Analyzing sibship correlations in birth weight using large sibships from Norway.

Data from the Medical Birth Registry of Norway were used to estimate sibship correlations in large sibships (each with > or = 5 infants among singleton live births surviving the first year of life), while adjusting for covariates such as infant gender, gestational age, maternal age, parity, and time since last pregnancy. This sample of 12,356 full sibs in 2,462 sibships born in Norway between 1968 and 1989 was selected to maximize the information on parity, and a robust approach to estimating both regression coefficients and the sibship correlation using generalized estimating equations (GEE) was employed. In concordance with previous studies, these data showed a high overall correlation in birth weight among full sibs (0.48 +/- 0.01), but this sibship correlation was influenced by parity. In particular, the correlation between the firstborn infant and a subsequent infant was slightly lower than between two subsequent sibs (0.44 +/- 0.01 vs. 0.50 +/- 0.01, respectively). The effect of time between pregnancies was statistically significant, but its predicted impact was modest over the period in which most of these large families were completed. While these data cannot discriminate whether factors influencing birth weight are maternal or fetal in nature, this analysis does illustrate how robust statistical models can be used to estimate sibship correlations while adjusting for covariates in family studies.

Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations.

To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum IgE concentration. Sib-pair analyses of 10 markers in 345 full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to this region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15-q24.1 region may contain a gene(s) controlling asthma and the associated "high total IgE" trait.

Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian population

To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum Ige concentration. Sib-pair analyses of 10 markers in 345 full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to his region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15-q24.1 region may contain a gene(s) contolling asthma and the associated high total IgE. trait.(AU)

Local recurrence and survival following nerve sparing radical cystoprostatectomy for bladder cancer: 10-year followup.

PURPOSE: The efficacy of nerve sparing radical cystoprostatectomy for the treatment of bladder cancer has been evaluated. We reviewed our 10-year experience with this technique to ascertain survival and local recurrence rates. MATERIALS AND METHODS: The charts of 101 patients treated with nerve sparing cystoprostatectomy between March 1982 and November 1989 were reviewed and updated. RESULTS: The disease-specific 10-year survival rate for all stages of bladder cancer treated was 69% and the 10-year survival rate free of local recurrence was 94%. Recovery of sexual function following nerve sparing cystectomy correlated with patient age: 62% in men 40 to 49 years old, 47% in men 50 to 59 years old, 43% in men 60 to 69 years old and 20% in men 70 to 79 years old. CONCLUSIONS: Nerve sparing radical cystoprostatectomy does not compromise cancer control and provides improved postoperative quality of life.

Genetic basis of IgE responsiveness: relevance to the atopic diseases.

Genetic analysis of 170 subjects in 11 extended Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum IgE levels. No linkage was found between these markers and specific IgE antibody levels. Analysis of total IgE within a subset of 128 IgE-antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially IL4 (p = 4 x 10(-6)). These and other data suggest that IL4 or a nearby gene regulates IgE production in a non-antigen-specific (noncognate) fashion and provide evidence for a possible link between asthma and the IL4 gene.

Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations.

Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum immunoglobulin E (IgE) concentration. No linkage was found between these markers and specific IgE antibody concentrations. Analysis of total IgE within a subset of 128 IgE antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially to the interleukin-4 gene (IL4). A combination of segregation and maximum likelihood analyses provided further evidence for this linkage. These analyses suggest that IL4 or a nearby gene in 5q31.1 regulates IgE production in a nonantigen-specific (noncognate) fashion.

Diastolic mechanical properties of the left ventricle after global ischemia.

The purpose of this study was to evaluate left ventricular (LV) diastolic mechanical properties after induced global ischemia using reliable new methods. The diastolic function of nonoxygenated crystalloid solution (CC sO2) was compared with those of oxygenated crystalloid (CC cO2) and oxygenated fluorocarbon cardioplegic (FC cO2) solutions. Postischemic ventricular performance was studied in 3 equal (no. 7) groups of dogs subjected to 120 minutes of global ischemia induced at an average myocardial temperature of 18.5 +/- 1.4 degrees C. LV diastolic function (chamber and myocardial stiffness) and relaxation (the exponential fall in LV pressure) were evaluated by sonomicrometry and Millar micrometers before ischemia and at 45 and 60 minutes after ischemia. LV chamber and myocardial stiffness in the CC sO2 group was significantly (p less than 0.05) elevated after ischemia, while the CC cO2 and FC cO2 groups did not show increases in LV chamber and myocardial stiffness after ischemia. LV relaxation before and after ischemia was not changed in any group. The myocardial water content of the CC sO2 group was significantly higher than that of the CC cO2 and FC cO2 groups (p less than 0.05). We conclude that (1) the postischemic increase in LV chamber stiffness in the CC sO2 group was dependent not only on the increase in intrinsic myocardial stiffness but also due to an increase in myocardial edema, and (2) there was no correlation between the LV relaxation rate and the leftward shift of diastolic compliance curves in the CC sO2 group.

