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PubMed2000

Combined immunodeficiencies due to defects in signal transduction: defects of the gammac-JAK3 signaling pathway as a model.

Combined immune deficiencies comprise a spectrum of genetic disorders characterized by developmental or functional defects of both T and B lymphocytes. Recent progress in cell biology and molecular genetics has unraveled the pathophysiology of most of these defects. In particular, the most common form of severe combined immune deficiency in humans, with lack of circulating T cells, a normal or increased number of B lymphocytes, and an X-linked pattern of inheritance (SCIDXI) has been shown to be due to defects of the IL2RG gene, encoding for the common gamma chain (gammac), shared by several cytokine receptors. Furthermore, defects of the JAK3 gene, encoding for an intracellular tyrosine kinase required for signal transduction through gammac-containing cytokine receptors, have been identified in patients with autosomal recessive T-B+ SCID. Characterization of the functional properties of cytokines that signal through the gammac-JAK3 signaling pathway has been favored by the detailed analysis of SCID patients. Specifically, the key role of IL-7 in promoting T cell development has been substantiated by the identification of rare patients with T-B+ SCID who have a defect in the alpha subunit of the IL-7 receptor (IL7Ralpha). The heterogeneity of genetic defects along the same signaling pathway that may lead to combined immune deficiency is paralleled by the heterogeneity of immunological phenotypes that may associate with defects in the same gene, thus creating a need for detailed immunological and molecular investigations in order to dissect the spectrum of combined immune deficiencies in humans.

Animals↗

PubMed2006

From planar defect in opal to planar defect in inverse opal.

We demonstrate a facile method of fabricating opal and inverse opal structures with a planar defect. A single layer of silica beads was embedded into polystyrene opals by combining an inward-growing self-assembly method with spin-coating technique. After the infiltration of silica followed by the removal of the polystyrene beads by calcination, an inverted structure was obtained. The silica beads were connected together by the infiltrated silica, thus a solid silica phase with the silica beads as a planar defect embedded in the inverse silica opal was obtained. The thickness of the defect layer can be adjusted by changing the size of the silica beads. Scanning electron microscope images showed the good quality of the crystal and the uniformity of the defect layer. Optical transmission spectra indicated the existence of a defect state induced by the defect layer in both the opal and inverse opal structures. High-cost techniques such as lithography and chemical vapor deposition are not involved in the fabrication of inverse opals with planar defects.

Journal Article↗

PubMed1999

Estimation of defect volume in segmental defects of the tibia and femur.

BACKGROUND: With the advent of modern limb salvage techniques, segmental bone loss in the lower extremity has become more common. METHODS: To aid preoperative planning when dealing with segmental bone loss in the femur and tibia, we performed a cadaveric study to estimate the volume of autogenous or allograft material required to fill defects located in various areas of the bones. RESULTS: The greatest volume was generally required in metaphyseal defects, with an average of 12 cc/cm in the distal femur and proximal tibia, 11 cc/cm in the proximal femur, and 6 cc/cm in the distal tibia. Diaphyseal defects were found to have the least variability with regard to the volume of graft material required for different specimens. Femoral diaphyseal defects required 7 cc/cm and tibial diaphyseal defects required 5 cc/cm. A slightly larger volume of allograft material was needed to fill all defects compared with autograft. CONCLUSION: This method allows one to estimate the amount of graft required for a defect of the femur and the tibia.

Anthropometry↗

PubMed2002

Secretory-defect distal renal tubular acidosis is associated with transporter defect in H(+)-ATPase and anion exchanger-1.

Recent progress in molecular physiology has permitted us to understand pathophysiology of various channelopathies at a molecular level. The secretion of H(+) from alpha-intercalated cells is mediated by apical plasma membrane H(+)-ATPase and basolateral plasma membrane anion exchanger-1 (AE1). Studies have demonstrated the lack of H(+)-ATPase immunostaining in the intercalated cells in a few patients with distal renal tubular acidosis (dRTA). Mutations in H(+)-ATPase and AE1 gene have recently been reported to cause dRTA. This study extends the investigation of the role of transporter defect in dRTA by using immunohistochemical methods. Eleven patients with hyperchloremic metabolic acidosis were diagnosed functionally to have secretory-defect dRTA: urine pH >5.5 during acidemia, normokalemia or hypokalemia, and urine-to-blood pCO(2) <25 mmHg during bicarbonaturia. Renal biopsy tissue was obtained from each patient, and immunohistochemistry was carried out using antibodies to H(+)-ATPase and AE1. For comparison, renal tissues from the patients who had no evidences of distal acidification defect by functional studies were used: four with glomerulopathy or tubulointerstitial nephritis (disease controls) and three from nephrectomized kidneys for renal cell carcinoma (normal controls). The H(+)-ATPase immunoreactivity in alpha-intercalated cells was almost absent in all of the 11 patients with secretory-defect dRTA. In addition, 7 of 11 patients with secretory-defect dRTA were accompanied by negative AE1 immunoreactivity. In both disease controls and normal controls, the immunoreactivity of H(+)-ATPase and AE1 was strong in alpha-intercalated cells. In conclusion, significant defect in acid-base transporters is the major cause of secretory-defect dRTA.

