Etiologic theories of idiopathic scoliosis: autonomic nervous system and the leptin-sympathetic nervous system concept for the pathogenesis of adolescent idiopathic scoliosis.

The autonomic nervous system through its hypothalamic neuroendocrine control of puberty, skeletal growth and menarche contributes importantly to the pathogenesis of adolescent idiopathic scoliosis (AIS). Melatonin dysfunction detected in AIS subjects also involves the autonomic nervous system. The thoracospinal concept for the pathogenesis of right thoracic AIS in girls thought by some to result from dysfunction of the sympathetic nervous system (SNS), is supported by recent vascular and peripheral nerve studies. Lower body mass index (BMI).in girls with AIS is associated with decreased circulating leptin levels. Leptin, secreted by adipocytes, is a master hormone with many regulatory functions for growth and reproduction, including: 1) appetite repression, anorexigenic; 2) initiation of puberty in girls in a permissive action, and 3) in mice, longitudinal bone growth, chondrogenic and angiogenic, and in bone formation, antiosteogenic acting centrally through the SNS and possibly directly. In AIS girls, autonomic nervous system activity was reported to be higher than in controls. We suggest that in AIS susceptible girls, given adequate nutrition and energy stores, circulating leptin talks to the hypothalamus where dysfunction leads to an altered sensitivity to leptin resulting in increased SNS activity contributing with neuroendocrine mechanisms to: 1) earlier age at, and increased peak height velocity, 2) general skeletal overgrowth, 3) earlier skeletal maturation, 4) extra-spinal skeletal length asymmetries, including periapical ribs and ilia, 5) generalized osteopenia, and 6) lower BMI. The SNS-driven effects may also add adventitious changes to the spine including asymmetries complicating the neuroendocrine effects on adolescent spinal growth. In AIS pathogenesis, the leptin-SNS concept is complementary to our NOTOM escalator concept involving the somatic nervous system. Together these two concepts view AIS in girls as being initiated by a hypothalamic dysfunction of energy metabolism (bioenergetics) affecting skeletal growth in the trunk. Where, in susceptible girls, the postural mechanisms of the somatic nervous system fail to control the asymmetric spinal and/or rib growth changes in a rapidly enlarging adolescent spine; this failure becomes evident as mild back-shape shape asymmetry, or scoliosis. The environmentally-enhanced stature of normal subjects in the last 300 years, in girls susceptible to AIS, may have exaggerated any developmental dysharmony between the autonomic and somatic nervous systems being fought out in the spine and trunk of the girl - possibly making mild back-shape asymmetry, or scoliosis more prevalent today than hitherto.

Body mass index of girls in health influences menarche and skeletal maturation: a leptin-sympathetic nervous system focus on the trunk with hypothalamic asymmetric dysfunction in the pathogenesis of adolescent idiopathic scoliosis?

Lower body mass index (BMI) and lower circulating leptin levels have been reported in girls with AIS. In this paper we evaluate skeletal sizes and asymmetries by higher and lower BMI subsets about the means for each of three groups of girls age 11-18 years: 1) normals, 2) school screening referrals, and 3) preoperative girls. Higher and lower BMI subsets, likely to have separated subjects with higher from those with lower circulating leptin levels, identify: 1) girls with relatively earlier and later menarche; 2) trunk width size greater in the higher than in the lower BMI subset, of all three groups; 3) abnormal upper arm length (UAL) asymmetries (right minus left) in the lower BMI subset of the preoperative girls; and 4) in thoracic AIS of screened and preoperative girls, Cobb angle and apical vertebral rotation each significantly and positively correlate with UAL asymmetry in the lower BMI subset but not in the higher BMI subset. In preoperative girls, the lower BMI subset shows the combination of relatively reduced pelvic width and abnormal UAL asymmetry, suggesting that both are linked to lower circulating leptin levels. An earlier puberty with hormonal changes provides a plausible explanation for the larger trunk width at the shoulders and pelvis especially at the younger ages in the higher BMI subsets. At the shoulders, this widening is driven by the ribcage which, in human evolution was acquired with decoupling of head and trunk movements required for efficient bipedal gait. The UAL asymmetry patterns within the groups and BMI subsets are not explained by hormonal mechanisms. It is hypothesized that 1) normal trunk widening of the thoracic cage by hormones in human adolescence is supplemented via the sympathetic nervous system under leptin-hypothalamic control influenced by energy stores (metabolic fuel); and 2) hypothalamic dysfunction with altered hypothalamic sensitivity to leptin through a SNS-driven asymmetric effect may create skeletal length asymmetries in upper arms, ribs, ilia and vertebrae, and initiate AIS. Additional mechanisms acting in the spine and trunk may be required for AIS to progress including 1) somatic nervous system dysfunction, 2) biomechanical spinal growth modulation, and 3) osteopenia.

