T‐cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site

Summary. Background: Development of neutralizing anti‐factor (F)VIII antibodies (‘inhibitors’) is a serious clinical problem in hemophilia A. Increased inhibitor risk has been associated with certain FVIII missense substitutions, including R593C in the A2 domain. Objectives: The aim of the present study was to identify T‐cell epitopes in FVIII and characterize T‐cell responses in two unrelated hemophilia A subjects sharing F8‐R593C and HLA‐DRB1*1101 genotypes. We hypothesized that the hemophilic substitution site coincides with an important T‐cell epitope. Patients/methods: The binding affinities of peptides for recombinant HLA‐DR proteins were measured and compared with epitope prediction results. CD4+ T cells were stimulated using peptides and stained with fluorescent, peptide‐loaded tetramers. Results: The inhibitor subjects, but not HLA‐matched controls, had high‐avidity HLA‐DRB1*1101‐restricted T‐cell responses against FVIII_589–608, which contains the hemophilic missense site. Antigen‐specific T cells secreted Th1 and Th2 cytokines and proliferated in response to FVIII and FVIII_592–603. FVIII_589–608 bound with physiologically relevant (micromolar) IC₅₀ values to recombinant DR0101, DR1101 and DR1501 proteins. Conclusions: Hemophilia A patients with R593C missense substitutions and these HLA haplotypes had an increased incidence of inhibitors in our cohorts, supporting a paradigm in which presentation of FVIII epitopes containing the wild‐type R593 influences inhibitor risk in this hemophilia A sub‐population.     

Children’s experiences of participation in the cleft lip and palate care pathway

International Journal of Paediatric Dentistry 2012; 22: 442–450 Aim. This qualitative study sought to explore children’s perspectives on their participation in the cleft lip and palate care pathway. Design. Eight boys and nine girls (aged 8–17 years), with a range of cleft types and who were patients at a British dental hospital each took part in two child‐centred interviews which incorporated participatory activities. An initial interview focused on children’s general life stories, and these often encompassed a discussion about cleft lip and/or palate. A follow‐up interview explored specific aspects of the condition and its related treatment. Results. Data revealed the varying roles that young people can play in decision‐making, which can be described as active or passive. In addition, the dynamic degree of participation was highlighted with patients occupying different roles throughout the care pathway. Conclusion. The research provides an insight into treatment decisions, and how young people, their families, and clinicians interact to arrive at these. Findings provide further evidence to support the important contribution young patients can make in their own treatment choices.     

Predictors of Mortality in Patients with Lower Extremity Peripheral Arterial Disease: 5‐Year Follow‐up

Background: Peripheral arterial disease (PAD) is associated with increased mortality. Lower extremity (LE) revascularization improves symptoms, but less is known about long‐term survival benefits of LE arterial revascularization. Methods: Two hundred and eighty‐three patients with an ankle brachial index (ABI) ≤0.9 were identified at the Veterans Administration Hospital, Danville, Illinois, and rates of LE arterial revascularization and all‐cause mortality were measured at 5 years. Results: Of 283 patients identified, 42 (15%) underwent LE revascularization including 39 surgical procedures and 18 percutaneous interventions for symptomatic PAD. Eleven (26%) patients underwent repeat procedures over the 5 years of follow‐up. Those undergoing revascularization were more often Caucasian (95% vs. 79%, P = 0.01) and had lower ABIs (ABI ≤ 0.4, 45% vs. 17%, P = <0.001). At 44 ± 19 months follow‐up, there were fewer deaths in patients that underwent revascularization compared to patients who did not undergo revascularization; 10/42 (24%) versus 107/241 (44%) patients, P = 0.012. In a multivariate model LE arterial revascularization was associated with a trend toward lower all‐cause mortality (HR 0.51 [95% CI 0.26–1.02], P = 0.056). Independent predictors of mortality were age ≥65 years (HR 2.42 [95% CI 1.52–3.85], P < 0.001), history of coronary artery disease (HR 1.67 [95% CI 1.13–2.46], P = 0.010), chronic kidney disease (HR 1.75 [95% CI 1.15–2.67], P = 0.010), and an ABI ≤ 0.4 (HR 1.88 [95% CI 1.19–2.96], P = 0.006). Conclusion: Few patients at this center with LE‐PAD underwent arterial revascularization. After adjusting for baseline differences, there is a trend toward lower 5‐year mortality in those undergoing LE arterial revascularization when compared to those who do not.     

