involved in neoplasia. Chromosomal variants, such as deficiencies, are commonly exploited in genetic screens in organisms such as Drosophila because a small portion of the genome is functionally hemizygous. In the mouse, deficiencies are not generally available, thus genetic screens for recessive mutations are cumbersome. We report here that defined deficiencies, inversions and duplications extending to 3-4 cM can be constructed in embryonic stem cells. This was achieved by consecutive targeting of loxP recombination substrates to the end points of a genetic interval followed by Cre-induced recombination. This reconstructs a positive selectable marker which facilitates direct selection of clones with a chromosome structure specific to the relative orientation of the loxP sites. Duplication and deletion alleles have been transmitted into the mouse germ line. The availability of mice with defined regions of segmental haploidy will allow their use in genetic screens and enable accurate models of human 'chromosomal' diseases to be generated.

Animals↗
PubMed1995

Compartmentalized production of ceramide at the cell surface.

Ceramide produced by the hydrolysis of sphingomyelin is an important cellular intermediate in hormone action. Here, we present evidence that interleukin 1 beta (IL-1 beta) binding to normal human fibroblasts initiates a lipid messenger cascade that takes place in a sphingomyelin-rich plasma membrane domain with the characteristics of caveolae. Hormone binding first stimulated the appearance of diacylglycerol (DAG) in a caveolearich membrane fraction isolated from whole cells. This was immediately followed by the loss of a resident population of sphingomyelin from the fraction and the concomitant appearance of ceramide. The ceramide produced in response to IL-1 beta blocked platelet-derived growth factor-stimulated DNA synthesis. IL-1 beta stimulated the appearance of DAG in other fractions from the same cell, but this DAG was not coupled to ceramide production. This indicates that ceramide production is highly compartmentalized at the cell surface. Since caveolae are known to be involved in membrane internalization, they may be essential for the delivery of ceramide to a site of action within the cell.

Cell Compartmentation↗
PubMed1995

Characterization of ATP receptor responsible for the activation of phospholipase A2 and stimulation of prostaglandin E2 production in thymic epithelial cells.

In TEA3A1 rat thymic epithelial cells, ATP stimulates prostaglandin E2 (PGE2) production through activation of phospholipase A2 (PLA2) enzymic activity. The stimulation of PGE2 production tested with other nucleotides indicated the agonist potency of adenosine 5'-[gamma-thio]triphosphate (ATP[S]) > or = UTP > ATP, with ED50 of about 10 microM for ATP[S]. In TEA3A1 cells, cross-linking studies with ATP[35S] revealed the presence of four cell-surface cross-linked bands of 42 kDa, 53 kDa, 83 kDa and 100 kDa in Triton X-100 extracts of TEA3A1 cells by fluorography. Guanosine 5'-[gamma-thio]triphosphate specifically blocked the cross-linking of ATP[35S] to the 53 kDa, 83 kDa and 100 kDa ATP-binding proteins, and inhibited the ATP[S]-mediated stimulation of PGE2 production with an ED50 of about 25 microM. On the other hand, 2-methylthioadenosine triphosphate (2MeSATP) blocked ATP[35S] cross-linking to the 42 kDa protein, but had no effect on ATP[S]-mediated stimulation of PGE2 production. In a variant cell line, TEAvarl, derived from TEA3A1 cells that lost their response to ATP in the activation of PLA2, the presence of 83 kDa ATP-binding protein was not detected. Results from our study suggest that ATP activates PLA2 enzymic activity in TEA3A1 cells by binding to an atypical ATP receptor that has not been described previously.

Animals↗
PubMed1995

Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites.