Ultrasound femoral anteversion (FAV) relative to tibial torsion (TT) is abnormal after school screening for adolescent idiopathic scoliosis (AIS): evaluation by two methods.

In the scoliotic spine, torsion is generally evaluated in relation to axial rotation of the apical vertebra. In the lower limbs, the changes in torsion by age of femoral anteversion (FAV) relative to tibial torsion (TT) have been studied in dried bones, normal growing subjects and adults and subjects with osteoarthritis of the hip or the knee. This paper reports the application of real-time ultrasound to FAV and TT in normal children age 11-18 years and in scoliosis screening referrals with particular reference to how FAV relates to TT as 1) ratios, and 2) tibio-femoral index (TFI) of torsion, calculated as TT minus femoral FAV. The FAV/TT ratio findings show an abnormal normal relationship of FAV to TT both proximo-distally and in left-right asymmetry. These may express torsional abnormalities in femoral and/or tibial growth plates with left-right asynchrony suggesting the possibility of similar torsional abnormalities in vertebral end-plates and/or rib growth plates initiating the deformity of AIS. TFI of the right limb in the scoliosis girls is greater than in the normals that is interpreted as resulting from earlier skeletal maturation of FAV. FAV/TT ratios and TFI are unrelated to the spinal deformity (Cobb angle and apical vertebral rotation) except for boys where TFI is associated with apical vertebral rotation. FAV/TT ratios may be a more accurate method estimating the relationship of FAV to TT. than TFIs.

Leg-arm length ratios correlate with severity of apical vertebral rotation in girls after school screening for adolescent idiopathic scoliosis (AIS): a dynamic pathomechanism in the initiation of the deformity?

There is increasing support for the view that the unique human bipedalism and the erect posture are prerequisites for the pathogenesis of adolescent idiopathic scoliosis (AIS). How human bipedalism may contribute to the pathogenesis of AIS is not clear. In normal humans, axial rotations and counter-rotations of the trunk are carried out frequently and forcibly in activities that are not performed by quadrupeds. Some workers have analysed gait in AIS subjects, others have studied torsions in lower limb bones, but there are only two reports on leg-arm ratios in relation to AIS. In this paper, leg-arm ratios studied in relation to the spinal deformity in scoliosis screening referrals, reveal a highly significant correlation with the apical vertebral rotation but not the Cobb angle of the scoliosis curves. We suggest that leg-arm proportions and movements during gait involving pelvi-spinal axial rotations and thoracic counter-rotations contribute a dynamic pathomechanism to early AIS from whatever cause and involving the thoracic cage. Curve progression needs other mechanisms that may include a central nervous system failure to control structural asymmetry of vertebral axial rotation, and biomechanical spinal growth modulation.

Ultrasound femoral anteversion (FAV) and tibial torsion (TT) after school screening for adolescent idiopathic scoliosis (AIS).