Salivary oestriol in normal and abnormal pregnancies

Summary. Profiles of daily salivary oestriol concentrations throughout the third trimester of pregnancy have been constructed for 14 normal and 11 abnormal pregnancies. Day-to-day variations were significantly higher than those reported for unconjugated oestriol in plasma or serum. A sustained decline in salivary oestriol concentrations was observed in one pregnancy in which intrauterine death occurred. Sustained falls were also observed in two pregnancies in which a healthy infant was born at term. In all other patients a normal salivary oestriol profile correlated with a favourable outcome. Salivary oestriol measurements provide similar information to plasma unconjugated oestriol measurements while offering the advantages of a simple, non-invasive sample collection procedure.     

ERYTHROPOIETIN LEVELS IN CORD BLOOD OF CONTROL INFANTS AND INFANTS WITH RESPIRATORY DISTRESS SYNDROME

Erythropoietin levels (ESF) were measured in premature infants with and without the respiratory distress syndrome in an effort to define the role of intrauterine hypoxia in the genesis of the disease. No difference in levels could be detected between infants with and without the: respiratory distress syndrome. This suggests that either intrauterine hypoxia plays no role in the genesis of the respiratory distress syndrome or that the hypoxia is (1) of short duration, (2) of relatively long duration, or (3) remote with respect to the time of birth. The higher levels found in full-term infants suggested that hypoxia before birth is a more common feature of the term delivery than the premature delivery.     

Stimulation Hierarchy: Optimal Sequence for Double and Triple Extrastimuli During Electrophysiological Studies

To determine the optimal ventricular stimulation sequence, an 11-step programmed electrical stimulation (PES) protocol was completed, even if a ventricular arrhythmia (VA) was induced with earlier steps. The protocol consisted of one, two, and three extrastimuli during sinus rhythm (SR), and at two drive pacing rates (VP1 and VP2) plus rapid burst and ramp pacing. By analyzing the 79 completed protocols that induced the clinical arrhythmia, the following were determined: (1) the frequency of induced clinical and nonclinical VA with each stimulation step; (2) the yield ratio (YR) of each step, defined as the probability of inducing clinical versus nonclinical arrhythmia; (3) the cumulative yield of induced clinical and nonclinical arrhythmia with two widely used stimulation sequences, i.e., triple extrastimuli delivered early in the stimulation protocol (MMC sequence) and triple extrastimuli delayed until after double extrastimuli failed to induce the clinical arrhythmia (B sequence); (4) the relative efficiency of these sequences were determined. The percentage of induced clinical and nonclinical arrhythmia with SR + 3 extrastimuli, VP1 + 2 extrastimuli, and VP2 + 2 extrastimuli were (53%, 5%), (36%, 5%), and (41%, 9%), respectively. The cumulative yield of induced clinical VA with the MMC-type sequence reached 55% by the third step of the protocol, whereas 50% was attained only at the eighth step of the B-type sequence. The cumulative percentage of induced nonclinical VA with either sequence was similar during the early steps of the protocol. The MMC sequence was more efficient, requiring overall 36% of potential steps for clinical arrhythmia induction, compared with 48% for the B sequence (P less than 0.001). For questionable arrhythmia states, e.g., syncope of unknown origin and nonsustained VT, a modified sequence is proposed that may further reduce the induction of uninterpretable arrhythmias.     

Primary Hypothyroidism with Pituitary Enlargement and a Visual Field Abnormality

A 23 year old man presented with classical hypothyroidism of 9 years duration. This was associated with pituitary enlargement, documented on magnetic resonance imaging (MRI), and abnormal half-field visual evoked responses (VERs). Following the initiation of thyroxine therapy the pituitary enlargement and the VER abnormalities resolved. The final diagnosis was of primary hypothyroidism with secondary pituitary hyperplasia.