Myocardial preservation: a comparison of oxygenated crystalloid and blood cardioplegia.

The purpose of this experiment was to compare myocardial protective effect after global ischemia using oxygenated crystalloid (CCcO2) and an oxygenated blood (BCcO2) cardioplegic solutions. Post-ischemic ventricular performance was studied in 2 equal (n = 7) groups of dogs subjected to 120 min of global ischemia induced at average myocardial temperatures of 8 degrees C in the CCcO2 group and 18 degrees C in the BCcO2 group. Left ventricular (LV) function included analysis of LV systolic function (global and regional function), LV diastolic function (chamber and myocardial stiffness) and LV relaxation was measured by sonomicrometry and Millar micrometers. Data were processed with a Dec PDP-11/23 computer. In vitro oxygen content (Vol%) measured 3.2 +/- 1.0 (CCcO2) and 9.5 +/- 0.3 (BCcO2). Percent recoveries of LV global function (LVSP, loop area, % shortening, LV dp/dt, mean VCF and E max) in the CCcO2 group were approximately the same as those in the BCcO2 group. There were no significant differences in LV regional function (loop area and % shortening) after ischemia between the two groups. The chamber and myocardial stiffness after ischemia in the CCcO2 group were almost the same as the baseline values. Values in the BCcO2 group were reduced significantly compared to the baseline level. There were significant differences in post-ischemic chamber and myocardial stiffness between the two groups. Post-ischemic maximum negative LV dp/dt in both groups decreased significantly compared to the baseline values. However, the time constant and diastolic interval after ischemia in both groups were approximately the same as the baseline values. We conclude that there were no significant differences in myocardial protective effect between the CCcO2 and BCcO2 groups, and both methods preserved the ischemic myocardium well.

The significance of colloid osmotic pressure during induced hypothermia.

Colloid osmotic pressure (COP) during hypothermia with and without total circulatory arrest was evaluated in 20 adult mongrel dogs (average body weight = 18.6 kg). All animals were surface-cooled to 20 degrees C (rectal temperature) under halothane-diethyl ether azeotrope anesthesia and divided into 4 equal groups. In Groups I (non-arrest) and II (60 minute-arrest) 10% low molecular weight dextran (LMWD; 1 gm/kg = 10 ml/kg) was administered during cooling. Physiological saline (10 ml/kg) was given in Groups III (non-arrest) and IV (60 minute-arrest) during cooling. COP in LMWD groups increased significantly during cooling and was consistently higher than it was in the saline groups during rewarming. There were no significant differences in heart rate (HR), mean arterial pressure (MAP), central venous (CVP) and pulmonary artery wedge pressures (PAW) between the 4 groups during cooling. The increase in hematocrit (Hct) in animals that received saline was significant at the end of cooling and during rewarming. Hct was not significantly changed in Group I throughout the procedure, whereas in Group II (60 minute-arrest) it increased significantly during rewarming despite the administration of LMWD. Rewarming time in Group II was significantly shorter than in Group IV (144.2 +/- 9.6 min vs 193.2 +/- 32.6 min, respectively). We conclude that the administration of LMWD effectively reduces hemoconcentration and is also beneficial for maintaining better peripheral circulation.

Effects of pulsatile reperfusion on postischemic recovery of myocardial function after global hypothermic cardiac arrest.

It has been postulated that pulsatile blood flow helps to preserve the myocardium after ischemia. However, its effect on postischemic myocardium during cardiopulmonary bypass has not been clearly defined. To determine if pulsatile reperfusion improves postischemic recovery of cardiac metabolism and performance, we subjected 20 dogs to 60 minutes of aortic cross-clamping followed by 45 minutes of pulsatile (P group; 10 dogs) or nonpulsatile (NP group; 10 dogs) reperfusion. Left ventricular function was measured at a controlled preload in both groups before induction of global ischemia and after termination of bypass. Segmental length (assessed by sonomicrometry) was used to determine dimensional changes. Ventricular pressures were measured with solid-state micromanometers. Percent recovery of left ventricular peak systolic pressure, its first derivative, and stroke work were 66%, 59%, and 38%, respectively in the NP group and 82%, 76%, and 65% in the P group. The postarrest decrease in segmental shortening was minimized in the P group; left ventricular function curves and the slope of the end-systolic pressure-length relationship also indicated better performance after pulsatile reperfusion than after nonpulsatile reperfusion. Myocardial lactate extraction was transiently improved during the early pulsatile reperfusion period. We conclude that pulsatile reperfusion provides better myocardial preservation than nonpulsatile perfusion after 60 minutes of induced global ischemia.

