Biomedical subjects
Publications and source records attributed to D Jones.
Vancouver's Downtown Eastside, the city's skid row, is in a state of emergency. Some 7000 injection drug users, about 40% of whom are HIV positive, mingle with prostitutes and the city's street people. The doctors who care for them say it is a potent and dangerous mix.
tsg101 was recently identified as a tumor susceptibility gene by functional inactivation of allelic loci in mouse 3T3 fibroblasts. Although previous studies suggested that homozygous intragenic deletion of TSG101 is rare in breast cancer cells and specimens, the neoplastic phenotype caused by tsg101 inactivation implicated that tsg101 may play a significant role in cell growth control. Here, we characterize mouse polyclonal and monoclonal antibodies that specifically recognize the TSG101 protein (molecular mass, 46 kDa) in whole-cell lysates by straight Western blot analysis. By indirect immunofluorescence staining, TSG101 was found to be localized in the cytoplasm throughout the entire cell cycle. However, the nuclear staining increases from G1 to S phase and becomes dominant in late S phase. TSG101 is mainly distributed surrounding the chromosomes during M phase. The expression level of TSG101 is not cell cycle dependent. It is possible that the relocalization of TSG101 from the cytoplasm into the nucleus may be relevant to its function. Microinjection of both polyclonal and monoclonal antibodies specific to TSG101 into cells during G1 or S phase results in cell cycle arrest. Furthermore, overexpression of TSG101 leads to cell death, suggesting that the appropriate amount of TSG101 is critical for cell cycle progression. Taken together, these results suggest that neoplastic transformation caused by TSG101 deficiency may result from bypassing of the cell cycle checkpoints.
Activation of intact human neutrophils by fMLP stimulates phospholipase D (PLD) by an unknown signaling pathway. The small GTPase, ADP-ribosylation factor (ARF), and Rho proteins regulate the activity of PLD1 directly. Cell permeabilization with streptolysin O leads to loss of cytosolic proteins including ARF but not Rho proteins from the human neutrophils. PLD activation by fMLP is refractory in these cytosol-depleted cells. Readdition of myr-ARF1 but not non-myr-ARF1 restores fMLP-stimulated PLD activity. C3 toxin, which inactivates Rho proteins, reduces the ARF-reconstituted PLD activity, illustrating that although Rho alone does not stimulate PLD activity, it synergizes with ARF. To identify the signaling pathway to ARF and Rho activation by fMLP, we used pertussis toxin and wortmannin to examine the requirement for heterotrimeric G proteins of the Gi family and for phosphoinositide 3-kinase, respectively. PLD activity in both intact cells and the ARF-restored response in cytosol-depleted cells is inhibited by pertussis toxin, indicating a requirement for Gi2/Gi3 protein. In contrast, wortmannin inhibited only fMLP-stimulated PLD activity in intact neutrophils, but it has no effect on myr-ARF1-reconstituted activity. fMLP-stimulated translocation of ARF and Rho proteins to membranes is not inhibited by wortmannin. It is concluded that activation of Gi proteins is obligatory for ARF/Rho activation by fMLP, but activation of phosphoinositide 3-kinase is not required.
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BACKGROUND: Although previous research has delineated medical, cognitive, and neuropsychologic late effects of central nervous system (CNS) prophylaxis for childhood acute lymphoblastic leukemia (ALL), it has been difficult to draw conclusions about the long term psychosocial sequelae of these treatments due to methodologic problems that led to inconclusive results in past studies. In the current study, the authors examined the long term psychosocial functioning of childhood ALL survivors who had been treated on a Phase III clinical protocol (Cancer and Leukemia Group B [CALGB] 7611) between 1976 and 1979, in which they were randomized to receive either 2400 centigray of cranial radiation (CRT) with intrathecal methotrexate (IT-MTX) or intermediate dose systemic methotrexate (IV-MTX) with IT-MTX. METHODS: One hundred ten survivors of childhood ALL (mean age, 20.8 years) treated on CALGB 7611 who were age 14 years or older and disease free for at least 1 year were studied a mean of 14.7 years after their entry on CALGB 7611. In a telephone interview, a psychosocial assessment battery was administered to the patients, consisting of measures that assessed psychologic, sexual, social, and vocational functioning as well as any delayed physical effects. RESULTS: Survivors who had received CRT + IT-MTX had significantly poorer academic achievement (P = 0.0001), poorer self-images with regard to their bodies (P = 0.001), and greater psychologic distress (P = 0.005). CONCLUSIONS: Cranial radiation used to treat children with ALL has significant long term sequelae in terms of poorer academic achievement and psychosocial functioning. These data add weight to the conclusion that CRT prophylaxis should only be used to treat children who are at high risk of CNS relapse.
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Proteus syndrome is a multi-organ disorder, a prime feature of which is localized gigantism, usually clinically obvious. Symptoms secondary to hypertrophy of nerves has not been previously recognized as a part of the syndrome.