Torsion and counter-torsion in the spine are features of the three-dimensional deformity of adolescent idiopathic scoliosis, Vertebral axial rotation has recently been found in the normal adult thoracic spine. Torsion in the lower limbs, femora and tibiae is a feature of normal human skeletal postnatal development. In recent years, femoral anteversion (FAV) and tibial torsion (TT) have been studied in normal children by imaging techniques, especially ultrasound. This paper reports summaries of the application of real-time ultrasound to FAV and TT of normal children and scoliosis school screening referrals. In the scoliosis girls and boys, the FAV decrease and FAV asymmetry compared with normals may result from abnormally increased femoral detorsion maturationally earlier with left-right asynchrony which, if repeated as a growth plate anomaly in the trunk (spine and/or periapical ribs), might initiate the AIS deformity, given other requirements. In scoliosis boys relative to girls, the TT decrease without asymmetry may result from sexually dimorphic maturation at knee tibial growth plates ? maturationally delayed TT with left-right synchrony.

The posterior skeletal thorax: rib-vertebral angle and axial vertebral rotation asymmetries in adolescent idiopathic scoliosis.

The deformity of the ribcage in thoracic adolescent idiopathic scoliosis (AIS) is viewed by most as being secondary to the spinal deformity, though a few consider it primary or involved in curve aggravation. Those who consider it primary ascribe pathogenetic significance to rib-vertebra angle asymmetry. In thoracic AIS, supra-apical rib-vertebra angle differences (RVADs) are reported to be associated with the severity of the Cobb angle. In this paper we attempt to evaluate rib and spinal pathomechanisms in thoracic and thnoracolumbar AIS using spinal radiographs and real-time ultrasound. On the radiographs by costo-vertebral angle asymmetries (rib-vertebral angle differences RVADs, and rib-spinal angle differences RSADs), apical vertebral rotation (AV) and apical vertebral translation (AVT) were measured; and by ultrasound, spine-rib rotation differences (SRRDs) were estimated. RVADs are largest at two and three vertebral levels above the apex where they correlate significantly and positively with Cobb angle and AVT but not AVR. In right thoracic AIS, the cause(s) of the RVA asymmetries is unknown: it may result from trunk muscle imbalance, or from ribs adjusting passively within the constraint of the fourth column of the spine to increasing spinal curvature from whatever cause. Several possible mechanisms may drive axial vertebral rotation including, biplanar spinal asymmetry, relative anterior spinal overgrowth, dorsal shear forces in the presence of normal vertebral axial rotation, asymmetry of rib linear growth, trunk muscle imbalance causing rib-vertebra angle asymmetry weakening the spinal rotation-defending system of bipedal gait, and CNS mechanisms.

Patterns of extra-spinal left-right skeletal asymmetries in adolescent girls with lower spine scoliosis: relative lengthening of the ilium on the curve concavity & of right lower limb segments.

Extra-spinal skeletal length asymmetry have been reported for the upper limbs and periapical ribs of patients with thoracic adolescent idiopathic scoliosis. This paper reports (1) a third pattern with relative lengthening of the ilium on the concavity of lower spine scolioses, and (2) a fourth pattern of relative lengthening of the right total leg and right tibia unrelated statistically to the severity or side of lower spinal scolioses. The findings pose the question: are these anomalous extra-spinal left-right skeletal length asymmetries unconnected with the pathogenesis of AIS. Or, are they indicative of what may also be happening to some vertebral physes as an initiating pathogenic mechanism for the scoliosis?

Left-right upper arm length asymmetry associated with apical vertebral rotation in subjects with thoracic scoliosis: anomaly of bilateral symmetry affecting vertebral, costal and upper arm physes?

