Array-CGH is an effective first-tier diagnostic test for EFTUD2-associated congenital mandibulofacial dysostosis with microcephaly.

Mandibulofacial dysostosis with microcephaly (MFDM) is a sporadic malformation syndrome with severe craniofacial abnormalities, microcephaly, developmental delay, and dysmorphic features. Most cases of clinically diagnosed MFDM remain genetically unexplained, and to the best of our knowledge a total of 35 patients, 31 different mutations, 4 deletions, and 6 reports have been published. Our proband was born at 36 weeks gestation with microcephaly, microcrania, cleft palate, severe retrognathia, oral and pharyngeal dysphagia, bilateral proximal radioulnar synostosis, 11 thoracic ribs, abnormal magnetic resonance imaging (MRI) findings including simplified gyral pattern and mild dilatation of the posterior bodies of the lateral ventricles secondary to thinning of the white matter, high-pitched cry due to unilateral vocal cord paralysis, and dysmorphic features. Array comparative genomic hybridization (aCGH) + single nucleotide polymorphism (SNP) analysis identified a likely de novo pathogenic deletion on chromosome 17q21.31, encompassing the EFTUD2 gene. Our case represents the fifth reported proband to have MFDM caused by small deletions involving EFTUD2. All known mutations involving EFTUD2 result in genetic haploinsufficiency, consistent with our proband's case as well. Her phenotypic features both overlap and expand on the clinical features of previously reported cases, and her genetic diagnosis also supports the use of aCGH as a first-tier testing option for this disorder.

Carotid sinus syncope induced by malignant tumors in the neck. Emergence of vasodepressor manifestations following pacemaker therapy.

Three patients had carotid sinus syncope secondary to malignant neoplasms in the neck. Pacemaker therapy controlled the cardioinhibitory reflex with bradycardia, but the patients manifested varying episodes of hypotension due to a vasodepressor reflex that most likely resulted from persistent irritation of the carotid sinus by the tumor. These episodes seemed to be self-limiting. Surgical treatment in resistant cases is a possibility.

Impact of intraventricular hemorrhage on cognitive and behavioral outcomes at 18 years of age in low birth weight preterm infants.

OBJECTIVE: Although high-grade intraventricular hemorrhage (IVH; grades III-IV) in preterm and low birth weight infants are clearly associated with increased risk of long-term adverse neurodevelopmental sequelae, the impact of low-grade IVH (grades I-II) has been less clear. Some studies have followed these infants through early school age and have shown some conflicting results regarding cognitive outcome. Such studies that assess children at younger ages may not accurately predict outcomes in later childhood, as it is known that fluid and crystallized intelligence peak at age 26 years. There is paucity of data in current medical literature, which correlates low-grade IVH with outcomes in early adulthood. To determine the link between the occurrence of low-grade IVH in low birth weight (birth weight ⩽2500 g) infants born prematurely (gestational age <37 weeks) and intellectual function, academic achievement, and behavioral problems to the age of 18 years. STUDY DESIGN: This study is an analysis of data derived from the Infant Health and Development Program (IHDP), a multisite national collaborative study and a randomized controlled trial of education intervention for low birth weight infants from birth until 3 years of age with follow-up through 18 years of age. A total of 985 infants were enrolled in the IHDP. Of the 462 infants tested for IVH, 99 demonstrated sonographic evidence of low-grade IVH, whereas 291 showed no sonographic evidence of IVH. Several outcomes were compared between these two groups. Intelligence was assessed using Stanford-Binet Intelligence scales at age 3 years, Wechsler Intelligence Scale for Children (WISC-III) at age 8 years, Wechsler Abbreviated Scale of Intelligence (WASI) at age 18 years and Woodcock Johnson Tests of Achievement at age 8 and 18 years. Behavior was measured using the Achenbach Behavior Checklist at age 3 years and Child Behavior Checklist (CBCL) at age 8 and 18 years. Outcomes were compared between the IVH-positive and IVH-negative groups using analysis of covariance after adjusting for the presence or absence of intervention, birth weight, gestational age, gender, severity of neonatal course, race and maternal education. RESULTS: No statistically significant difference in intelligence as measured by Stanford-Binet Intelligence scales, WISC-III, WASI and Woodcock-Johnson Tests of Achievement could be appreciated between IVH-positive patients and controls at any age group (36 months, 8 years and 18 years of age). In addition, there was no significant difference in problem behavior as assessed by the Achenbach Behavior Checklist and Child Behavior Checklist (CBCL) comparing IVH patients with controls. CONCLUSION: Low-grade IVH was not demonstrated in our study to be an independent risk factor associated with lower outcomes in intelligence, academic achievement or problem behavior at age 3, 8 and 18 years.

