Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase

We have previously reported that greater than 60% of human leukemic T- cell lines possess mutations in the p53 tumor suppressor gene. To determine whether T-cell acute lymphoblastic leukemia (T-ALL) patient samples possess p53 mutations, we screened peripheral blood-and bone marrow-derived leukemia samples, taken at diagnosis and at relapse, for p53 mutations. Exons 4 through 9 and selected intron regions of the p53 gene were analyzed using polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. p53 mutations were found in 0 of 15 T-ALL diagnosis samples, as compared with 10 of 36 (28%) T-ALL relapse samples. To determine whether p53 mutations play a role in the recurrence (relapse) of T-ALL, two special groups of T-ALL patients were studied: (1) a group of 8 relapse patients whose disease was refractory to chemotherapeutic treatment, and (2) a group of 6 "paired" T-ALL cell samples from patients for whom we possess both diagnosis and relapse samples. Three of 8 relapsed patients (37.5%) whose disease was refractory to the reinduction of remission by chemotherapy possessed missense mutations of the p53 gene. All 3 cases had mutations in exon 5. Among the paired samples, 3 of 6 patients harbored p53 mutations at disease recurrence, but possessed only wild- type p53 alleles at diagnosis. One case had mutation on exon 4, 1 case in exon 5, and 1 case in exon 8 with loss of heterozygosity. These data clearly indicate that recurrence of T-ALL is associated with missense mutations in p53. Our results indicate that (1) mutations of p53 do occur in T-ALL in vivo, and such mutations are associated with the relapse phase of the disease; and (2) p53 mutation is involved in the progression of T-ALL. This conclusion is supported by our observation that the introduction of T-ALL-derived mutant p53 expression constructs into T-ALL cell lines further increases their growth rate in culture, enhances cell cloning in methylcellulose, and increases tumor formation in nude mice.     

Predominance of a single genotype of Mycobacterium tuberculosis in countries of east Asia.

Analysis of the population structure of Mycobacterium tuberculosis strains from the People's Republic of China showed that the vast majority belong to a genetically closely related group. These strains shared the majority of their IS6110 DNA-containing restriction fragments, and also, the DNA polymorphism associated with other repetitive DNA elements, like the polymorphic GC-rich sequence and the direct repeat, was very limited. Because the majority of these strains originated from the province of Beijing, we designated this grouping the "Beijing family" of M. tuberculosis strains. Strains of this family were also found to dominate in neighboring countries such as Mongolia, South Korea, and Thailand, whereas a low prevalence of such strains was observed in countries on other continents. These data indicate that strains of the Beijing family recently expanded from a single ancestor which had a selective advantage. It is speculated that long-term Mycobacterium bovis BCG vaccination may be one of the selective forces implicated in the successful spread of the Beijing genotype.     

NRE,the major nitrogen regulatory protein of Penicillium chrysogenum,binds specifically to elements in the intergenic promoter regions of nitrate assimilation and penicillin biosynthetic gene clusters

NRE, the nitrogen regulatory protein of Penicillium chrysogenum, contains a single Cys2/Cys2-type zinc-finger motif followed immediately by a highly basic region. The zinc-finger domain was expressed to Escherichia coli as a fusion protein with -galactosidase. In order to test the putative DNA-binding ability of NRE, the intergenic promoter region of the nitrate reductase/nitrite reductase gene cluster (niiA-niaD) of Penicillium was sequenced. Our results show that NRE is a DNA-binding protein and binds to the intergenic promoter regions of the P. chrysogenum niiA-niaD and acvA-pcbC gene cluster, encoding the first two enzymes in penicillin biosynthesis. Three of the four high-affinity NRE-binding sites contained two GATA core elements. In one of the recognition sites for NRE, one GATA motif was replaced by GATT. The two GATA elements showed all possible orientations, head-to-head, head-to-tail and tail-to-tail, and were separated by between 4 and 27 bp. Missing-contact analysis showed that all three purines in both of the GATA core sequences and the single adenine residue in each of the complementary TATC sequences were involved in the binding of NRE. Moreover, loss of purines in the flanking regions of the GATA elements also affect binding of NRE, as their loss causes reduced affinity.     

Adhesive function of newcastle-disease virus hemagglutinin in tumor-host interaction

Infection of metastatic lymphoma cells (ESbL) by a low dose of a non-lytic strain of Newcastle disease virus (NDV) leads to viral replication followed by strong cell surface expression of viral antigens, especially hemagglutinin neuraminidase (HN). The expressed HN was functional and facilitated cell-cell interactions and cell attachment. This was shown for NDV infected tumor cells, lymphocytes, fibroblasts and endothelial cells. The interactions could be strongly inhibited by antibodies against the viral HN protein. Increased binding was also seen with HN c-DNA transfectants expressing the HN as the only viral protein. Viral infection did not influence proliferation and lysability of the infected tumor cells. Following intravenous injection of tumor cells, the number of hepatic metastases was significantly reduced when the cells had been pre-infected with NDV. This reduction of metastases correlated with an increased survival time of the animals. As potential mechanisms of these NDV effects we propose augmentation of cell-eel interactions and immune functions and reduction of invasive capacity of NDV infected, as compared to non-infected tumor cells.     

"Abdominal crunch"-induced rhabdomyolysis presenting as right upper quadrant pain

A young, active duty sailor presented with right upper quadrant abdominal pain. History, physical, and laboratory findings initially suggested cholecystitis or related disease. Further evaluation found myoglobinuria and a recently increased exercise program, leading to the diagnosis of exercise-induced right upper abdominal wall rhabdomyolysis. Although not a common cause of abdominal pain, this diagnosis should be considered in the patient with abdominal pain and a recently increased exercise program, particularly exercises of the abdominal wall such as "abdominal crunches."     