OBJECTIVE: To assess the effects of transjugular intrahepatic portosystemic shunt (TIPS) on systemic and renal hemodynamics, neurohumoral factors, and sodium homeostasis in patients with cirrhosis and refractory ascites. DESIGN: Prospective study with 1-year follow-up. SETTING: Tertiary referral center and university-affiliated hospital. PATIENTS: 7 patients with cirrhosis and refractory ascites had metabolic studies done while receiving a 22 mmol/d sodium, 1 L/d fluid diet. INTERVENTION: TIPS insertion. MEASUREMENTS: Urinary sodium excretion, systemic and renal hemodynamics, hormonal profile, and central blood volume were measured before, at day 1 after, and at 1 month after TIPS insertion. RESULTS: Immediately after TIPS insertion, mean corrected sinusoid pressure decreased from 18.2 +/- 2.2 mm Hg to 7.7 +/- 1.3 mm Hg (P < 0.001); mean cardiac output increased from 6.83 +/- 0.68 L/min to 8.62 L/min (P = 0.005); and mean systemic vascular resistance decreased from 1018 +/- 103 dyne.s.cm-5 to 762 +/- 46 dyne.s.cm-5 (P = 0.011). Mean plasma renin activity, serum aldosterone levels, and 24-hour urinary sodium excretion (5.8 +/- 0.7 mmol/d before TIPS insertion compared with 6.0 +/- 1.8 mmol/d 1 day after insertion) were unchanged; mean elevated plasma norepinephrine levels significantly increased. By 1 month after insertion, mean proximal tubular reabsorption of sodium had decreased, and this had led to a mean natriuresis of 15.1 +/- 3.1 mmol/d (P = 0.02 compared with baseline), which was associated with a decrease in plasma renin activity and aldosterone levels to within the normal range. CONCLUSIONS: Our results suggest that natriuresis associated with TIPS is delayed and occurs in the presence of increased systemic vasodilatation at 1 month after insertion and that TIPS insertion should not be done in any patients with refractory ascites without careful attention to cardiac and renal status. However, in carefully selected patients, TIPS is a safe and effective means of managing refractory ascites.

Adult↗
PubMed1995

Cyclosporin A and FK506 block induction of the Epstein-Barr virus lytic cycle by anti-immunoglobulin.

The Epstein-Barr virus (EBV) BZLF1 gene is expressed early upon induction of the viral lytic cycle and its protein product is unique in its ability to disrupt viral latency in some latently infected cell lines. Anti-immunoglobulin (anti-Ig) treatment of the Burkitt's lymphoma cell line Akata, which bears surface IgG, has previously been shown to synchronously induce transcription of the BZLF1 gene (K. Takada and Y. Ono, 1989, J. Virol. 63, 445-449). We have previously shown that anti-Ig induction of Akata cells activates expression of the tumor necrosis factor alpha (TNF-alpha) gene via a calcineurin-dependent mechanism (Goldfeld et al., 1992, Proc. Natl. Acad. Sci. USA 89, 12198-12201). Here, we report that anti-Ig induction of the EBV lytic cycle in Akata cells can be blocked by the immunosuppressants cyclosporin A and FK506. Furthermore, we demonstrate that synergistic induction by phorbol ester and calcium ionophore of a BZLF1 promoter-driven reporter construct in an EBV-negative BL cell line can be inhibited by addition of cyclosporin A. Thus, analogous to activation of TNF-alpha gene in Akata cells, anti-Ig induction of the BZLF1 promoter is most likely mediated by calcineurin and probably involves translocation to the nucleus of a transcription factor sequestered in the cytoplasm. As such, immunosuppressants may be useful probes for dissecting B cell activation pathways involved in regulating EBV gene transcription.

Antibodies, Anti-Idiotypic↗
PubMed1995

Identification of a new murine runt domain-containing gene, Cbfa3, and localization of the human homolog, CBFA3, to chromosome 1p35-pter.

Core binding factor (CBF) is a heterodimeric transcription factor composed of two distinct subunits. The monomeric beta subunit is ubiquitously expressed, whereas expression of the three alpha subunits isolated previously seems to be restricted mainly to hematopoietic tissues. To isolate additional alpha genes, degenerate oligonucleotides derived from the runt domain--a region shared by all alpha genes--were used for screening cDNA libraries. A 228-bp fragment was isolated from a mouse thymus cDNA library, which showed 82 and 76% DNA sequence identity to the previously isolated murine alpha genes, Cbfa1 and Cbfa2. This novel alpha gene was named Cbfa3. The corresponding sequence from the human homolog CBFA3 was obtained by cosmid cloning and sequencing of the appropriate restriction fragment. The corresponding regions of mouse Cbfa3 and human CBFA3 show 91% nucleotide identity and 100% protein identity. In situ hybridization and physical mapping of somatic cell hybrids localized CBFA3 to chromosome 1p35-pter.

Amino Acid Sequence↗
PubMed1995

Molecular characterization of 16p deletions associated with inversion 16 defines the critical fusion for leukemogenesis.