Improved pacing tolerance of the ischemic human myocardium after administration of carnitine.

The possibility that DL-carnitine has a protective effect during myocardial ischemia was evaluated by performing two rapid coronary sinus pacing studies 15 minutes apart in 21 patients with coronary artery disease. Eleven patients received DL-carnitine (20 or 40 mg/kg) before the second pacing study. The treated group had a significant increase in mean heart rate (12.5 beats/min, P less than 0.001), pressure-rate product (1,912 units, P less than 0.01) and pacing duration (3.2 minutes, P less than 0.001) after the administration of carnitine. The treated group also had improvements in percent myocardial lactate extraction (8.8 percent increase, P less than 0.001) and left ventricular end-diastolic pressure (a decrease of 5.3 mm Hg, P less than 0.05). There was significantly less S-T segment depression during the second pacing period in both the untreated and treated groups. The results of this study suggest that in ischemic human hearts with reasonably well preserved left ventricular function, DL-carnitine may improve the tolerance for stress associated with an increase in heart rate and pressure-rate product.

Comparison of direct and indirect measurements of respiratory airflow: implications for hypopneas.

The purpose of this study was to compare indirect methods for measuring respiratory airflow, such as temperature difference between inspired and expired air, thoracoabdominal movements, and nasal respiratory-airflow pressures-with a more direct measurement of minute ventilation using a head-out body plethysmograph. Measurements were obtained in healthy, awake, seated subjects during sequences of different levels of voluntary hypoventilations at 20 breaths/minute and analyzed to determine how well different methods could identify hypopneas (defined as reduction in minute ventilation by 50% or more). The results varied widely between different methods. Sensitivities ranged from 0 to 1, specificity ranged from 0.33 to 1, positive predictive values (PPV) ranged from 0 to 0.73, negative predictive values (NPV) ranged from 0.68 to 0.93. Cohen's kappa varied between 0 and 0.65 The poorest agreement was for the thermistor method, and the best agreement was obtained when a combination of thoraco-abdominal movements and nasal respiratory-airflow pressure was employed (sensitivity = 0.86, specificity = 0.83, PPV = 0.71, NPV = 0.92, Cohen's kappa = 0.65). We conclude that none of the indirect methods investigated, individually or in combination, proved adequate for identification of voluntary hypopneas in awake individuals.

Adverse effects of right ventricular pacing in a patient with aortic stenosis, Hemodynamic documentation and management.

A patient with moderate aortic stenosis, left ventricular hypertrophy, and a permanent right ventricular pacemaker for a sick sinus node presented with hypotension, dizziness, and angina pectoris with paced beats. The hemodynamics of pacing were documented with non-invasive and invasive studies. The patient was successfully treated with a programmable generator and pacing at a lower rate. The neccessity of evaluating the effects of a temporary pacemaker before insertion of a permanent one and of a reevaluation of the hemodynamic status in the presence of unexplained cardiac failure in a patient with permanent pacemaker are emphasized in this case report.

The hemodynamic effects and mechanism of action of pulmonary artery balloon counterpulsation in the treatment of right ventricular failure during left heart bypass.

The efficacy of pulmonary artery balloon counterpulsation (PABC) was evaluated in improving right ventricular (RV) output during left heart bypass for global cardiac failure. In 13 pigs, a 40-ml balloon was positioned within a graft anastomosed to the pulmonary artery distal to the pulmonary valve, and left heart bypass was instituted from the left atrium to the carotid artery. Global myocardial failure was produced by an infusion of propranolol (range, 25 to 78 mg). In this model, RV output decreased despite volume loading to a right atrial pressure of 15 mm Hg and atrioventricular sequential pacing at 100 beats per minute. Pulmonary artery balloon counterpulsation increased both RV output (from 519 +/- 76 to 1,117 +/- 110 ml/min; p less than 0.01) and RV systolic stroke work (from 1.3 +/- 0.4 to 2.3 +/- 0.6 gm-m; p less than 0.01). Right atrial pressure decreased (from 15.5 +/- 0.9 to 10.7 +/- 1.0 mm Hg; p less than 0.01) in 8 of the pigs studied during RV failure. In 5 pigs, ventricular fibrillation occurred without a stable model of RV failure, and there was no cardiac output before or after counterpulsation. The mechanism of action of PABC was studied by placing a flow probe around a large branch of the right pulmonary artery. During RV failure, balloon inflation caused flow through the pulmonary circulation, and ventricular systole resulted in filling of the graft. During ventricular fibrillation, balloon inflation and deflation produced only a to-and-fro movement of blood in the pulmonary artery branch without net forward flow.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of cardioplegic arrest on right atrial function.