The occupational risk to dental anesthesiologists of acquiring 3 bloodborne pathogens

OBJECTIVE: To estimate the occupational risk to dental anesthesiologists of contracting 3 bloodborne pathogens: hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency virus (HIV). METHODS: Through an anonymously returned, mailed questionnaire, dental anesthesiologists in Canada and the United States provided information regarding percutaneous and mucocutaneous contacts with contaminated fluid during the treatment of patients under deep sedation and general anesthesia as well as other general practice information. A mathematical model was applied to determine the occupational risk. RESULTS: Of the 101 (65%) returned questionnaires, 98 reported having treated patients within the previous 6 months. Of these, 41 (42%) had at least one percutaneous accident (89 accidents in total), and the projected mean annual injury rate for dental anesthesiologists overall was 1.82. The most common causes of injury were burs, intraoral needles, and dental instruments. Operator error during use was associated with 31% of reported accidents. Significantly more injuries were reported by those who also reported a mucocutaneous contact and by those working more than 25 hours per week. The projected mean annual number of mucocutaneous exposures was 0.88 for dental anesthesiologists overall. CONCLUSIONS: The calculated annual risk to the average dental anesthesiologist of acquiring HBV (if not immune), HCV, and HIV following percutaneous injury was very low for all infections (HBV the most; HIV the least). The risk of contracting HIV following mucocutaneous contact was extremely low.     

Channel properties determine the transient activation kinetics of recombinant GABA(A) receptors

To understand the mechanisms underlying activation and deactivation of GABA(A) receptor (GABAR) channels, we studied the properties of an identified GABAR isoform under conditions similar to those present at central GABAergic synapses. Recombinant alpha5beta3gamma2L GABARs were expressed in L929 fibroblasts and studied using patch-clamp recording techniques. Brief application of a high GABA concentration to outside-out membrane patches elicited transient currents that resembled those reported for miniature inhibitory postsynaptic currents (mIPSCs), as well as native GABAR currents recorded under similar conditions. Characteristic of these currents was a rapid activation phase followed by a prolonged biphasic deactivation phase that far outlasted GABA application. Single-channel recordings revealed unique patterns of channel activity with two channel conductance states of 22 and 16 pS. The prolonged deactivation phase appeared to be sustained by entry into and reopening from long-lasting closures or desensitized states. Agonist affinity determined the time course of deactivation, indicating that occupied receptors drove the channel activity underlying the decay of current. The time course of deactivation was also longer at depolarized membrane potentials. The similarities between transient activation kinetics of recombinant alpha5beta3gamma2L GABARs to activation of synaptic GABARs (rapid activation and prolonged, voltage-dependent deactivation) suggest that intrinsic channel properties determine much of the response patterns of native GABARs.     

Trends and geographical disparities in coronary heart disease in France: are results concordant when different definitions of events are used?

OBJECTIVES: To assess whether different definitions of acute coronary events yielded concordant results concerning trends and geographical disparities in coronary heart disease (CHD) mortality and morbidity in France. STUDY DESIGN: Data from three French CHD registries participating in the WHO MONICA Project during the period 1985-1992. SETTING: Three areas of about one million inhabitants each in the North, South and East of France. SUBJECTS: About 2,000 acute coronary events each year. MAIN OUTCOME MEASURES: Mortality, annual rate of fatal and non-fatal events, incidence of first and recurrent events, case-fatality rates. RESULTS: For incidence and mortality, the broader the broader the definition of the acute event, the higher the reported rates. The same tendency was not observed for case-fatality rates. Comparing between-registry rates for mortality, 28-day case-fatality and hospital case fatality yielded relatively concordant results whatever the definition of event. As a whole, the higher mortality rate in Lille and its intermediate rank in Strasbourg were related more to disparities in case-fatality rates, with only small variations in incidence rates, independently of the definition used. Comparing temporal trends in rates within and between regions, a consistent decrease in annual mortality rates and case-fatality rates was observed, whatever the definition. In contrast, the incidence of non-fatal probable myocardial infarction did not change during the period in any register. CONCLUSIONS: Although the absolute estimates of rates were variable with the definition of the event, major findings in relation to trends and geographical disparities were fairly consistent across the definitions: the North-South gradient in mortality observed in France was found to be much more pronounced for case fatality than for incidence. The proportion of milder acute myocardial infarction is currently increasing and this element should be taken into account when analysing CHD rates.     

Outcomes and health status of socially disadvantaged women during pregnancy

We sought to examine the health status of disadvantaged pregnant women more broadly and to consider if poor maternal health predisposes a woman to an adverse birth outcome. We surveyed 250 women recruited from six health centers in the greater Boston area during their third trimester. The main predictor variables were maternal physical functioning (PF), emotional health (EH), and overall health status in the month prior to pregnancy. The main outcome variables were the decline of maternal PF and EH during pregnancy and adverse birth outcomes. Mean PF scores fell from 91.9 prior to pregnancy to 63.7 during the third trimester (mean scores transformed 0 to 100, where a higher score represents better health). EH remained unchanged during pregnancy. After adjustment, women with a preexisting medical condition reported a lower PF score prior to pregnancy (87.8 versus 94.5, p < 0.05). Poor PF prior to pregnancy or during the third trimester was associated with an increased risk of preterm labor (odds ratio 2.02, 95% confidence interval 1.03-3.97). This study is the first to employ general health status measures to examine changes in health during pregnancy. Our findings support the use of preconception care to improve the health status of disadvantaged women with pre-existing conditions. This study suggests that poor maternal health may predispose a woman to an increased risk of preterm labor.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.