The inversion of chromosome 16 [inv(16)] in acute myeloid leukemia (AML) is associated with a p-arm deletion in a subset of patients. The inversion results in two fusion genes: 5'-CBFB/MYH11-3' on 16p and 5'-MYH11/CBFB-3' on 16q. We have studied cells from 42 patients with inv(16) (38 patients) or t(16;16) (four patients) to define the frequency and characteristics of the deletion further. Using fluorescence in situ hybridization (FISH) with probes from cosmids, cosmid contigs, and yeast artificial chromosomes (YACs), we found that six patients with inv(16) had a deletion of between 150 and 350 kb centromeric to the p-arm inversion breakpoint cluster region (p-ibc). This region was shown to contain the 5' portion of the myosin heavy chain (MYH11) gene. YACs containing the p-ibc, which had been useful as FISH probes in the diagnosis of inv(16), detected the inversion in deletion as well as nondeletion patient cells. Thus, the deleted region identified in patients is entirely contained within the human genomic content of the YACs. Southern blot experiments using probes flanking the p-ibc indicated that the deletion removes segments within 10 kb centromeric of the p-ibc. Reverse transcription-polymerase chain reaction (RT-PCR) using primers from the 5' region of CBFB and the 3' region of MYH11 (distal to the p-ibc) produced the 5'-CBFB/MYH11-3' chimeric transcript in inv(16)/del patients. These data confirm that the 5'-CBFB/MYH11-3' chimeric transcript, rather than the reciprocal 5'-MYH11/CBFB-3', is the critical product for chromosome 16-related leukemogenesis.

Acute Disease↗
PubMed1995

Pattern of sodium handling and its consequences in patients with preascitic cirrhosis.

BACKGROUND/AIMS: The initial abnormalities in the renal sodium handling in patients with cirrhosis before developing ascites remain unknown. The aim of this study is to further characterize sodium metabolism and the effects of sodium loading in preascitic cirrhosis. METHODS: Eight male, preascitic patients with cirrhosis and 6 volunteers had their daily urinary sodium excretion level measured while on a strictly metabolically controlled diet, first consisting of 20 mmol then of 200 mmol sodium per day each for 7 days. Central blood volume, plasma norepinephrine, and atrial natriuretic factor levels were measured during each diet. RESULTS: Preascitic patients with cirrhosis had significantly less daily urinary sodium excretion on both diets. Volume expansion in the patients with cirrhosis was indicated by significantly greater weight gain and higher atrial natriuretic factor levels for each diet. Patients with cirrhosis had central blood volume expansion (1725 +/- 54 mL/m2) compared with controls (1495 +/- 81 mL/m2; P = 0.03) on a low-sodium diet. This increased significantly in the controls (1864 +/- 164 mL/m2; P = 0.04) on a high-sodium diet, associated with suppression of plasma norepinephrine, but not in the patients with cirrhosis (1679 +/- 107 mL/m2; P > 0.05). CONCLUSIONS: Failure of further central blood volume expansion in the patients with cirrhosis on high-sodium diet in the presence of significant weight gain suggests maldistribution away from the effective arterial blood volume. This study provides further reasons why preascitic patients with cirrhosis might benefit from sodium restriction.

Adult↗
PubMed1995

Cardiopulmonary function in adult patients late after Fontan repair.

OBJECTIVES: The clinical status and exercise assessment of adult patients late after the Fontan operation were reviewed to determine cardiovascular function. BACKGROUND: The Fontan operation is the final operation for many patients with tricuspid atresia or a single ventricle. Follow-up reports describe most patients to be in Canadian Cardiovascular Society functional class I or II. Objective measures of cardiac performance in the pediatric age group have shown significant dysfunction. METHODS: Forty-seven adult patients were seen late after the Fontan operation at the Toronto Congenital Cardiac Centre for Adults. Thirty of these underwent cycle ergometry to determine maximal exercise capacity. Maximal ventilation, maximal oxygen uptake and anaerobic threshold were determined from a ramp exercise protocol. Ejection fraction at rest and during exercise was measured with gated radionuclide angiography. Results were compared with those of eight normal volunteers. Results are given as mean +/- SD. RESULTS: Thirty patients underwent cardiopulmonary exercise testing 6.7 +/- 3.9 years after a first Fontan operation. Clinically 93% were in functional class I or II. The Fontan group patients had a significantly lower maximal work load (548 +/- 171 vs. 1,094 +/- 190 kilopond-meters, p < 0.00001), anaerobic threshold (11.2 +/- 2.9 vs. 23.6 +/- 4.6 ml/kg per min) and maximal oxygen consumption (14.8 +/- 4.5 vs. 42.1 +/- 10.0 ml/kg per min). Systemic ventricular ejection fraction was lower at rest (38 +/- 12% vs. 58 +/- 7%) and during exercise (40 +/- 15% vs. 70 +/- 8%). CONCLUSIONS: Despite a clinical impression of good function, by objective measures adult patients continue to have significant cardiovascular limitation late after the Fontan operation.