Atrial electrical and mechanical activity persists during cardioplegic arrest. It has been postulated that atrial ischemia may occur and cause deterioration in atrial function. This study was designed to assess the effect of cardioplegic arrest on right atrial function. Twenty-one pigs were placed on cardiopulmonary bypass (CPB), and the right atrium was isolated from the circulation by snaring both venae cavae and incising the coronary sinus. The tricuspid valve was closed through a small right ventriculotomy, and baseline atrial function was assessed using a compliant balloon in the atrium. Fourteen pigs underwent one hour of cardioplegic arrest (7 with cardioplegia alone [CCA group] and 7 with the addition of topical hypothermia [CCA + TH group]) followed by one hour of normothermic reperfusion. Seven other pigs were placed on CPB for the same period of time (CPB group). Atrial electrical and mechanical activity persisted at 45 beats per minute in the CCA group but was virtually abolished in the CCA + TH group. Cardioplegic arrest caused considerable deterioration in right atrial function (developed pressure, 18.9 +/- 0.8 [baseline] versus 14.1 +/- 0.7 mm Hg; p less than 0.05; first derivative of atrial pressure [dP/dt], 187 +/- 19 versus 134 +/- 25 mm Hg per second; p less than 0.05; 60 minutes of reperfusion and balloon volume of 20 ml). It was not affected by topical cooling. Right atrial developed pressure was maintained, but dP/dt was significantly reduced in the CPB group. This study suggests that cardioplegic arrest does not protect the atrium.

Statistical analysis of binary data generated from multilocus dominant DNA markers.

The use of methodologies such as RAPD and AFLP for studying genetic variation in natural populations is widespread in the ecology community. Because data generated using these methods exhibit dominance, their statistical treatment is less straightforward. Several estimators have been proposed for estimating population genetic parameters, assuming simple random sampling and the Hardy-Weinberg (HW) law. The merits of these estimators remain unclear because no comparative studies of their theoretical properties have been carried out. Furthermore, ascertainment bias has not been explicitly modelled. Here, we present a comparison of a set of candidate estimators of null allele frequency (q), locus-specific heterozygosity (h) and average heterozygosity () in terms of their bias, standard error, and root mean square error (RMSE). For estimating q and h, we show that none of the estimators considered has the least RMSE over the parameter space. Our proposed zero-correction procedure, however, generally leads to estimators with improved RMSE. Assuming a beta model for the distribution of null homozygote proportions, we show how correction for ascertainment bias can be carried out using a linear transform of the sample average of h and the truncated beta-binomial likelihood. Simulation results indicate that the maximum likelihood and empirical Bayes estimator of have negligible bias and similar RMSE. Ascertainment bias in estimators of is most pronounced when the beta distribution is J-shaped and negligible when the latter is inverse J-shaped. The validity of the current findings depends importantly on the HW assumption-a point that we illustrate using data from two published studies.

Determination of skin repigmentation progression.

In this paper, we describe an image processing scheme to analyze and determine areas of skin that have undergone repigmentation in particular, during the treatment of vitiligo. In vitiligo cases, areas of skin become pale or white due to the lack of skin pigment called melanin. Vitiligo treatment causes skin repigmentation resulting in a normal skin color. However, it is difficult to determine and quantify the amount of repigmentation visually during treatment because the repigmentation progress is slow and moreover changes in skin color can only be discerned over a longer time frame typically 6 months. Here, we develop a digital image analysis scheme that can identify and determine vitiligo skin areas and repigmentation progression on a shorter time period. The technique is based on principal component analysis and independent component analysis which converts the RGB skin image into a skin image that represent skin areas due to melanin and haemoglobin only, followed by segmentation process. Vitiligo skin lesions are identified as skin areas that lack melanin (non-melanin areas). In the initial studies of 4 patients, the method has been able to quantify repigmentation in vitiligo lesion. Hence it is now possible to determine repigmentation progression objectively and treatment efficacy on a shorter time cycle.

