A Separate Role for ICAM‐1 and Fluid Shear in Regulating Leukocyte Interactions with Straight Regions of Venular Wall and Venular Convergences

Objective: Variation in expression of adhesion molecules plays a key role in regulating leukocyte behavior, but the contribution of fluid shear to these interactions cannot be ignored. Here, we dissected the effects of each of these factors on leukocyte behavior in different venular regions. Materials and Methods: Leukocyte behavior was quantified in blood‐perfused microvascular networks in anesthetized mouse cremaster muscle, using intravital confocal microscopy. ICAM‐1 expression and fluid shear rate were quantified by using ICAM‐1 fluorescent labeling, fluorescent particle tracking, and computational fluid dynamics. Results: Tumor necrosis factor alpha induced an increase in ICAM‐1 expression and abolished the differences observed among control venules of different sizes. Consequently, leukocyte adhesion was increased to a similar level across all vessel sizes [5.1±0.46 leukocytes/100 μm vs. 2.1±0.47 (control)], but remained significantly higher in venular convergences (7.8±0.4). Leukocyte transmigration occurred primarily in the smallest venules and venular convergences (23.9±5.1 and 31.9±2.7 leukocytes/10,000 μm² tissue, respectively). In venular convergences, the two inlet vessels are predicted to create a region of low velocity, increasing leukocyte adhesion probability. Conclusions: In straight regions of different‐sized venules, the variability in ICAM‐1 expression accounts for the differences in leukocyte behavior; in converging regions, fluid shear potentially has a greater effect on leukocyte endothelial cell interactions.     

Projecting Demand for Cardiac Pacemakers

A cardiac pacemaker implantation program involves substantial resources of money, facilities, and manpower. This paper presents a model for forecasting future numbers of implants, thus enabling the more efficient use of such resources. The model embraces both new implants and replacements, both short-term and long-term planning, and can be used with relevant data from any source.     

ANEURYSM OF THE NONPATENT DUCTUS ARTERIOSUS IN THE NEWBORN

F. WYLER¹
Abstract. Aneurysm of the nonpatent ductus arteriosus in the newborn is a rare, but potentially fatal condition. Of reported ductal aneurysm up to 1969, diagnosis was made at autopsy only. We report here to our knowledge for the first time on a two week old infant with correct preoperative angiographic diagnosis followed by a successful surgical cure.     

Pacing from the Right Ventricular Septum: Is There a Danger to the Coronary Arteries?

Background: Pacing from right ventricular (RV) septal sites has been suggested as an alternative to RV apical pacing in an attempt to avoid long-term adverse consequences on left ventricular function. Concern has been raised as to the relationship of the left anterior descending coronary artery (LAD) to pacing leads in these positions.
Methods and Results: We retrospectively analyzed three cases in which patients with RV active-fixation leads in situ also had coronary angiography. Multiple fluoroscopic views were used to determine the relationship of the lead tip at various pacing sites to the coronary arteries. A lead placed on the anterior wall was in close proximity to the LAD, whereas septal and free wall positioning was not.
Conclusion: Placement of RV active-fixation leads on the septum avoids potential coronary artery compromise.     

Quality of life instruments for children and adolescents with neurodisabilities: how to choose the appropriate instrument

Aim  There are many misconceptions about what constitutes 'quality of life' (QoL). It is often difficult for researchers and clinicians to determine which instruments will be most appropriate to their purpose. The aim of the current paper is to describe QoL instruments for children and adolescents with neurodisabilities against criteria that we think are important when choosing or developing a QoL instrument.
Method  QoL instruments for children and adolescents with neurodisabilities were reviewed and described based on their purpose, conceptual focus, origin of domains and items, opportunity for self report, clarity (lack of ambiguity), potential threat to self-esteem, cognitive or emotional burden, number of items and time to complete, and psychometric properties.
Results  Several generic and condition-specific instruments were identified for administration to children and adolescents with neurodisabilities – cerebral palsy, epilepsy and spina bifida, and hydrocephalus. Many have parent-proxy and self-report versions and adequate reliability and validity. However, they were often developed with minimal involvement from families, focus on functioning rather than well-being, and have items that may produce emotional upset.
Interpretation  As well as ensuring that a QoL instrument has sound psychometric properties, researchers and clinicians should understand how an instrument's theoretical focus will have influenced domains, items, and scoring.     

