Epitope mapping of inhibitory antibodies against platelet glycoprotein Ibalpha reveals interaction between the leucine-rich repeat N-terminal and C-terminal flanking domains of glycoprotein Ibalpha

The interaction of von Willebrand factor (vWF) with the platelet receptor glycoprotein Ibalpha (GPIbalpha) is important for platelet adhesion at high shear stress. Two functionally important antigenic areas within GPIbalpha were identified through the characterization of 5 new inhibitory anti-GPIb monoclonal antibodies (mAbs). The binding sites of 3 of these anti-GPIb mAbs, which were intercompeting and potently inhibiting shear stress-induced binding of vWF, were mapped within the N-terminal amino acid (aa) 1-59 area by the use of canine-human chimeras. These antibodies, however, had little or no effect (approximately 40% inhibition) on the binding of vWF induced by either botrocetin or ristocetin. On the other hand, the anti-GPIb mAbs 24G10 and 6B4, which blocked GPIb-vWF binding under all conditions examined, bound to 2 different regions of GPIbalpha, aa 1-81 and aa 201-268, respectively. The epitope for 6B4 was further narrowed by phage display revealing 2 sets of peptide sequences aligning within aa 259-262 and aa 230-242. In the latter region of GPIbalpha, the gain-of-function platelet-type von Willebrand disease (PT-vWD) mutations have been identified. Alignment was partially confirmed because the binding of 6B4 to recombinant GPIbalpha fragments carrying either one of the PT-vWD mutations was considerably impaired but not completely abolished. In contrast, mAb 24G10 bound more strongly to mutant PT-vWD GPIbalpha. However, although 24G10 competed with 6B4 for binding to platelets, it bound to an epitope within aa 1-81 of GPIbalpha. In conclusion, 2 functionally important areas within GPIbalpha were identified: one localized within the leucine-rich repeat N-terminal aa 1-59 area and one composed of residues aa 1-81 in close contact with aa 201-268. Moreover, further support is provided for the existence of an intramolecular interaction between the N-terminal flanking (aa 1-81) and C-terminal flanking (aa 201-268) regions. (Blood. 2001;98:652-660)     

Short-term, light- to moderate-intensity exercise training improves leg muscle strength in the oldest old: a randomized controlled trial

OBJECTIVES: To assess the effects of an 8‐week exercise training program with a special focus on light‐ to moderate‐intensity resistance exercises (30–70% of one repetition maximum, 1RM) and a subsequent 4‐week training cessation period (detraining) on muscle strength and functional capacity in participants aged 90 and older. DESIGN: Randomized controlled trial performed during March to September 2009. SETTING: Geriatric nursing home. PARTICIPANTS: Forty nonagenarians (90–97) were randomly assigned to an intervention or control group (16 women and 4 men per group). INTERVENTION: Eight‐week muscle strength exercise intervention focused on lower limb strength exercises of light to moderate intensity. MEASUREMENTS: Primary outcome: 1RM leg press. Secondary outcomes: handgrip strength, 8‐m walk test, 4‐step stairs test, Timed Up and Go test, and number of falls. RESULTS: A significant group by time interaction effect (P=.02) was observed only for the 1RM leg press. In the intervention group, 1RM leg press increased significantly with training by 10.6 kg [95% confidence interval (CI)=4.1–17.1 kg; P=.01]. Except for the mean group number of falls, which were 1.2 falls fewer per participant in the intervention group (95% CI=0.0–3.0; P=.03), no significant training effect on the secondary outcome measures was found. CONCLUSION: Exercise training, even of short duration and light to moderate intensity, can increase muscle strength while decreasing fall risk in nonagenarians.     

Can cardiovascular MRI be used to more definitively characterize cardiac masses initially identified using echocardiography?

In diagnosing cardiac and paracardiac masses, cardiac MRI (CMR) has gained acceptance as the gold standard. CMR has been observed to be superior to echocardiography in characterizing soft‐tissue structures and, specifically, in classifying cardiac masses. The aim of our study was to evaluate the association between mortality and cardiac or paracardiac masses initially identified by echocardiography (ECHO) and confirmed by CMR. Between January 2002 and August 2007, a total of 158 patients underwent both ECHO and CMR for the evaluation of cardiac masses that were equivocal or undefined by ECHO. The primary study endpoints were 5‐year all‐cause mortality and 5‐year cardiac mortality. Causes of death as of April 1, 2015 were obtained from medical records or the National Death Index. Patients were analyzed according to mass type determined by CMR using the Kruskal–Wallis test, Kaplan–Meier curves, and the log‐rank test. Over a mean duration of follow‐up of 10.4 ± 2.9 years (range: 0.01–12 years) post‐CMR, the overall all‐cause mortality rate was 25.9% (41/158). Median age at death was 76 years and there were 21 females (51.2%). Mortality rates in the different classifications of cardiac masses by CMR were as follows: 20% (1/5) in patients with a Nondiagnostic CMR; 20% (1/5) in Other Diagnoses; 17.9% (7/39) in No Masses (includes Normal Anatomical Variants); 16.7% (3/18) in Benign Masses; 23.8% (15/63) in Fat; 50% (5/10) in Thrombus; and 61.5% (8/13) in Malignant Mass. The mean survival time in patients with No Mass (n = 39) was not significantly longer than patients with any type of cardiac mass (n = 114) (P = .16). No significant difference was found in age at death between patients when grouped by CMR classification (P = .40). However, among CMR‐confirmed masses, there were some significant differences by mass classification type (P = .006). During the follow‐up period, 26% (41/158) of patients died and 22% (9/41) of the deaths were cardiovascular related; there was no significant difference in mean survival times with respect to cause of mortality (P = .23). In patients with cardiac masses, dually confirmed by ECHO and CMR, significant differences in survival time were observed based upon CMR classified type of mass while CMR was instrumental in obviating invasive biopsy.     

