to determine whether the age and medical condition of a patient influences hospital-based doctors' decision making when advising patients to stop smoking cigarettes.
we presented 142 doctors from ...four grades (consultant, registrar, senior house officer and house officer) and four specialities (medicine, surgery, psychiatry and anaesthetics), based in a Dublin teaching hospital, with 20 clinical vignettes. Each vignette described a patient from one of five age groups with one of four levels of health. The vignettes were randomly mixed. We asked doctors to say whether they would advise the patient in each case to quit smoking.
hospital-based doctors are significantly less likely to advise patients aged over 65 years than younger patients of the hazards of cigarette smoking, irrespective of the person's physical or mental health (P < 0.001).
the advice given to patients about their cigarette smoking habits by hospital doctors is strongly influenced not only by the patient's health, but also by the patient's chronological age.
Bernard-Soulier syndrome is a rare bleeding disorder caused by a quantitative or qualitative defect in the platelet glycoprotein (GP) Ib-IX-V complex. The complex, which serves as a platelet receptor ...for von Willebrand factor, is composed of 4 subunits: GPIb alpha, GPIb beta, GPIX, and GPV. We here describe the molecular basis of a novel form of Bernard-Soulier syndrome in a patient in whom the components of the GPIb-IX-V complex were undetectable on the platelet surface. Although confocal imaging confirmed that GPIb alpha was not present on the platelet surface, GPIb alpha was readily detectable in the patient's platelets. Moreover, immunoprecipitation of plasma with specific monoclonal antibodies identified circulating, soluble GPIb alpha. DNA-sequence analysis revealed normal sequences for GPIb alpha and GPIX. There was a G to A substitution at position 159 of the gene encoding GPIb beta, resulting in a premature termination of translation at amino acid 21. Studies of transient coexpression of this mutant, W21stop-GPIb beta, together with wild-type GPIbalpha and GPIX, demonstrated a failure of GPIX expression on the surface of HEK 293T cells. Similar results were obtained with Chinese hamster ovary alpha IX cells, a stable cell line expressing GPIbalpha that retains the capacity to re-express GPIX. Thus, we found that GPIbbeta affects the surface expression of the GPIb-IX complex by failing to support the insertion of GPIb alpha and GPIX into the platelet membrane. (Blood. 2000;96:532-539)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
INTRODUCTIONLosartan is an angiotensin II receptor blocker indicated for treatment of hypertension. It also inhibits platelet agreggation through blockade of thromboxane A2/prostaglandin H2 ...receptors, and has a uricosuric effect. We determined the effect on ambulatory blood pressure (ABP) of 100 mg losartan monotherapy (L100) versus 50 mg losartan/12.5 mg hydrochlorothiazide (HCTZ) combination therapy (L50H12.5C), in patients uncontrolled on 50 mg losartan. We also assessed the effects of losartan on platelet aggregation and serum urate at these clinically relevant doses.
METHODSThis was a randomized, double-blind trial of L100 versus L50H12.5C, in moderate hypertensives (sitting diastolic blood pressure (DBP) ≥ 95 mmHg and <120 mmHg). After 4 weeks of placebo run-in, patients received 50 mg losartan for 6 weeks; patients uncontrolled (sitting DBP ≥ 95 mmHg) were randomized to L100 or L50H12.5C for a further 6 weeks. Platelet function was assessed by measuring percentage inhibition of platelet aggregation, and serum uric acid was also measured.
RESULTSMonotherapy with 50 mg losartan reduced ABP by 16.0/9.9 mmHg during the day and 9.8/5.5 mmHg at night. However, 16 out of 24 (66%) patients had uncontrolled blood pressure on this treatment. L50H12.5C further reduced daytime ABP by 10.7(10.7)/8.4(6.5) mmHg mean (SEM) compared with L100 (25.3(9.7)/22.3(4.8), P = 0.013). 50 mg losartan and L100 did not affect platelet function or uric acid levels beyond placebo values; treatment with L50H12.5C was associated with a significant rise in serum urate above levels obtained on 50 mg losartan (366.9(67.6) versus 331.6(65.0), P = 0.006), to levels similar to placebo (358.8(80.9)).