Acidosis, Renal Tubular↗

PubMed1999

Birth defects: prevention of neural tube defects by periconceptional use of folic acid and screening.

Folate deficiency is one of today's most common vitamin deficiencies in women. Women who consume a low level of folate during pregnancy are at risk for poor pregnancy outcomes including birth defects. Birth defects are the leading cause of fetal and infant deaths throughout the world. Neural tube defects comprise a major portion of the birth tube defects. Neural tube defects are common and serious malformations that originate early in pregnancy. Each year in the US, about 4000 babies are born with these two most common neural tube defects, spina bifida and anencephaly. Spina bifida is the leading cause of childhood paralysis. Several studies showed that about 70% of the neural tube defects could be prevented if all women capable of becoming pregnant consumed 0.4 mg of folic acid daily before and during early pregnancy. This paper reports results from various human and animal studies.

Biology↗

PubMed1986

Mechanism of defective NK cell activity in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. I. Defective trigger on NK cells for NKCF production by target cells, and partial restoration by IL 2.

Peripheral blood from patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) exhibits poor NK activity in the 51Cr-release assay. The present studies were undertaken to investigate the mechanism underlying the observed defective NK cytotoxic activity. On the basis of our studies on the mechanism of natural killer cell-mediated cytotoxicity (NKCMC), a defective NK cell can result from lack or decreased frequency of effector cells, inability to recognize and bind the target cell, failure to be activated for the release of NK cytotoxic factors (NKCF), and/or failure to synthesize or secrete NKCF. Each of these various possibilities was examined. Single cell analysis revealed that the frequency of NK cells was comparable to controls, and although the NK cells bind to the NK-sensitive target, the bound target is not lysed. These results suggested that the defect in NK cells was not due to depletion of NK cells or to a defect in recognition structures, but that it was located at the postrecognition event. We previously demonstrated that after binding to target, the NK cell is stimulated to release NKCF in the supernatants and NKCF lyse specifically NK-sensitive targets. Accordingly, we investigated the activation of NK cells from AIDS and ARC patients for release of NKCF. After coculture with the stimulator cell, the patients' NK cells failed to release active NKCF in the supernatant. However, the cells released NKCF after stimulation with the lectin Con A or a mixture of TPA and ionophore, albeit to a lesser extent than controls. These results suggested that AIDS and ARC NK cells are defective in the trigger involved in release of NKCF. Further studies were done to investigate whether the immunomodulator IL 2 can restore the functional activity of the defective NK cells. Treatment with IL 2 resulted in augmented NK cytolytic activity, but did not reach control levels of activated cells from normal controls. Furthermore, the patients' IL 2-treated cells recover partially the ability to be stimulated by NK cells and to release NKCF. These results suggest that the trigger for NKCF production and the cytolytic function of the patients' NK cells are regulated by IL 2. By delineating the stage at which the AIDS and ARC NK cells are defective, it is now possible to monitor their recovery and to investigate the effect of various biologic response modifiers in restoring NK activity.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Frequency of circumferential pericardial effusion by echocardiography in adults with foramen ovale type atrial septal defect versus ventricular septal defect.

Many published reports have described pericardial effusions in patients with secundum atrial septal defects. This study investigated their associated prevalence echocardiographically using 40 patients with isolated ventricular septal defects as controls in an adult patient population. Pericardial effusions accompanied atrial septal defects in 13 patients and ventricular septal defects in only 3 patients (p <0.0001). In conclusion, pericardial effusions are much more common (p <0.005) with uncomplicated secundum atrial septal defects than with uncomplicated ventricular septal defects.

Adult↗

PubMed2004

Does Down syndrome affect the long-term results of complete atrioventricular septal defect when the defect is repaired during the first year of life?

