Biomedical subjects
Publications and source records attributed to D Huff.
Biventricular hypertrophy was noted at 24 weeks' gestation in a fetus with isolated cytochrome-c oxidase (COX) deficiency. Shock, caused by hypertrophic cardiomyopathy and severe pulmonary hypertension, led to the patient's death on day 6. His phenotype defines a new lethal variant of COX deficiency characterized by prenatal-onset cardiopulmonary pathophysiology.
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The WT1 gene encodes a transcription factor implicated in normal and neoplastic development. The purpose of this study was to evaluate the diagnostic utility of a commercial WT1 antibody on a variety of pediatric small round blue cell tumors (SRBCT). A mouse monoclonal antibody (clone: 6F-H2, DAKO) raised against the N-terminal amino acids 1-181 of the human WT1 protein was tested. Microscopic sections from 66 specimens were stained using an antigen retrieval protocol with trypsin. The tumors included peripheral neuroectodermal tumors (PNET/Ewing's), neuroblastomas, desmoplastic small round cell tumors (DSRCT), lymphomas, Wilms' tumors, and rhabdomyosarcomas (RMS). One RMS case was investigated by Western blot analysis and RT-PCR to confirm the antibody specificity. A strong cytoplasmic staining was demonstrated in all RMS (11/11). The Western blot analysis confirmed the WT1 protein in the tissue, and the RT-PCR confirmed the presence of WT1 mRNA in the peripheral blood and tissue of one RMS patient. The Wilms' tumors had a variable nuclear and/or cytoplasmic positivity in most (17/24) cases. All PNET/Ewing's were negative. The nuclei of two lymphoblastic lymphomas stained strongly. A weak nuclear or cytoplasmic staining was reported in a few DSRCT (3/5), lymphomas (2/10), and neuroblastomas (2/8). This is a useful antibody in the differentiation of RMS from other SRBCTs. A strong cytoplasmic staining favors an RMS, and a strong nuclear staining is suggestive of a Wilms' tumor. A role for WT1 in the pathogenesis of rhabdomyosarcomas is raised. The limited sampling precludes any conclusions regarding the value of tissue or peripheral blood analysis for WT1 mRNA in patients with rhabdomyosarcoma.
A potential consequence of systemic administration of viral vectors is the inadvertent introduction of foreign DNA into recipient germ cells. To evaluate the safety of in vivo recombinant adeno-associated virus (rAAV) mediated gene transfer approaches for hemophilia B, we explored the risk of germline transmission of vector sequences following intramuscular (IM) injection of rAAV in four species of male animals (mouse, rat, rabbit and dog). In vector biodistribution studies in mice and rats, there is a dose-dependent increase in the likelihood that vector sequences can be detected in gonadal DNA using a sensitive PCR technique. However, in dogs DNA extracted from semen is negative for vector sequences. To address this discrepancy, studies were done in rabbits, and both semen and testicular DNAs were analyzed for the presence of vector sequences. These studies showed that no AAV vector sequences were detected in DNA extracted from rabbit semen samples collected at time points ranging from 7 to 90 days following IM injection of 1 x 10(13) vector genomes rAAV (vg) per kg. In contrast, DNA extracted from gonadal tissue was positive for vector sequences, but the positive signals diminished in number and strength with time. By FISH analysis, AAV signals were localized to the testis basement membrane and the interstitial space; no intracellular signal was observed. We observed similar findings following hepatic artery administration of rAAV in rats and dogs, suggesting that our findings are independent of the route of administration of vector. Attempts to transduce isolated murine spermatogonia directly with AAV-lacZ were unsuccessful. In clinical studies human subjects injected IM with an AAV vector at doses up to 2 x 10(12) vg/kg have shown no evidence of vector sequences in semen. Together, these studies suggest that rAAV introduced into skeletal muscle or the hepatic artery does not transduce male germ cells efficiently. We conclude that the risk of inadvertent germline transmission of vector sequences following IM or hepatic artery injection of AAV-2 vectors is extremely low.
Human parvovirus B19 can cause congenital infection with variable morbidity and mortality in the fetus and neonate. Although much information exists on the B19-specific antibody response in pregnant women, little information is available describing the cell-mediated immune (CMI) response at the maternal-fetal interface. The focus of this study was to characterize the CMI response within placentas from women who seroconverted to B19 during their pregnancies and compare it to controls. Immunohistochemical techniques were used to identify the various immune cells and the inflammatory cytokine present within placental tissue sections. Group 1 consisted of placentas from 25 women whose pregnancies were complicated by B19 infection; 6 women with good outcome (near-term or term delivery), and 19 with poor outcome (spontaneous abortion, nonimmune hydrops fetalis, or fetal death). Group 2 consisted of placentas from 20 women whose pregnancies were complicated with nonimmune hydrops fetalis of known, noninfectious etiology. Group 3 consisted of placentas from eight women whose pregnancies ended in either term delivery or elective abortion. The results of the study revealed a statistically significant increase in the number of CD3-positive T cells present within placentas from group 1 compared to group 2 or 3 (13.3 versus 2 and 1, respectively) (P < 0.001). In addition, the inflammatory cytokine interleukin 2 was detected in every placenta within group 1 but was absent from all placentas evaluated from groups 2 and 3. Together, these findings demonstrate evidence for an inflammation-mediated cellular immune response within placentas from women whose pregnancies are complicated with B19 infection.