Left-right skeletal length asymmetries in upper limbs related to curve side and severity have been detected with adolescent idiopathic scoliosis (AIS). This paper reports upper arm length asymmetry in thoracic scoliosis related significantly to apical vertebral rotation in school screening referrals. The reason(s) for the association of upper arm length asymmetry with apical vertebral rotation is unknown and three factors are considered: (1) neuromuscular mechanisms from primary or secondary causes, (2) relative concave neurocentral synchondrosis overgrowth, and (3) relative concave periapical rib length overgrowth, A putative anomaly of growth plates (physes) of ribs, neurocentral synchondroses and upper arms, would account for the findings. A solution to this dilemma may emerge from the results of surgery should concave periapical rib resections become evaluated further for right thoracic AIS in girls.

Patterns of extra-spinal left-right skeletal asymmetries and proximo-distal disproportion in adolescent girls with lower spine scoliosis: ilio-femoral length asymmetry & bilateral tibial/foot length disproportion.

Anomalous extra-spinal left-right skeletal length asymmetries have been detected in girls with adolescent idiopathic (AIS) in four sites (1) upper limbs, (2) periapical ribs, (3) ilium, and (4) right leg and right tibia. This paper on adolescent girls with lower spine scoliosis reports (1) a fifth pattern of left-right ilio-femoral length asymmetry associated with sacral alar height asymmetry, and (2) bilateral anomalous lengthening of the tibia relative to the foot. The findings are consistent with the hypothesis that at the time of diagnosis of AIS in girls there are anomalies of skeletal proportions associated with a predisposition to curve progression; these proportions are in three dimensions--left-right, cephalo-caudal in the trunk (proximo-distal in the lower limbs), and front-back in the trunk. The origin of these anomalies is unknown but possible causes, and of the associated AIS, are genetic and environmental factors acting in embryonic life not expressed phenotypically until years after birth.

Etiologic theories of idiopathic scoliosis: the breaking of bilateral symmetry in relation to left-right asymmetry of internal organs, right thoracic adolescent idiopathic scoliosis (AIS) and vertebrate evolution.

In the search to understand the etiology and pathogenesis of adolescent idiopathic scoliosis (AIS) some workers have focused on mechanisms initiated in embryonic life including a disturbance of bilateral (left-right or mirror-image) symmetry highly conserved in vertebrates. The normal external bilateral symmetry of vertebrates results from a default process involving mesodermal somites. The normal internal asymmetry of the heart, major blood vessels, lungs and gut with its glands is also highly conserved among vertebrates. It results from the breaking of the initial bilateral symmetry by a binary asymmetry switch mechanism producing asymmetric gene expression around the embryonic node and/or in the lateral plate mesoderm. In the mouse this switch occurs during gastrulation by cilia driving a leftward flow of fluid and morphogen(s) at the embryonic node (nodal flow) that favors precursors of the heart, great vessels and viscera on the left. Based on the non-random laterality of thoracic AIS curves, the hypothesis is suggested that an anomaly of the binary asymmetry switch explains the excess of right/left thoracic AIS. Some support for this hypothesis is the prevalence of right and left scoliosis curve laterality associated with situs inversus. There is recent evidence that vertebrates within their bilateralised shell retain an archaic left-right asymmetric visceral body organization evident in thoracic and abdominal organs.

Etiologic theories of idiopathic scoliosis: enantiomorph disorder concept of bilateral symmetry, physeally-created growth conflicts and possible prevention.

The detection of anomalous extra-spinal left-right skeletal length asymmetries in the upper limbs, periapical ribs, ilia and lower limbs of subjects with adolescent idiopathic scoliosis (AIS) raises questions about skeletal bilateral symmetry of vertebrates in health and disorder, its origin and control. The vertebrate body plan externally has mirror-image bilateral symmetries that are highly conserved culminating in the adult form. The normal human body can be viewed as containing paired skeletal structures in the axial and appendicular skeleton as 1) separate left and right paired forms (eg long limb bones, ribs, ilia), and 2) united in paired forms (eg vertebrae, sternum, skull, mandible). Each of these separate and united pairs are mirror-image forms--enantiomorphs. Left-right asymmetries of growth plates (physes) may cause (1) in long bones length asymmetries, (2) within one or more vertebral physes putative growth conflict with distortion as deformity, and (3) between ribs and vertebrae putative growth conflict that triggers thoracic AIS suggesting preventive surgery on spine and ribs. There is evidence of a possible role for environmental factors in AIS development. Genes and the environment (nature/nurture) may interact pre- and/or post-natally to explain both the deformity of AIS and its association with widespread anomalous skeletal length asymmetries. If substantiated there may ultimately be a place for the prevention of AIS in some subjects.