Whole body protection during three hours of total circulatory arrest: an experimental study.

Survival following 3 hr of total circulatory arrest under profound hypothermic conditions was explored in 19 adult mongrel dogs. Thermoregulatory management included combined surface/perfusion hypothermia and azeotrope anesthesia in 95% O2/5% CO2. All animals were resuscitated and survived for at least 12 hr. During the last seven trials (Group II) the following principles were applied: uniform whole-body cooling where differences between rectal, esophageal, and pharyngeal temperatures averaged less than 1 degree C, induction of circulatory arrest at approximately 3 degrees C, constant lung inflation (10-12 cm H2O between 20 degrees C cooling and 20 degrees C rewarming, including the 3-hr arrest period) and ventilation assistance with positive end-expiratory pressure (4 cm H2O) after 20 degrees C rewarming, intraoperative maintenance of colloid osmotic pressure (COP) above 11 mm Hg, replacement of the cooling perfusate with a colloid-rich rewarming prime (COP = 15 mm Hg) and restoration of hemostasis with fresh whole blood transfusions. The application of these principles resulted in the long-term survival of five animals with four survivors displaying no clinically detectable neurological abnormalities. However, two animals developed optic impairment and one animal died from intusseption on the fourth postoperative day. Despite the improved results, it should also be noted that during pilot (Group I) studies (from which the aforementioned principles were derived) fatalities from complications attributed to systemic edema, central nervous system, or pulmonary or coagulation dysfunctions occurred in 9 out of 12 trials. We conclude that whole body protection following 3 hr of total circulatory arrest at a uniform temperature less than 5 degrees C can be successfully accomplished.

Effects of varying electrode configuration with catheter-mediated defibrillator pulses at the coronary sinus orifice in dogs.

We compared two methods of delivering single damped sine-wave defibrillator pulses to the coronary sinus orifice in 20 dogs. Ten dogs had "unipolar" (coronary sinus to precordial disc) and 10 had "bipolar" (coronary sinus proximal to coronary sinus distal electrode) discharges. Delivered voltage, current, and energy were recorded during each pulse. Electrophysiologic testing was done before and 4 weeks after the procedure. Histologic examination of the atrioventricular groove was done at 1 mm serial sections. For the unipolar configuration a 200 J defibrillator pulse resulted in a peak voltage of 3370 +/- 125 V, a peak current of 21 +/- 4 A, and a delivered energy of 253 +/- 29 J as compared with 3010 +/- 99 V, 70 +/- 4 A, and 144 +/- 18 J, respectively, for the bipolar configuration (p less than .001). Three dogs (two with bipolar, one with unipolar pulses) had gross coronary sinus rupture and died from acute pericardial tamponade. In addition, irrespective of electrode configuration, all dogs showed microscopic rupture of the coronary sinus internal elastic membrane. Transmural atrial scarring occurred in all 10 dogs that received a unipolar pulse but in only two dogs that received a bipolar pulse (p = .0004). Unlike the atrium, injury to the left ventricle was limited in both groups. Similarly, injury to the periannular myocardium was inconsistent and not transmural in either group. No significant electrophysiologic changes were observed. With the present technique, unipolar rather than bipolar catheter-mediated defibrillator pulses result in transmural atrial injury that might prevent accessory pathway conduction. Regardless of electrode configuration, high-energy defibrillator pulses consistently cause some degree of coronary sinus rupture, most likely related to a barotraumatic mechanism.

Effect of verapamil on regional myocardial contraction during graded ischemia in the dog.

Verapamil benefits patients with angina pectoris during exercise. The mechanism underlying this effect is controversial. A direct oxygen-sparing effect on ischemic myocardium has been proposed, but previous studies seeking to demonstrate this effect have been inconclusive because of inadequate control of systemic hemodynamics. This study has assessed the direct effects of verapamil on regional myocardial contraction during graded coronary flow reductions while blood pressure and heart rate were held constant. Verapamil caused a decrease in regional contraction at normal levels of coronary flow, a finding consistent with a negative inotropic effect. At lower coronary flows, however, ischemic dysfunction was similar in the presence and absence of verapamil. These findings fail to support the concept that verapamil either selectively depresses ischemic myocardium or enhances myocardial function during ischemia. Thus, these direct mechanisms would seem unlikely causes of the observed beneficial effect during exercise in patients with coronary artery disease.