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In order to study the pathogenesis of prenatal deformities, we reviewed maternal histories, delivery records, pathology reports, radiographs, and photographs of 90 fetuses with prenatally documented oligohydramnios at gestational ages from 14 weeks to term. The causes of oligohydramnios included premature rupture of membranes (44 cases), fetal renal insufficiency (25 cases), idiopathic (15 cases), and twin-twin transfusion (6 cases). The fetuses were grouped according to gestational age at delivery and duration of oligohydramnios. Sixty-three fetuses (70%) had documented contractures. As expected, contractures were more frequent with earlier onset and longer duration of oligohydramnios. During the 2nd trimester, the frequency of contractures in fetuses with oligohydramnios was 77% compared to 52% in the 3rd trimester (chi(2) = 5.33, 1 df, P =.02). Considering all gestational ages together, 57% of fetuses had contractures after less than 2 weeks of oligohydramnios compared to 81% of fetuses with a longer duration of oligohydramnios (chi2 = 6.23, 1 df, P <.02). The type of contracture varied with gestational age. Clubfoot was the most frequent at all ages, but hand contractures such as camptodactyly were common only in the 2nd trimester while the broad flat hand originally described in Potter sequence was found almost exclusively in the fetuses with oligohydramnios in the 3rd trimester. Of the 63 fetuses with oligohydramnios and contractures, 25 (40%) had either additional malformations or family history that could explain contractures independent of oligohydramnios.
The perception of face gender was examined in the context of extending "face space" models of human face representations to include the perceptual categories defined by male and female faces. We collected data on the recognizability, gender classifiability (reaction time to classify a face as male/female), attractiveness, and masculinity/femininity of individual male and female faces. Factor analyses applied separately to the data for male and female faces yielded the following results. First, for both male and female faces, the recognizability and gender classifiability of faces were independent--a result inconsistent with the hypothesis that both recognizability and gender classifiability depend on a face's "distance" from the subcategory gender prototype. Instead, caricatured aspects of gender (femininity/masculinity ratings) related to the gender classifiability of the faces. Second, facial attractiveness related inversely to face recognizability for male, but not for female, faces--a result that resolves inconsistencies in previous studies. Third, attractiveness and femininity for female faces were nearly equivalent, but attractiveness and masculinity for male faces were not equivalent. Finally, we applied principal component analysis to the pixel-coded face images with the aim of extracting measures related to the gender classifiability and recognizability of individual faces. We incorporated these model-derived measures into the factor analysis with the human rating and performance measures. This combined analysis indicated that face recognizability is related to the distinctiveness of a face with respect to its gender subcategory prototype. Additionally, the gender classifiability of faces related to at least one caricatured aspect of face gender.
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We describe a reaction tray for a heterogeneous chemiluminescence (CL) immunoassay having the following features: separate sample incubation and signal detection wells; a design that allows for noncontact transfer of the reaction mixture from incubation wells to detection wells; surface features to mate with a detector and create a light-tight seal for CL detection; and self-contained means for liquid removal. The reaction mixture is transferred by injecting a wash solution from a group of nozzles into the incubation well. Quantitative transfer of microparticles (transfer efficiencies greater than 95% and CV less than 5%) is achieved by injecting two 300-microL pulses of transfer solution at a rate of 2.1 m/s. The performance of the tray and method of transfer is tested by determining the precision of CL signal for a sample containing a concentration of anti-hepatitis B core antigen (anti-HBc) or hepatitis B surface antigen (HBsAg) close to the cutoff value for the assay.
Here we describe a fetus in whom a cystic hygroma was detected by ultrasound during the second trimester. Autopsy demonstrated a female fetus with manifestations of Ullrich-Turner syndrome, including gonadal dysgenesis, generalized lymphedema, and preductal aortic coarctation. Surprisingly, the karyotype was 46,XY, with no evidence of mosaicism for a 45,X cell line. Y-DNA hybridization studies demonstrated a deletion of the sex-determining segment of the short arm of the Y chromosome. This is the first report, in a fetus, of XY Ullrich-Turner syndrome due to a Y chromosome deletion.
This interlaboratory study was conducted to examine four erythrocyte protoporphyrin control materials from Aviv Biomedical, Helena Laboratories, Kaulson Laboratories, and the New York State Department of Health for use with hematofluorometers. Our principal aims were to monitor the stability of these materials at three different storage temperatures (room, refrigerator, freezer) and, where appropriate, to validate the manufacturer's target values. Measurements for the study were generated in three reference laboratories that used a total of five hematofluorometers, three from Environmental Science Associates and two from Aviv Biomedical. Each instrument was calibrated against a consensus acetic acid-ethyl acetate extraction procedure. We found the materials from Aviv to be the most stable, followed by the New York State material. However, the target values assigned by Aviv were not within the acceptable range determined by consensus. The target values assigned by Kaulson Laboratories for their materials did fall within the acceptable consensus range, but they were the least stable of the materials evaluated. The materials from Helena Laboratories were originally designed for use as calibrators with Helena's "ProtoFluor Z" hematofluorometer, which reports in different units. They were deemed unsuitable for use as control materials with the Aviv or Environmental Science Associates hematofluorometers because of the narrow range of values and the wide scatter of results.