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Recently recognised structural and amino acid sequence similarities between plant disease resistance (R) proteins and animal proteins such as Apaf-1 and CED-4 are providing conceptual models for resistance protein function. Data from extensive DNA sequencing of resistance gene families are indicating that the leucine-rich repeat motif is an important determinant of gene-for-gene specificity and that intergenic DNA sequence exchange is a major contributor to R gene diversity.
OBJECTIVE: To evaluate the pregnancy results of an ovarian hyperstimulation protocol for IVF-ET that combines GnRH agonist down-regulation, cessation of GnRH agonist therapy with the onset of menstruation, and high-dose gonadotropin administration in low responders. DESIGN: Prospective analysis. SETTING: Academic IVF program. PATIENT(S): One hundred eighty-two low responders undergoing 224 IVF-ET cycles. INTERVENTION(S): Down-regulation was obtained with the administration of leuprolide acetate beginning in the midluteal phase and ending with the onset of menses. Daily administration of 6 ampules of FSH alone or in combination with hMG was initiated on cycle day 3. MAIN OUTCOME MEASURE(S): Stimulation characteristics and pregnancy rates (PRs) were compared between fresh cycles in which pure FSH alone was used and 35 cycles in which a combination of FSH and hMG was administered. RESULT(S): The clinical PR per transfer, the ongoing PR per transfer, and the implantation rate were 32%, 24%, and 9%, respectively. No differences were noted between cycles in which pure FSH alone was used in comparison with cycles in which a combination of FSH and hMG was administered. CONCLUSION(S): Short-term ovarian suppression begun in the luteal phase and discontinued with the onset of menses followed by high-dose stimulation with gonadotropins yields favorable pregnancy results in low responders.
In normally regulated larval metamorphosis of Trichoplusia ni, a 4th, 5th or other numbered instar is a 'preultimate' instar, and will normally continue larval molting, if the larva has not yet surpassed the critical (minimal) size threshold corresponding to attainment of the 'ultimate' (metamorphic) instar. Natural injection of T. ni embryos with venom/calyx fluid of female Chelonus sp. near curvimaculatus caused 'penultimate' 4th or 5th instar larvae that would normally molt at least once more, to a 5th/6th instar, to instead precociously metamorphose without another larval molt. These effects were observed in naturally-injected insects that never contained either a parasite larva, a viable parasite embryo, or a parasite egg. These data demonstrate that this effect of venom/calyx fluid of this wasp to induce precocious metamorphosis, at an instar earlier than would otherwise have typically occurred under normal growth conditions, does not require the presence of a parasite larva. Other data did indicate the parasite larva contributes an additional effect that causes a 4th instar host (that from its size would normally require not just one, but at least two more larval molts to reach the metamorphic instar) to not grow to the size metamorphic threshold, but to instead, precociously metamorphose at an even smaller size than occurs with the venom/calyx fluid alone. Additionally, arylphorin was precociously highly expressed in parasitized hosts in a manner independent of a decline in the host JH titer. Therefore, the main target of the venom/calyx fluid activity to induce precocious metamorphosis appears to be an event upstream of the decline in JH production by the corpora allata. Pseudoparasitized hosts become developmentally arrested as precocious prepupae and express a 2.7kb polydnavirus transcript. The larger (but still subthreshold size) larvae showed less suppressed prepupal ecdysteroid titers, less developmental suppression, and a much weaker expression of that transcript. A general model for mechanisms of action of chelonine venom/calyx fluid, and larvae, to cause precocious host metamorphosis and suppressed prepupal development is presented that is based on the current 'size threshold' model of normal lepidopteran development, rather than the older, displaced 'instar count' model. By basing the model for chelonine regulation of host development on the current 'size threshold' model for normal development, the proposed model for chelonine action both accounts for observations reported on various species of that subfamily and makes useful, testable predictions.
OBJECTIVE: To determine whether fetal splenic enlargement predicts anemia in Rh-alloimmunized nonhydropic singleton fetuses. METHODS: Splenic circumference was measured before funipuncture in 21 singleton pregnancies on 47 occasions. The spleen was imaged in an axial section of the fetal abdomen close to the level used for measurement of the abdominal circumference. The splenic length and width were measured and the circumference calculated by the formula (length and width x 1.57). One measurement per patient was used for each analysis. Splenic circumference was measured and expressed as multiples of the normal median (MoM) for gestational age. One hundred twenty-one cases were used to provide cross-sectional normative data. The expected median splenic circumference values were derived from a normal group. Fetal anemia was defined as hemoglobin deficit, ie, mean hemoglobin concentration for gestation minus the measured value. Anemia was defined as hemoglobin deficit exceeding 2 g/dL, and severe anemia as hemoglobin deficit exceeding 5 g/dL. Receiver operator characteristics curves for the prediction of anemia using different splenic circumference (MoM) values were constructed. RESULTS: Splenic circumference was an excellent predictor of severe anemia in cases with no prior transfusion: sensitivity 100% and specificity 94.7% (area under the curve = .97, P < .03). The measurement did not correlate significantly with severe anemia in the group with prior transfusion (area under the curve = .73, P = .19). CONCLUSION: Splenomegaly is sensitive for the detection of severe anemia in nonhydropic Rh sensitized cases without prior transfusion. The splenic enlargement could be explained by extramedullary erythropoiesis.