Catheter-mediated electrical ablation of the posterior septum via the coronary sinus: electrophysiologic and histologic observations in dogs.

In a series of 12 dogs, the electrophysiologic and histologic effects of a single damped sine-wave shock delivered via standard electrocatheters to the region of the coronary sinus orifice were investigated. Six dogs received 200 J and six received 360 J of stored energy. The shock was delivered to two consecutive proximal poles of a standard quadripolar catheter positioned at the coronary sinus orifice and connected to the positive output (anode) of a defibrillator. A disc electrode positioned on the anterior chest wall served as the cathode (negative pole). During the shock, voltage and current were recorded. Electrophysiologic testing was done before and 4 weeks after the shock. At 4 weeks, animals were killed and serial sections of the atrioventricular groove and conduction system were performed. No significant long-term change in atrioventricular conduction, spontaneous or induced atrial or ventricular arrhythmias was observed. However, transient atrioventricular block was seen in five and idioventricular rhythms in six animals in the short term. No persistent electrocardiographic changes were observed, and no sudden deaths occurred. Microscopically, transmural injury at the anulus proper or basilar ventricular epicardium was inconstant and infrequent. However, transmural atrial injury at the level of the coronary sinus was produced over a 10 +/- 5 mm length with the 200 J shock and a 21 +/- 6 mm length with the 360 J shock. Neither coronary artery injury nor damage to the conduction system was seen and cardiac tamponade did not occur. However, localized intramural atrial rupture of the coronary sinus wall (on the endocardial aspect only) was observed in each dog, consistent with barotrauma. With the present technique, atrial injury potentially capable of blocking the effects of accessory pathway conduction could be produced without other electrophysiologic alterations or complications. Injury to the anulus proper (and therefore to any accessory pathway per se) is probably unlikely. Barotrauma may play a significant role in the type of injury observed in this study.

The importance of appropriate concentrations of inspired carbon dioxide on induced hypothermia under halothane-ether azeotrope anesthesia.

Thirty adult mongrel dogs were divided into 3 equal groups and studied to define the optimal PCO2 level with azeotrope (halothane-diethyl ether) anesthesia under surface hypothermia (Groups I, II and III = F1CO2 0%, 5% and 10%, respectively). All animals were cooled to 18-20 degrees C and were subjected to 30 (Group I) or 60 minutes (Groups II and III) of total circulatory arrest. Group I animals had frequent arrhythmic episodes during cooling and postoperative motor disturbances occurred in 80% despite only 30 minutes of circulatory arrest. By contrast Group II animals were less arrhythmic during cooling; were easily resuscitated following 60 minutes of arrest and only 30% developed moderate reversible motor disturbances postoperatively. Hemodynamics were similar between Groups II and III during cooling but resuscitation using an F1CO2 of 10% (Group III) was extremely difficult and required massive cardiotonic support throughout rewarming. Furthermore, two dogs in Group III died within the first two postoperative days. However, none of the 8 survivors displayed neurological abnormalities. On balance, a ventilatory regimen utilizing 5% CO2 during surface-induced hypothermia under azeotrope anesthesia resulted in optimum intraoperative management and a satisfactory postoperative course and although some CNS disturbance (high-stepping gait) was noted, all animals recovered completely.

The role of respiratory infection in intrathoracic petechiae. Implications for sudden infant death.

Intrathoracic petechiae are characteristic of the postmortem changes found in sudden infant death syndrome. The presence and distribution of these petechiae have been claimed as evidence for airway obstruction as the mechanism of death. In a group of young, mature rats that were free of infection, hypoxic asphyxia produced an insignificant number of petechiae, whereas in all littermates infected with an enzootic virus (Sendai) large numbers of petechiae with hypoxic asphyxia developed. Rats similarly infected, but killed with an overdose of pentobarbital sodium, had no petechiae. Most importantly, infected rats with unremitting airway obstruction were free of petechiae. Thus, the experimental conditions necessary for the presence of intrathoracic petechiae are profound hypoxia and infection, with persistent circulation and respiratory effort; persistent airway obstruction does not produce petechiae, with or without infection.