Etiologic theories of idiopathic scoliosis: neurodevelopmental concept of maturational delay of the CNS body schema ("body-in-the-brain").

Several workers consider that the etiology of adolescent idiopathic scoliosis (AIS) involves undetected neuromuscular dysfunction. During normal development the central nervous system (CNS) has to adapt to the rapidly growing skeleton of adolescence, and in AIS to developing spinal asymmetry from whatever cause. Examination of evidence from (1) anomalous extra-spinal left-right skeletal length asymmetries, (2) growth velocity and curve progression, and (3) the CNS body schema, parietal lobe and temporoparietal junction, led us to propose a new etiologic concept namely of delay in maturation of the CNS body schema during adolescence. In particular, the development of an early AIS deformity at a time of rapid spinal growth the association of CNS maturational delay results in the CNS attempting to balance a lateral spinal deformity in a moving upright trunk that is larger than the information on personal space (self) already established in the brain by that time of development. It is postulated that the CNS maturational delay allows scoliosis curve progression to occur - unless the delay is temporary when curve progression would cease. The putative maturational delay in the CNS body schema may arise (1) from impaired sensory input: (2) primarily in the brain; and/or (3) from impaired motor output. Oxidative stress with lipid peroxidation in the nervous system may be involved in some patients. The concept brings together many findings relating AIS to the nervous and musculo-skeletal systems and suggests brain morphometric studies in subjects with progressive AIS.

Diabetic myocardial infarction. Interaction of diabetes with other preinfarction risk factors.

To assess the effect of diabetes on outcome after acute myocardial infarction (MI), we compared a cohort of 228 type II (non-insulin-dependent) diabetic patients who had sustained acute MI with a similar number of nondiabetic patients with MI. Thirty-day mortality was greater in the diabetic group (27 vs. 17%). However, diabetic patients were older and had more cardiovascular disease before MI. Analyses accounting for such baseline risk revealed a complex effect of diabetes. The relative risk (RR) of dying from MI due to diabetes was greatest among patients with lowest baseline risk (RR 7.3) and least among those at highest baseline risk (RR 0.83). These effects were most striking with transmural MI, which was highly lethal for those with diabetes. Analyses with pulmonary edema as the endpoint support the significant risk conferred by diabetes and its interaction with baseline risk. Diabetes is a risk factor for poor outcome after MI, particularly among patients whose pre-MI cardiovascular status otherwise appears normal.

Risk factors for stroke in patients with nonrheumatic atrial fibrillation: a case-control study.

PURPOSE: Randomized controlled trials have demonstrated that anticoagulant therapy is very effective at preventing stroke among patients with nonrheumatic atrial fibrillation. However, these trials have reported too few strokes for powerful risk factor analysis. Observational studies may provide additional information. The purpose of this study was to identify risk factors in a larger number of patients with stroke and nonrheumatic atrial fibrillation, using case-control methodology. PATIENTS AND METHODS: We identified all patients discharged from one hospital over an 8-year period who met our case definition of nonrheumatic atrial fibrillation and ischemic stroke (n = 134), and compared them with contemporaneous control subjects who were discharged with nonrheumatic atrial fibrillation without stroke (n = 131). RESULTS: Cases and controls were similar in terms of duration of atrial fibrillation; proportion with paroxysmal atrial fibrillation; percentage with a past medical history of angina, myocardial infarction, congestive heart failure, diabetes, or smoking; and mean left atrial size. In contrast, cases were significantly older than controls (78.5 versus 74.8 years, p = 0.002) and more likely to have a history of hypertension (55% versus 38%, p = 0.0093). The relative odds for stroke was 1.91 for patients with hypertension, 1.73 for patients older than 75 years, and 3.26 for patients with both factors. CONCLUSIONS: Our analysis suggests that age and hypertension should be considered when deciding upon long-term anticoagulant therapy to prevent stroke in patients with nonrheumatic atrial fibrillation.