CONCLUSIONL50H12.5C is an effective antihypertensive regimen in patients with moderate hypertension that is uncontrolled on 50 mg losartan monotherapy, and is the preferred treatment option in these patients compared with increasing the dose of losartan. The additional benefit of losartan on platelet inhibition was not evident in our population at these doses; however, there was evidence to suggest that the uricosuric effects of losartan might ameliorate the uric acid retention effects of therapy with hydrochlorothiazide.
To determine the role of cyclooxygenase (COX)-2 in anthracycline-induced cardiac toxicity, we administered doxorubicin (Dox) to mice with genetic disruption of COX-2 (COX-2 super(-/-)). After ...treatment with Dox, COX-2 super(-/-) mice had increased cardiac dysfunction and cardiac cell apoptosis compared with Dox-treated wild-type mice. The expression of the death-associated protein kinase-related apoptosis-inducing protein kinase-2 was also increased in Dox-treated COX-2 super(-/-) animals. The altered gene expression, cardiac injury, and dysfunction after Dox treatment in COX-2 super(-/-) mice was attenuated by a stable prostacyclin analog, iloprost. Wild-type mice treated with Dox developed cardiac fibrosis that was absent in COX-2 super(-/-) mice and unaffected by iloprost. These results suggest that genetic disruption of COX-2 increases the cardiac dysfunction after treatment with Dox by an increase in cardiac cell apoptosis. This Dox-induced cardiotoxicity in COX-2 super(-/-) mice was attenuated by a prostacyclin analog, suggesting a protective role for prostaglandins in this setting.
We report the first molecular image of melanin using a novel extension of OCT, pump-probe OCT. Melanin, an abundant endogenous chromophore, could provide general contrast in OCT imaging and means to ...diagnose and/or monitor melanomas.
Integrins are cysteine-rich heterodimeric cell-surface adhesion molecules that alter their affinity for ligands in response
to cellular activation. The molecular mechanisms involved in this ...activation of integrins are not understood. Treatment with
the thiol-reducing agent, dithiothreitol, can induce an activation-like state in many integrins suggesting that cysteine-cysteine
dithiol bonds are important for the receptor's tertiary structure and may be involved in activation-induced conformational
changes. Here we demonstrate that the platelet-specific integrin, α IIb β 3 , contains an endogenous thiol isomerase activity, predicted from the presence of the tetrapeptide motif, C XX C, in each of the cysteine-rich repeats of the β 3 polypeptide. This motif comprises the active site in enzymes involved in disulfide exchange reactions, including protein-disulfide
isomerase (EC 5.3.4.1 ) and thioredoxin. Intrinsic thiol isomerase activity is also observed in the related integrin, α v β 3 , which shares a common β-subunit. Thiol isomerase activity within α IIb β 3 is time-dependent and saturable, and is inhibited by the protein-disulfide isomerase inhibitor, bacitracin. Furthermore,
this activity is calcium-sensitive and is regulated in the EDTA-stabilized conformation of the integrin. This novel demonstration
of an enzymatic activity associated with an integrin subunit suggests that altered thiol bonding within the integrin or its
substrates may be locally modified during α IIb β 3 activation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Integrins are cysteine-rich heterodimeric cell-surface adhesion molecules that alter their affinity for ligands in response to cellular activation. The molecular mechanisms involved in this ...activation of integrins are not understood. Treatment with the thiol-reducing agent, dithiothreitol, can induce an activation-like state in many integrins suggesting that cysteine-cysteine dithiol bonds are important for the receptor's tertiary structure and may be involved in activation-induced conformational changes. Here we demonstrate that the platelet-specific integrin, αIIbβ3, contains an endogenous thiol isomerase activity, predicted from the presence of the tetrapeptide motif, CXXC, in each of the cysteine-rich repeats of the β3 polypeptide. This motif comprises the active site in enzymes involved in disulfide exchange reactions, including protein-disulfide isomerase (EC 5.3.4.1) and thioredoxin. Intrinsic thiol isomerase activity is also observed in the related integrin, αvβ3, which shares a common β-subunit. Thiol isomerase activity within αIIbβ3 is time-dependent and saturable, and is inhibited by the protein-disulfide isomerase inhibitor, bacitracin. Furthermore, this activity is calcium-sensitive and is regulated in the EDTA-stabilized conformation of the integrin. This novel demonstration of an enzymatic activity associated with an integrin subunit suggests that altered thiol bonding within the integrin or its substrates may be locally modified during αIIbβ3 activation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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