Hyperkalemia with cardiac arrhythmia. Induction by salt substitutes, spironolactone, and azotemia.

In two patients, severe hyperkalemia and serious cardiac arrhythmia developed after excessive use of potassium-containing salt substitutes. Both had impaired ability to handle and excrete additional potassium load due to chronic congestive heart failure, azotemia, and administration of spironolactone. Prompt recognition of the arrhythmia and immediate restoration of the cardiac rate and rhythm by pacemaker support followed by intensive regimen to lower the serum potassium prevented a potentially fatal outcome. These cases emphasize the potential danger of salt substitutes when used by patients who are predisposed to retain potassium.

Scoring pairwise genomic sequence alignments.

The parameters by which alignments are scored can strongly affect sensitivity and specificity of alignment procedures. While appropriate parameter choices are well understood for protein alignments, much less is known for genomic DNA sequences. We describe a straightforward approach to scoring nucleotide substitutions in genomic sequence alignments, especially human-mouse comparisons. Scores are obtained from relative frequencies of aligned nucleotides observed in alignments of non-coding, non-repetitive genomic regions, and can be theoretically motivated through substitution models. Additional accuracy can be attained by down-weighting alignments characterized by low compositional complexity. We also describe an evaluation protocol that is relevant when alignments are intended to identify all and only the orthologous positions. One particular scoring matrix, called HOXD70, has proven to be generally effective for human-mouse comparisons, and has been used by the PipMaker server since July, 2000. We discuss but leave open the problem of effectively scoring regions of strongly biased nucleotide composition, such as low G + C content.

Preformed catheters for simplified transbrachial coronary arteriography.

The experience in 700 patients of transbrachial selective coronary arteriography using a preformed catheter is described. The excellent plastic memory of torque control of the polyurethane catheter combined with the characteristic gentle curve permit rapid and easy intubation of the coronary arteries. The so-called "difficult" cases encountered with the classic Sones technique have been catheterized with ease employing the technique described in this report. The exceptionally low complication rate (no deaths), abbreviated catheterization time, a success rate of 99.2%, and the high quality cine angiographic films make this technique a highly useful and effective method of transbrachial coronary arteriography.

Association between divergence and interspersed repeats in mammalian noncoding genomic DNA.

The amount of noncoding genomic DNA sequence that aligns between human and mouse varies substantially in different regions of their genomes, and the amount of repetitive DNA also varies. In this report, we show that divergence in noncoding nonrepetitive DNA is strongly correlated with the amount of repetitive DNA in a region. We investigated aligned DNA in four large genomic regions with finished human sequence and almost or completely finished mouse sequence. These regions, totaling 5.89 Mb of DNA, are on different chromosomes and vary in their base composition. An analysis based on sliding windows of 10 kb shows that the fraction of aligned noncoding nonrepetitive DNA and the fraction of repetitive DNA are negatively correlated, both at the level of an entire region and locally within it. This conclusion is strongly supported by a randomization study, in which repetitive elements are removed and randomly relocated along the sequences. Thus, regions of noncoding genomic DNA that accumulated fewer point mutations since the primate-rodent divergence also suffered fewer retrotransposition events. These results indicate that some regions of the genome are more "flexible" over the time scale of mammalian evolution, being able to accommodate many point mutations and insertions, whereas other regions are more "rigid" and accumulate fewer changes. Stronger conservation is generally interpreted as indicating more extensive or more important function. The evidence presented here of correlated variation in the rates of different evolutionary processes across noncoding DNA must be considered in assessing such conservation for evidence of selection.

Comprehensive presentation of semicircular canal sensitivity.