BACKGROUND: Down syndrome is known to affect the natural history of complete atrioventricular septal defect. We analyzed whether Down syndrome affect the long-term results of complete atrioventricular septal defect when the defect is repaired during the first year of life. METHODS: Repairs of complete atrioventricular septal defect were performed in 64 infants. Thirty-four infants were associated with Down syndrome, while the other 30 were non-Down patients. RESULTS: Complete follow-up rate was 95% with mean follow-up period of 99+/-47 months (maximum 169 months) in Down patients and 80+/-64 months (maximum 213 months) in non-Down patients. There was one operative death in each group (mortality rate of 2.9% in Down patients and 3.3% in non-Down patients), and three patients died at the late phase (one in Down patients and two in non-Down patients). Five patients underwent re-operation due to postoperative left atrioventricular valve regurgitation (one in Down patients and four in non-Down patients). Freedom from re-operation for left atrioventricular valve regurgitation and actuarial survival rate at 13 years were 96+/-4 and 94+/-4% in Down patients and 85+/-7 and 90+/-5% in non-Down patients (not significantly different). CONCLUSIONS: Down syndrome does not affect the long-term results of complete atrioventricular septal defect when the defect is repaired during the first year of life.

Age Factors↗

PubMed1987

Severity and recurrence risk of congenital heart defects exemplified by atrial septal defect secundum.

It has been reported that the frequency of congenital heart defects (CHD) in children of an affected parent is now three to five times what it was 20 years ago. One conceivable cause of this is that patients with CHD of a severity that would have precluded parenthood before the advent of treatment are now able to (and consequently do) have children once the defect has been corrected. The mean severity of CHD among parents who have it would have thereby increased and this might, in turn, have increased the frequency of CHD in their children. But the latter would occur only if severely affected parents confer a greater risk on their children than parents who are mildly affected. To determine whether this is the case, we investigated 83 probands, each of whom had had an atrial septal defect secundum whose dimensions had been recorded at the time of operation. Of their 166 children, 17 had CHD. The defects of probands with affected children were not found to be significantly different in size from the defects in probands whose children were all normal. Analysis of the hemodynamic data available yielded a similar result. Our findings decisively exclude surgical correction as a significant explanation for the increased recurrence of atrial septal defect.

Canada↗

PubMed1996

Does periconceptional multivitamin use reduce the risk of neural tube defects associated with other birth defects? data from two population-based case-control studies.

The role of periconceptional folic acid in the prevention of neural tube defects (NTDs) is well established. However, it is not clear whether a protective effect exists for the subset of nonsyndromic NTD with other "unrelated" major structural birth defects (NTD-multiples). This question is important to investigate because of shared pathogenetic mechanisms between NTD and other types of birth defects, and because of the epidemiologic differences that have been shown between NTD-multiples and NTD-singles. We analyzed data from two population-based case-control studies of NTDs, Atlanta 1968-1980, and California 1989-1991, to assess whether periconceptional multivitamin use reduces the risk of NTD-multiples. Maternal vitamin histories were assessed for 47 and 65 NTD-multiples cases and 3,029 and 539 control babies in Atlanta, and California, respectively. There was a substantial risk reduction associated with periconceptional multivitamin use (-3 to +3 months) for NTD-multiples (pooled odds ratio = 0.36, 95% C.I. 0.18-0.72) that persisted after adjustment for maternal race/ethnicity and education. Also, no specific types of NTDs or NTDs with specific defects explained the risk reduction with vitamin use. These data suggest that multivitamins reduce the risk of nonsyndromic NTD cases associated with other major birth defects. The implication of this finding for the role of vitamins in the prevention of non-NTD birth defects should be further explored.

Abnormalities, Multiple↗

PubMed1993

A comparison of amniotic fluid alpha-fetoprotein and acetylcholinesterase in the prenatal diagnosis of open neural tube defects and anterior abdominal wall defects.

Amniotic fluid samples received for routine prenatal diagnosis of open neural tube defects were used for a study to compare amniotic fluid acetylcholinesterase (AChE) determination using a monoclonal antibody (4F19) enzyme antigen immunoassay and amniotic fluid alpha-fetoprotein (AFP) measurement as diagnostic tests for open neural tube defects. The study was based on 9964 women with singleton pregnancies and known outcome (including 6 with anencephaly and 18 with open spina bifida) having an amniocentesis at 14-23 weeks of gestation. The AChE immunoassay yielded detection rates for anencephaly of 100 per cent (95 per cent confidence interval (CI) 54.07-100 per cent), for open spina bifida of 100 per cent (95 per cent CI 81.47-100 per cent), for anterior abdominal wall defects of 20 per cent (95 per cent CI 0.51-71.64 per cent), and a false-positive rate of 0.22 per cent (95 per cent CI 0.14-0.34 per cent) excluding anencephaly, open spina bifida, and anterior abdominal wall defects. For similar detection rates the false-positive rate of the AFP test was significantly higher, 0.74 per cent (95 per cent CI 0.58-0.94 per cent). On the basis of these findings, it is recommended that the technically simple AChE immunoassay should be used on all samples; the AFP test should only be used on the 0.5 per cent of the samples with concentrations of AChE activity > or = 8.5 nkat/l for clear samples and blood-stained samples becoming clear after centrifugation, and > or = 25.0 nkat/l for blood-stained samples that are discoloured after centrifugation; an AFP cut-off level of 2.0 MOM is recommended for this policy. Thereby, the detection rates for anencephaly, open spina bifida, and anterior abdominal wall defects would be 100, 100, and 20 per cent, respectively (95 per cent CIs 54.07-100, 81.47-100, and 0.51-71.64 per cent, respectively), and the false-positive rate would be 0.08 per cent (95 per cent CI 0.03-0.16 per cent) (excluding anencephaly, open spina bifida, and anterior abdominal wall defects).