Specific prolongation of skin graft survival following retroviral transduction of bone marrow with an allogeneic major histocompatibility complex gene.

Engrafted allogeneic hematopoietic cells have a unique capacity to induce a state of donor-specific transplantation tolerance across major histocompatibility complex barriers. This state allows permanent acceptance of donor-type organ grafts, with otherwise normal immunocompetence. We hypothesized that introduction of allogeneic MHC genes into autologous bone marrow which is then returned to recipient mice might similarly induce specific tolerance to products of the introduced MHC genes, without the risk of graft-vs-host disease. We demonstrate here that the introduction of MHC class I Kb cDNA by retrovirus-mediated gene transfer into B10.AKM (Kk) hematopoietic cells confers specific hyporesponsiveness to allogeneic skin grafts expressing Kb.

Primary definitive repair of type B interrupted aortic arch, ventricular septal defect, and patient ductus arteriosus. Early and late results.

Since March, 1974, eight patients, aged 7 days to 5 months, with type B interrupted aortic arch (IAA), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) were treated at the Columbus-Presbyterian Medical Center and the University of Maryland Hospital. Six of these patients underwent definitive repair utilizing deep hypothermia and circulatory arrest. Correction involved resection of all ductal tissue, primary anastomosis of the aortic arch, closure of the foramen ovale, and patch closure of the VSD. In five patients, all arch vessels were preserved and no prosthetic material was used to reconstruct the aortic arch. One patient died 48 hours postoperatively of a coagulopathy. All others survived more than 30 days. One patient, 3 1/2 months old at repair, had undergone pulmonary artery banding at another institution at 11 days of age; he died of recurrent respiratory infections 8 months after correction. Three patients are alive and well 3 to 6 years after repair. Two have undergone repeat cardiac catheterization which demonstrated good growth of the anastomosis and no residual gradient. Primary definitive correction of type B IAA with VSD and PDA provides distinct advantages over palliative or other surgical procedures with excellent long-term results.

Pulmonary resection for invasive Aspergillus infections in immunocompromised patients.

Standard antifungal medical therapy of invasive pulmonary aspergillosis that occurs in immunocompromised patients with hematologic diseases with neutropenia or in liver transplant recipients results in less than a 5% survival. In view of these dismal mortality rates, we adopted an aggressive approach with resection of the involved area of lung along with systemic antifungal therapy when localized invasive pulmonary aspergillosis developed in these patients. Between January 1987 and December 1993, 14 patients with hematologic diseases and 2 liver transplant recipients underwent resection of acute localized pulmonary masses suggestive of invasive pulmonary aspergillosis a median of 7.5 days (range 1 to 45 days) after the diagnosis was clinically suggested and confirmed by chest computed tomographic scans. Operative procedures done included two pneumonectomies, one bilobectomy with limited thoracoplasty, nine lobectomies, and five wedge resections (one patient with hematologic disease had two procedures). All patients were treated before and after the operation with antifungal agents. Nine (64%) of 14 patients with hematologic disease and 2 (100%) of 2 liver transplant recipients survived the hospitalization with no evidence of recurrent Aspergillus infection after a median 8 months of follow-up (range 3 to 82 months). The five hospital deaths (all patients with hematologic diseases) occurred a median of 20 days after operation from diffuse alveolar hemorrhage in three, graft-versus-host disease in one, and multiple organ system failure with presumed disseminated Aspergillus infection in one. Four of the five deaths were in patients with allogeneic bone marrow transplants. Two of the three patients requiring resection of multiple foci of infection died, as did the only patient who was preoperatively ventilator dependent. In immunocompromised patients with hematologic diseases or liver transplantation with invasive pulmonary aspergillosis, early pulmonary resection should be strongly considered when the characteristic clinical and radiographic pictures appear.