Survival with Rett syndrome: comparing Rett’s original sample with data from the Australian Rett Syndrome Database

Aim Rett syndrome is a severe neurodevelopmental disorder that typically affects females. Little is known about the natural history and survival time of these females. Method We compared the survival of all Austrian female participants from Rett’s historical cohort (1966) with that of affected females registered in the Australian Rett Syndrome Database. The analysis included both Kaplan–Meier analysis and a log‐rank test for equality of survivor functions. Results Of females in the original Austrian group, three are still alive. The median age at death was 13 years 4.8 months. The probability of survival up to the age of 25 years was 21%, compared with 71% in the Australian cohort (p<0.001). We found no practical or statistically significant differences in survival between the various birth year groups within the Australian cohort. Interpretation Our data indicate that survival of females with Rett syndrome has improved since the late 1960s but that there has been shown no change in survival over the last 30 years, possibly because the follow‐up time has been too short.     

Chymotrypsin Output in the Stools in Pancreatic and Other Diseases

Chymotrypsin output in the stools (u./24 hr.) has been calculated from analysis of single stool samples, using cuprous isothiocyanate as a continuous marker. The values thus calculated agreed favorably with those calculated from three-day stool collections. In 45 controls, with and without steatorrhea, chymotrypsin ouput was above 10,000 u./24 hr. In six patients with pancreatic insufficiency the values were considerably lower. In 10 patients with pancreatic disease without insufficiency the values were in the normal range. The method was found very useful in the diagnosis of pancreatic insufficiency. It was not sensitive enough to detect lesser degrees of pancreatic damage.     

Novel ψ-S-CH2 peptide-bond replacement and its utilization in the synthesis of nonpeptidic surrogates of the Leu-Asp-Val sequence that exhibit specific inhibitory activities on CD4+ T cell binding to fibronectin

The Leu-Asp-Val-(LDV)-containing amino acid sequence, derived from the alternatively spliced first connecting segment region of fibronectin (FN), was shown to be recognized primarily by the α₄β₁-integrin receptor expressed on the surface of various cell types. This adhesion epitope may therefore inhibit integrin-mediated cell interactions with the extracellular matrix glycoprotein, including adhesion, migration, activation and differentiation. To probe the structural requirements for LDV recognition by integrins and examine the feasibility of inhibition of LDV-dependent cell-FN interactions, we have designed and constructed a novel ψ-S—CH₂ peptide bond surrogate that was employed in the formation of LDV surrogates. The synthesis of the ψ-S–CH₂ surrogates reported herein is based on Michael addition of 4-methylpentane thiol to an itaconic acid diester to form an S–CH₂ bond. We have found that the LDV surrogates comprises of 4-methylpentanoate-Asp-i-butyl amide and 8-methyl-3-(2-methylpropylaminocarbonyl)-5-thianonanoic acid interfered with CD4⁺ human T-cell adhesion to FN in vitro, with an ED₅₀ of 280 μg/mL. A control structural mimetic of the Leu-Glu-Val (LEV) peptide did not interfere with the T-cell-FN interaction. The specificity of the reaction was substantiated by the finding that the LDV mimetics did not interfere with T-cell adhesion to laminin, another major cell-adhesive glycoprotein of the extracellular matrix. That the nonpeptidic mimetics of LDV interfered markedly with T-cell-FN adhesive interactions indicate that the peptide bond and the amine and carboxyl end groups of the tripeptide makes only a minor contribution to the integrin binding affinity. Thus, consistent with our recent report on the production of Arg-Gly-Asp surrogates, we suggest that these constructs could provide novel insights into the fundamental mechanisms of integrin-ligand interactions, and serve as competitive antagonists of conceivable therapeutic value.