Adult↗
PubMed1995

Secular changes in the outcomes to eighteen to twenty-four months of age of extremely low birth weight infants, with adjustment for changes in risk factors and severity of illness.

OBJECTIVES: To analyze secular changes in the rates of death and of major impaired outcome in surviving outborn infants who weighted < or = 800 gm at birth and were admitted in 1980 to 1989, with adjustment for changes in risk factors and severity of illness around the time of birth; and to identify changes in these factors that might explain changes in outcomes. DESIGN: Retrospective cohort study with follow-up to a minimum of 18 months of postterm age. After preliminary screening, multivariate models of association between risk/severity of illness factors and outcomes were constructed, validated, and used to adjust outcomes (death and major impairment to 18 to 24 months of age). SETTING: Regional neonatal intensive care unit for referral of "outborn" infants. PATIENTS: Two hundred eighty-seven consecutively admitted infants who weighted < or = 800 gm at birth (97% follow-up). RESULTS: The death rate during the 1980s did not fall significantly (p adjusted for risk factors = 0.115). The major impairment rate fell (odds ratio, 0.24 (95% confidence interval, 0.10, 0.60); p = 0.002, adjusted for delivery route and respiratory failure measures), mainly because of a reduced rate of blindness, not attributable to cryotherapy. The risk factors that improved and were possibly related to the reduced impairment rate were blood pH and glucose concentration, and serum sodium concentration in the first 48 hours of life. CONCLUSIONS: Despite an increasing selection for referral of less mature and more severely ill outborn babies near the "limit of viability," and despite more aggressive care, the rate of major impairment fell significantly during the 1980s. This trend was enhanced by adjustment for severity of illness. The fall was attributable to a reduced rate of blindness, and was associated with evidence of improved control of physiologic balance after birth.

Apgar Score↗
PubMed1995

Social aspects of > 800 couples coming forward for gender selection of their children.

The social characteristics of 809 couples attending a sex preselection clinic have been studied. Their ethnic origins were: Indian 57.8%, European 32.0%, Chinese 3.6% and others 6.8%. The average number of boys and girls per family was 0.09 and 2.70 respectively for couples wanting a boy, and 2.46 and 0.14 for those wanting a girl. The average age of the wives was 34.0 years. These figures were not significantly different in any ethnic subgroup. Out of all the couples, 80.6% stated that they would have had another baby even had sex preselection not been on offer; 37.5% of the couples interviewed have been treated so far. The figures among those treated are substantially the same as those for the whole group. Asian and Middle Eastern couples overwhelmingly wanted boys, whereas European couples showed a slight preference for girls. These results suggest that, given certain guidelines, sex selection is unlikely to lead to a serious distortion of the sex ratio in Britain and other Western societies, but may need careful monitoring in other parts of the world.

Adult↗
PubMed1995

Expression of tumour necrosis factor alpha and accumulation of fibronectin in coronary artery restenotic lesions retrieved by atherectomy.

BACKGROUND: The formation of coronary artery neointima experimentally induced in piglets after cardiac transplantation is related to an immune-inflammatory reaction associated with increased expression of T cells and inflammatory mediators (tumour necrosis factor alpha and interleukin 1 beta) and upregulation of fibronectin. In vivo blockade of tumour necrosis factor alpha in rabbits after cardiac transplantation results in reduced neointimal formation. The objective of this study was to investigate the hypothesis that coronary restenosis after atherectomy or percutaneous balloon angioplasty is associated with a similar inflammatory cascade initiated by mechanical injury. METHODS: Specimens taken at coronary atherectomy were analysed from 16 patients. Nine had had the procedure performed twice, firstly, to remove a primary lesion, and secondly, to remove a restenotic lesion. Seven had percutaneous balloon angioplasty after removal of restenotic tissue. Coronary atherectomy specimens were analysed by immunohistochemistry for the presence of T cells, macrophages, major histocompatibility complex II, interleukin 1 beta, tumour necrosis factor alpha, fibronectin, and the receptor for hyaluronan mediated motility. RESULTS: The groups were clinically and angiographically similar with equivalent lumens before and after atherectomy. Restenotic lesions had increased expression of tumour necrosis factor alpha and fibronectin compared with the primary lesions (P < 0.05 for both). There was also a trend towards a greater number of T cells and increased expression of interleukin 1 beta. CONCLUSIONS: Restenosis is associated with increased expression of tumour necrosis factor alpha and fibronectin, suggesting that an immune-inflammatory reaction probably contributes to neointimal formation and may represent a form of wound healing and repair secondary to mechanical injury.