It is generally agreed that in order to determine any difference in vestibular sensitivity between the two inner ears, the best clinical procedure involves a quantitative expression of the slow phase nystagmus response to standardized caloric (or rotatory) stimulation. The preferred procedure has involved averaging the slopes of a few of the nystagmus responses during the period of most intense activity and this has been accomplished either arithmetically or by means of an electronic computer. Although, such a sampling is often sufficient to enable a reliable diagnosis, occasions do arise when the results can be misleading unless comprehensive total presentations of the responses from the two labyrinths are available for reliable comparative evaluation. Such a procedure has been developed at the University of Toronto and used for clinical assessment at St. Michael's Hospital. The reliability of the method has been established as the result of testing over 800 patients with various vestibular disorders.

Is atrial function affected by conventional cardioplegic arrest?

Conventional cardioplegic arrest results in persistent atrial electrical and mechanical activity. This activity has been postulated to result in atrial ischemia which can induce postoperative arrhythmias and impair the transport function of the atrium. In this study, the effects of simple cardiopulmonary bypass (CPB) (seven pigs) and conventional cardioplegic arrest (CCA) (seven pigs) on right atrial function were evaluated. Function was assessed in an isolated right atrial preparation with a compliant balloon inserted via the superior vena cava. CCA for 1 hr produced significant deterioration in right atrial function (developed pressure 14.1 +/- 0.7 vs 18.9 +/- 0.8 mm Hg, P less than 0.05, diastolic pressure 10.0 +/- 1 vs 4.5 +/- 1.4 mm Hg, P less than 0.05, dP/dt 134 +/- 25 vs 187 +/- 19 mm Hg/sec, P less than 0.05 at a balloon volume of 20 ml after 1 hr of reperfusion). CPB alone caused no alteration in pressures in the right atrium but was associated with a late decrease in dP/dt (developed pressure 19.3 +/- 1.8 vs 18.9 +/- 0.8 mm Hg, diastolic pressure 4.0 +/- 1.2 vs 4.5 +/- 1.4 mm Hg, dP/dt 148 +/- 18 vs 187 +/- 19, P less than 0.05 at a balloon volume of 20 ml at a time corresponding to 1 hr of reperfusion in the CCA group). These results are consistent with the postulate that conventional techniques of cardioplegic arrest are associated with ischemic dysfunction of the right atrium.

Correlation of plasma-derived GFR estimates to endogenous creatrune clearance

This study aimed to determine the correlation between the GFR estimates from plasma-derived formulas (Cockroft-Gault, MDRD, AASK, Nankivell) and the GFR estimates from the clinically conventional 24-hour creatinine clearance method and identify which formula could become a potential substitute for the creatinine clearance method. Another aim was to propose adjusted plasma-derived formulae that apply to the Filipino populationOne hundred and nine volunteers were asked to undergo 24-hour urine collection and blood extraction. The urine and blood samples were then examined by the PGH laboratories, where serum BUN. serum albumin, and serum and urine creatinine were determined. These values, in addition to age, weight, sex, and body surface area, were used to calculate GFR via the Cockroft-Gault, MDRD7, AASK, and Nankivell formulas, as well as via the creatinine clearance method. Subjects whose calculated total creatinine was lower than normal were excluded. A total of 44 subjects were included in the data analysisRegressional analysis was used to measure correlation. The null hypothesis is a=alpha and b=beta or the y-intercept and slope of the formulas and creatinine clearance are equal. A paired t-test with 42 degrees of freedom was used to calculate significance with the critical values t -2.0289 and t2.0189. Among the formulas evaluated, both the AASK formula (r=0.8836, a=0.0056, b=-0.4994) and the MDRD formula for African-Americans (r=0.8589, a=2.4514, b=-0.5998) consistently overestimate the creatinine clearance values. However, the overestimation of the AASK formula is statistically insignificant, while that of the MDRD for African Americans is significant. However, upon the addition of -21.3 for MDRD-African American and -12.99 for AASK equations, respectively, yielded a closer approximation of creatinine clearance values in the sample population (MDRD r=0.8545, a=-0.0004, b=0.1995; AASK: r=0.8589, a=-0.0001 , b=-0.5998), thus formula effectiveness studies on other populations are recommended. Both the Nankivell formula (r=0.8462, a=4.3836, b=-6.2810) and standard MDRD (r=0.8589, a=2.4514, b=-2.6643) formula do not closely correlate with creatinine clearance. The Cockroft-Gault equation (r=0.8836, a=0.0056, b=-0.4994) shows the highest correlation, unadjusted, with corrected creatinine clearance in the selected population and could be recommended as a substitute for creatinine clearance. (Author)