All pediatric autopsies of patients with hypoplastic left heart syndrome seen during an 11-year interval were reviewed to determine the frequency of underlying chromosomal and single-gene defects and idiopathic major extracardiac anomalies associated with this common, lethal congenital heart abnormality. Of 83 patients identified, nine had underlying chromosomal abnormalities, four had single-gene defects, ten had one or more major extracardiac anomalies without an identifiable chromosomal or mendelian disorder, and two were infants of insulin-dependent diabetic mothers. Overall, 23 patients (28%) had a genetic disorder and/or major extracardiac anomaly. The substantial prevalence of genetic causes of and major extracardiac anomalies associated with hypoplastic left heart syndrome underscores the need for a detailed genetic evaluation for all patients with hypoplastic left heart syndrome.
In a collaborative study, 48 prepubertal boys with undescended testes ranging in age from 15 months to 11 years were treated with low-dose intranasal buserelin following an every-other-day programme for a period of 6 months. Urinary LH, FSH, and testosterone were not altered during the treatment period. Boys over 7 years of age experienced a slight but significant rise in testosterone at the end of treatment. Testicular descent was achieved in only 17% of boys. In the remainder, bilateral testicular biopsies were obtained during orchiopexy. Grouped analysis showed a significant increase in the number of germ cells per tubule in both unilateral and bilateral cryptorchid boys, suggesting that buserelin treatment of the testis in a cryptorchid position is capable of improving fertility potential. If time-matched controls are compared to treated boys of the same age, again a significant difference is observed indicating that buserelin treatment does increase the germ cell count.
Nineteen male infants died with a large omphalocele and 52% had associated cryptorchidism. However, two different groups with both omphalocele and cryptorchidism were recognized: (1) Eleven patients with omphalocele without brain malformation and an incidence of undescended testes not significantly different from the normal population; (2) Eight patients with omphalocele and brain malformation all having cryptorchidism. A comparison of the groups indicated that intact intraabdominal pressure during intrauterine life is not a main driving force of testicular descent, whereas normal testicular descent may occur only when the brain is normally developed. Whenever a child with omphalocele and cryptorchidism is examined, careful evaluation of the central nervous system is indicated. This triad of malformations may have prognostic and therapeutic implications.
We studied 48 prepubertal boys with cryptorchidism between 1 year 3 months and 11 years old who were treated with buserelin every other day for 6 months. Urinary luteinizing and follicle-stimulating hormones, and testosterone remained unchanged during the entire treatment period. In boys older than 7 years a slight but significant increase in testosterone was noted in the first morning voided urine at the end of treatment. Testicular biopsies were obtained at orchiopexy in all patients in whom testicular descent was not complete (83 per cent). A significant increase in the number of germ cells was observed in patients with unilateral and those with bilateral cryptorchidism, indicating that 6 months of buserelin therapy improved the fertility status even when testes were in an undescended position during treatment.
The purpose of this study was to review the literature pertaining to non-surgical cure rates for strabismus published since 1958 and compare it to Flom's prognostic model. However, no studies were found that could be compared directly to Flom's model. One reason for this was due to the use of different definitions of a cure by different clinicians. Another reason was the failure to categorize the data according to the effect that retinal correspondence, frequency, and direction of the deviation had on the cure rates. From the studies which specified Flom's functional cure or its equivalent, it was determined that strabismic cure rates could be broken down as follows: Constant esotropia-29%; Intermittent esotropia-73% Constant exotropia-53%; Intermittent exotropia-62% Suggestions were made for the reporting of data to make future research more comparable and useful to the practitioner.
In 3 male patients, chronic pulmonary sequelae followed influenza virus infection at 5, 24, and 42 months of age. Varying degrees of interstitial fibrosis, bronchial and bronchiolar erosions and metaplasia, obliterative bronchiolitis, and interstitial chronic inflammatory infiltrates were found on lung biopsy. Influenza A/Hong Kong/68 (H3N2) virus was isolated from the lung tissue of one patient 8 weeks after the onset of illness. This is the longest persistence of infectious virus in lung tissue yet reported. Persistent radiographic abnormalities included peribronchial thickening, interstitial densities, bronchiectasis, obliterative bronchiolitis, and segmental atelectasis. Pulmonary function tests showed an obstructive restrictive pattern, with mild improvement after bronchodilation and with deterioration after exercise. These observations suggest that influenza virus infection may be more serious in infants and young children than has been previously recognized and may contribute to the pathogenesis of unexplained interstitial pneumonitis, pulmonary fibrosis, obliterative bronchiolitis, and bronchiectasis.