Abdominal Muscles↗

PubMed1986

Neural tube defects: a review of human and animal studies on the etiology of neural tube defects.

Although neural tube defects are a common congenital anomaly, their etiology is not known. Human studies have emphasized the pathology and epidemiology of the defects and suggest that in the majority of cases the etiology is multifactorial. Factors which appear possibly to be important are genetic predisposition, maternal illness, and fetal drug exposure. Animal studies have utilized naturally occurring neural tube defects and teratologically induced lesions. No animal model has been convincingly established as the equivalent of human neural tube defects. However, animal models have allowed investigation of the mechanisms of suggested human teratogens and determination of the pathogenesis of naturally occurring animal defects. Their most important contribution has been in furthering the understanding of the normal mechanisms of neural tube closure. It may be through this understanding that the etiology of human neural tube defects will be determined.

Animals↗

PubMed1992

Neural tube defects without neural crest defects in splotch mice.

Homozygous Splotch mutant mice (Sp/Sp) die on day 14 of gestation with neural tube defects, curly tail, and malformations of neural crest derivatives. Sp1H mice, which have a radiation-induced allele of Splotch with a similar phenotype, were used for this study. The neural tube defects are always located in the lumbosacral region and in 50% of the cases also in the region of the hindbrain. In this report, rare cases of neural tube defects and tail defects among the offspring of crosses between Splotch (Sp1H) heterozygotes are presented, which are not associated with a neural crest defect. This suggests that the development of the neural tube and neural crest defects in this mutant is caused by independent mechanisms or is dependent on the dosage of the mutant gene, with different thresholds being pathogenetic in the neural tube and neural crest, respectively.

Abnormalities, Multiple↗

PubMedDate not supplied

Spontaneous resolution of the septal defects in atrioventricular septal defect.

It is known that atrial septal defects of the secundum type and ventricular septal defects may undergo spontaneous closure. However, it is not well recognized that atrioventricular septal defects may infrequently also undergo spontaneous resolution. We report one case of complete atrioventricular septal defect that underwent spontaneous closure of the ventricular component. We also describe one case of partial atrioventricular septal defect with almost complete spontaneous resolution of the interatrial communication. Presence of shunting across the defects is demonstrated by color Doppler echocardiography, along with later absence of shunting. The rate of spontaneous resolution is estimated.

Echocardiography, Doppler, Color↗

PubMed2001

Direct closure of ostium primum defect in the repair of atrioventricular septal defect.

BACKGROUND: Patch closure is generally performed for atrial septation of an atrioventricular septal defect. We recently developed a new surgical technique for repairing atrioventricular septal defects that avoids the use of any patch material for closing the atrial septal defect. We report our experience with this procedure. METHODS: Seven patients (complete type: 5, partial type: 2) underwent this new operation. The diameters of the atrial septal defects were measured by transesophageal echocardiography. The preoperative electrocardiograms were compared with those taken after the operations. RESULTS: Diameters of the atrial defects ranged from 3 to 10 mm. Electrocardiograms before and after the operations did not change. No significant atrioventricular valve regurgitation and no residual shunts were detected by postoperative echocardiography. CONCLUSIONS: This method simplifies the repair of atrioventricular septal defects. In the short-term results, no arrhythmia and no valve regurgitation was seen.

Blood Vessel Prosthesis Implantation↗

PubMed1998

Left ventricular mechanics after closure of ventricular septal defect: influence of size of the defect and age at surgical repair.