OBJECTIVES: The goals of this study were to examine the safety and feasibility of a routine (primary) stent strategy in acute myocardial infarction (AMI). BACKGROUND: Limitations of reperfusion by primary percutaneous transluminal coronary angioplasty (PTCA) in AMI include in-hospital recurrent ischemia or reinfarction in 10% to 15% of patients, restenosis in 37% to 49% and late infarct-related artery reocclusion in 9% to 14%. By lowering the residual stenosis and sealing dissection planes created by PTCA, primary stenting may further improve short- and long-term outcomes after mechanical reperfusion. METHODS: Three hundred twelve consecutive patients treated with primary PTCA for AMI at nine international centers were prospectively enrolled. After PTCA, stenting was attempted in all eligible lesions (vessel size 3.0 to 4.0 mm; lesion length < or = 2 stents; and the absence of giant thrombus burden after PTCA, major side branch jeopardy or excessive proximal tortuosity or calcification). Patients with stents were treated with aspirin, ticlopidine and a 60-h tapering heparin regimen. RESULTS: Stenting was attempted in 240 (77%) of 312 patients, successfully in 236 (98%), with Thrombolysis in Myocardial Infarction grade 3 flow restored in 230 patients (96%). Patients with stents had low rates of in-hospital death (0.8%), reinfarction (1.7%), recurrent ischemia (3.8%) and predischarge target vessel revascularization for ischemia (1.3%). At 30-day follow-up, no additional deaths or reinfarctions occurred among patients with stents, and target vessel revascularization was required in only one additional patient (0.4%). CONCLUSIONS: Primary stenting is safe and feasible in the majority of patients with AMI and results in excellent short-term outcomes.
OBJECTIVES: The second Primary Angioplasty in Myocardial Infarction (PAMI-II) study evaluated the hypothesis that primary percutaneous transluminal coronary angioplasty (PTCA), with subsequent discharge from the hospital 3 days later, is safe and cost-effective in low risk patients. BACKGROUND: In low risk patients with myocardial infarction (MI), few data exist regarding the need for intensive care and noninvasive testing or the appropriate length of hospital stay. METHODS: Patients with acute MI underwent emergency catheterization with primary PTCA when appropriate. Low risk patients (age <70 years, left ventricular ejection fraction >45%, one- or two-vessel disease, successful PTCA, no persistent arrhythmias) were randomized to receive accelerated care (admission to a nonintensive care unit and day 3 hospital discharge without noninvasive testing [n = 237] or traditional care [n = 234]). RESULTS: Patients who received accelerated care had similar in-hospital outcomes but were discharged 3 days earlier (4.2+/-2.3 vs. 7.1+/-4.7 days, p = 0.0001) and had lower hospital costs ($9,658+/-5,287 vs. $11,604+/-6,125 p = 0.002) than the patients who received traditional care. At 6 months, accelerated and traditional care groups had a similar rate of mortality (0.8% vs. 0.4%, p = 1.00), unstable ischemia (10.1% vs. 12.0%, p = 0.52), reinfarction (0.8% vs. 0.4%, p = 1.00), stroke (0.4% vs. 2.6%, p = 0.07), congestive heart failure (4.6% vs. 4.3%, p = 0.85) or their combined occurrence (15.2% vs. 17.5%, p = 0.49). The study was designed to detect a 10% difference in event rates; at 6 months, only a 2.3% difference was measured between groups, indicating an actual power of 0.19. CONCLUSIONS: Early identification of low risk patients with MI allowed safe omission of the intensive care phase and noninvasive testing, and a day 3 hospital discharge strategy, resulting in substantial cost savings.
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Although there has been a great deal of research effort within the last two decades on identifying the active components of the saliva of blood-sucking ticks, mosquitoes, biting flies, fleas and bugs, essentially neglected have been the human lice. Despite initial reports in the early part of this century suggestive of vasodilatory, anticoagulant and immunosuppressive properties of the saliva, for the next 50 years there were no biochemical studies on the active principles. Very recently, anatomical and biochemical studies have begun to characterize the bioactive molecules in lice saliva. The louse stocks a salivary vasodilator in excess over what is needed for a single bite, and injects similar amounts at each successive bite. The vasodilator in lice saliva appears to have different pharmacological properties than peroxidative, oxidative and maxidilan types of vasodilators reported from other blood-sucking insects. Possible anticoagulant activities have also been characterized. This belated, but welcome, interest comes at a time of resurgence of lice-born disease in certain parts of Africa, and of resistance to chemical control in Europe and North America.