Angioplasty, Balloon, Coronary↗
PubMed1995

Clinical variability in two pairs of identical twins with the Charcot-Marie-Tooth disease type 1A duplication.

We report two pairs of male homozygotic twins in two unrelated families with the Charcot-Marie-Tooth disease type 1A duplication. Homozygosity was supported by DNA analysis. There was remarkable congruity of conduction velocities between the left and right side of each twin and between twin brothers. The similarity and symmetry of the electrophysiologic deficit contrast with the variable and asymmetric clinical presentations. Variability of clinical expression in these patients with identical mutations suggests the action of stochastic factors or environmental modulation of disease severity.

Adult↗
PubMed1995

Cardiovascular effects of varying G-suit pressure and coverage during +1 Gz positive pressure breathing.

With the continued evolution of anti-G suits, used to counter the cardiovascular dysfunction arising from +1 Gz hypoxia protection positive pressure breathing (PPB), it was hypothesized that full-coverage anti-G-suits would offer equal protection while using lower inflation pressures than the traditional 4:1 ratio. Nine experienced subjects were exposed to 2 min of 70 mm Hg PPB while wearing either the COMBAT EDGE (CE) and Tactical Life Support System (TLSS) garments with the G-suit inflated to 4 x breathing pressure, and the Advanced Tactical Anti-G-Suit (ATAGS) at 4, 3, 2, and 1 x the breathing pressure. All subjects were measured with impedance cardiography (IC), and six were measured simultaneously with both IC and the Cardioscint nuclear probe. IC-estimated stroke volume, relative left ventricular (LV) end-diastolic volume, LV ejection fraction, and peak filling rate were depressed most in the CE and ATAGS 1 conditions (p < 0.001). Heart rate and mean arterial blood pressure changes were highest and lowest, respectively, using the CE and ATAGS 1 garments (p < 0.001). There were no differences in these variables between the TLSS and ATAGS 2-4 conditions. Thus, protection against the PPB-induced fall in LV preload and cardiovascular function may still be adequately afforded by lower G-suit inflation pressures when using full-coverage anti-G suits during PPB intended for high altitude-protection.

Blood Pressure↗
PubMed1995

Repeated radial keratotomy.

38 cases 59 eyes received repeated radial keratotomy in which the secondary incisions were performed along the scars of old incisions. The average follow-up after the reoperation was 13 months. Before reoperation, the mean spherical equivalent of the refraction was -3.78D and the mean keratometry was 40.15D. 13 months after the reoperation, the mean spherical equivalent of the refraction decreased by 2.30D, and the mean keratometry decreased by 2.04D. After the reoperation, the mean uncorrected visual acuity increased by 5 lines. There was no relationship between the therapeutic effect of the reoperation and the degree of initial myopia or pre-reoperative keratometry. The repeated radial keratotomy can decrease the degree of astigmatism and its complications are few.

Adult↗
PubMed1995

[Refractory periods of cardiac tissues and the filtering properties of the atrioventricular node in the isolated rabbit heart].

It is generally believed that the atrioventricular node (AVN) possesses filtering properties (FP) capable of preventing excess atrial impulses or earlier atrial premature beat from reaching the ventricle. In the present study, the refractory periods (RP) of cardiac tissues and the FP of the AVN were investigated in isolated rabbit hearts (n = 18). It was found that: (1) The relative RP of AVN was the longest at shorter basic cycle lengths (BCL) (200-300 ms) while the relative RP of His-Purkinje system (HPS) was the longest at longer BCL (600, 700 ms). (2) The effective RP of AVN was shorter than the functional RP of the atrium in most cases (16/18) at any BCL. (3) During rapid atrial pacing at cycle length of 140 ms in 7 cases, AVN maintained 1:1 conduction. (4) The atrioventricular nodal conduction curve was smooth at BCL from 200 to 700 ms. The present results suggest that AVN in the isolated perfused rabbit heart do not have the FP and any dual atrioventricular pathways in a physiological sense.

Animals↗