To evaluate the influence of the size of the defect and the age of surgical repair on left ventricular mechanics, including geometry, shape, diastolic and systolic function as well as myocardial contractility, we used cross-sectional echo-Doppler to study 20 patients (12 males, 8 females) who had undergone successful surgical closure of a ventricular septal defect. The patients were divided in two groups, corrected early and late, on the basis of the degree of left-to-right shunting (ratio of pulmonary to systemic output of greater or less than 2.5/1) and the age at the surgical repair (older or younger than 2 years of age). The group undergoing early correction included 11 patients, mean age 7.1+/-1.8 years (range 4.2-11.8 years), having surgery at mean age of 1.3+/-0.6 years for a large ventricular septal defect (mean ratio of pulmonary to systemic output of 3.1/1; range 3.4-2.7/1) with a mean postoperative follow-up 4.6+/-1.9 years. The group of nine patients undergoing late correction had a mean age of 11.3+/-4.9 years (range 6.7-17.2 years), with a later surgical repair (mean age 4.7+/-2.7 years) for a moderate-sized ventricular septal defect (mean pulmonary/systemic output ratio 2.1/1; range 2.3-1.7) and a mean postoperative follow-up of 7+/-4.2 years. Each group of surgically repaired patients was compared with a control group matched for age, body surface area and gender. No significant differences were found between the normal controls and those undergoing early correction for any assessed functional index regarding left ventricular geometry (normalized volumes and mass for body surface area, mass/volume and thickness/radius ratios), shape (long axis-short axis ratio), diastolic (mitral and pulmonary venous flow patterns) and systolic (fractional shortening and rate-corrected mean velocity of circumferential fibre shortening) function. In addition, the data points for each patient for the rate-corrected mean velocity of circumferential fibre shortening to end-systolic stress relationship were within the 95% confidence limits of normal, suggesting normal left ventricular contractility. On the other hand, the patients undergoing surgery at a later age showed a persistent increase of the normalized left ventricular end-diastolic volume and mass, with an higher mass/volume ratio and reduced end-systolic stress compared with normal controls. Furthermore, left ventricular shape (long axis-short axis ratio) was abnormal at end-diastole but with its normal values at end-systole. Our data suggest that, in the presence of a large ventricular septal defect, early successful surgical repair <2 years of age results in complete recovery of left ventricular mechanics in the postoperative follow-up. In contrast, surgical closure at > 2 years of age, even for a moderately sized ventricular septal defect, deleteriously affects postoperative left ventricular geometry and shape. Since prolonged volume overload may be detrimental to myocardial function, earlier surgical repair should be recommended.

Adolescent↗

PubMed2004

Surgical treatment of an unusual atrial septal defect: the vestibular defect.

A 14-year-old female patient underwent surgical treatment of multiple atrial septal defects associated with unroofed coronary sinus and pulmonary valvar stenosis. One of the defects was that of the superior oval fossa and the other a large ellipsoidal defect positioned inferior to the inferior rim of the oval fossa. The patient underwent primary closure of the defects with a favorable result. To the best of our knowledge, this is the first surgical experience of an unusual atrial septal defect or the vestibular defect.

Adolescent↗

PubMed1999

Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention.

BACKGROUND AND METHODS: Periconceptional administration of folic acid can reduce a woman's risk of having a fetus or infant with a neural-tube defect. As part of a public health campaign conducted from 1993 to 1995 in an area of China with high rates of neural-tube defects (the northern region) and one with low rates (the southern region), we evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 microg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy. RESULTS: Among the fetuses or infants of 130,142 women who took folic acid at any time before or during pregnancy and 117,689 women who had not taken folic acid, we identified 102 and 173, respectively, with neural-tube defects. Among the fetuses or infants of women who registered before their last menstrual period and who did not take any folic acid, the rates of neural-tube defects were 4.8 per 1000 pregnancies of at least 20 weeks' gestation in the northern region and 1.0 per 1000 in the southern region. Among the fetuses or infants of the women with periconceptional use of folic acid, the rates were 1.0 per 1000 in the northern region and 0.6 per 1000 in the southern region. The greatest reduction in risk occurred among the fetuses or infants of a subgroup of women in the northern region with periconceptional use who took folic acid pills more than 80 percent of the time (reduction in risk, 85 percent as compared with the fetuses or infants of women who registered before their last menstrual period and who took no folic acid; 95 percent confidence interval, 62 to 94 percent) [corrected]. In the southern region the reduction in risk among the fetuses or infants of women with periconceptional use of folic acid was also significant (reduction in risk, 41 percent; 95 percent confidence interval, 3 to 64 percent). CONCLUSIONS: Periconceptional intake of 400 microg of folic acid daily can reduce the risk of neural-tube defects in areas with high rates of these defects and in areas with low rates.

Adult↗