Prognostic impact of baseline low blood pressure in hypertensive patients with stable coronary artery disease of daily clinical practice

J Clin Hypertens (Greenwich). 2012;00:00–00 ©2012 Wiley Periodicals, Inc. The authors’ aim was to investigate the prognostic value of first‐visit systolic and diastolic blood pressure (SBP/DBP) in hypertensive patients with stable coronary artery disease (sCAD) in conditions of contemporary daily clinical practice. From February 1, 2000, to January 31, 2004, 690 consecutive hypertensive patients with sCAD (mean age 68±10 years, 65% male) were prospectively followed in the outpatient cardiology clinic for major events (acute coronary syndrome, revascularization, stroke, heart failure, or death) and associations with baseline SBP/DBP were investigated. At first visit, median SBP/SDP were 130/75 mm Hg (interquartile range, 25–75; 120–140/70–80 mm Hg). After 25 months of follow‐up (median), 19 patients died (2.8%); 10 from cardiovascular causes (1.5%), 87 patients experienced a coronary event (13%), and 130 patients (19%) a major event. After adjusting for baseline variables, DBP <75 mm Hg or SBP <130 mm Hg resulted in independent predictors of major events (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.07–2.16, P=.02; HR, 1.68; 95% CI, 1.18–2.40, P=.004, respectively), coronary events (HR, 1.78; 95% CI, 1.15–2.75, P=.009; HR, 1.84; 95% CI, 1.20–2.83, P=.005, respectively), and cardiovascular mortality (HR, 7.02; 95% CI, 1.26–39.04, P=.03; HR, 9.26; 95% CI, 1.33–64.32, P=.02, respectively). In this study, a low first‐visit SBP or DBP was associated with an adverse prognosis in hypertensive patients with sCAD of contemporary daily clinical practice.     

Hypertensive retinopathy in patients with aortic coarctation

In order to assess the incidence and the determinants of hypertensive vascular changes in the retina of patients with coarctation of the aorta, fifty (37 male and 13 female) were analyzed. The mean age of the group was 18.7 +/- 10.3 years. No one had evidence of nephropathy. Different degrees of hypertensive retinopathy (Puig-Solanes classification) were observed in 54%. Of the patients, no one had papilledema. Retinal vascular damage was not related to either age or sex. The group of patients with retinal vascular lesions had a mean level of systolic arterial pressure higher than the group with normal retinas. Multivariant statistical analysis of the results permitted the identification of systolic arterial pressure higher than 150 mm Hg, age greater than 15 years and cardiomegaly as the three variables more frequently associated with retinal vascular lesions. Surgical correction of the aortic malformation resulted in normalization of both systolic and diastolic arterial pressures in 98% of the total number of patients as determined one year postoperatively. It is concluded that, in coarctation of the aorta, vascular damage of the retina appears to have an incidence that is similar to that observed in patients with other forms of systemic arterial hypertension. The development of these retinal lesions in patients with coarctation of the aorta would seem to be determined by the severity and duration of the hypertensive process.     

Exposure of young children working on Mexican tobacco plantations to organophosphorous and carbamic pesticides, indicated by cholinesterase depression

BACKGROUND: Organophosphorous (OP) and carbamic pesticides are used in large quantities on tobacco plantations in Nayarit State, Mexico, where up to 3000 children and their families work. OP and carbamic pesticides are easily inhaled or absorbed through the skin and children may be particularly vulnerable to pesticides because of their smaller body mass, their height and more regular hand-mouth contact. The aim of this study is to assess the effect of pesticide exposure on acetylcholinesterase levels of very young migrant Mexican tobacco workers and younger siblings. METHODS: Blood samples were collected from 160 children aged 0-14 years during harvest (exposure) and from 62 children in their home communities 6-9 months after harvest (baseline). Samples were tested for cholinesterase corrected for haemoglobin and ambient temperature. RESULTS: Fifteen per cent of children had depression scores ranging from -40% to 190% of their baseline levels. Thirty-three per cent of children had depression scores of at least 15% and 86% of children were anaemic. CONCLUSION: These results suggest that very young children are exposed to potentially harmful and toxic amounts of pesticides while working. Further research is needed to assess the actual acute and chronic health impacts of such exposures.