Pulmonary atresia with intact ventricular septum. Sixteen-year experience.

Infants with pulmonary atresia and intact ventricular septum (PA-IVS) usually require urgent surgical intervention. Thirty patients with this anomaly, seen at the Columbia-Presbyterian Medical Center between 1962 and 1978, had palliative operations, 26 within the first 3 days of life. Six underwent a closed pulmonary valvotomy alone, with no survivors; six had only a systemic--pulmonary artery shunt, with three early survivors. Because of this experience, 17 had a combined procedure of valvotomy and shunt, with 14 early survivors. One patient recently underwent a definitive right ventricular outflow patch procedure with cardiopulmonary bypass. Eight patients subsequently have had corrective open-heart procedures, with five patients surviving from 2 to 10 years. A unicusp aortic homograft was used for repair in five and a Hancock valved conduit in three. Four patients are presently awaiting operation. We conclude that the initial surgical management of these critically ill infants must not only increase pulmonary blood flow but in addition provide an opportunity for right ventricular growth. Thus we continue to advocate the combined procedure of a valvotomy plus a shunt to provide adequate palliation. Repeat catheterization should be performed within a year to confirm the adequacy of the valvotomy, since this is essential to maximal right ventricular enlargement and to allow for definitive correction at a later date.

Subclavian flap repair of coarctation of the aorta in neonates. Realization of growth potential?

The subclavian flap repair for coarctation of the aorta allows potential for growth by utilizing autogenous tissue. Although well documented in young children, its promise in the tiny neonate warrants further evaluation. Since August, 1979, 29 patients, including 24 infants, have undergone subclavian flap repair at the University of Maryland Hospital. Weights ranged from 1.4 to 5 kg (mean 3.2 kg). All patients less than 6 months old had associated intracardiac defects and were in severe congestive failure. Fifteen responded to preoperative prostaglandin infusions. The overall early mortality was 14%; among the neonates it was 21%; and among those operated upon within the first week of life, 33%. There was one intraoperative death among the eight patients who underwent simultaneous pulmonary artery banding. There were no deaths among patients older than 5 days at operation. Four of the five neonates who died had some variant of hypoplastic left heart syndrome, with severe stenosis or atresia of the systemic atrioventricular valve, critical aortic stenosis, or hypoplastic left ventricle. Twenty-two survivors continue to do well up to 3.7 years postoperatively (mean follow-up 26 months). At follow-up all patients are normotensive with brisk lower extremity pulses. Patients now weigh 1.3 to 6.9 (mean 2.3) times their operative weight, and only one patient has a measured arm-to-leg gradient greater than 10 mm Hg (mean gradient 3.7 mm Hg). Seven of the neonates have undergone repeat catheterization, and all had satisfactory growth of the subclavian flap segment of repair and no gradient. Two older patients (3 and 4 years old at operation) have undergone exercise testing 3.7 years after repair, with peak exercise gradients of only 7 and 15 mm Hg. We therefore continue to utilize this technique for the treatment of coarctation even in tiny neonates.

Development of databases and registries. International issues.

This paper describes the U.S. Public Health Service (PHS) efforts to develop a National Xenotransplantation Registry (NXR). The function of the registry is discussed, paying particular attention to data collection and harmonization issues. The need for standardization and coordination on an international scale is presented and the benefits of such efforts are discussed. Finally, a recommendation for an international effort aimed at harmonization is made.