Biomedical subjects
Publications and source records attributed to A Lerner.
Developmental dislocation of the hip (DDH) is 1 of the commonest problems of the infant locomotive system. While its natural history is usually unpredictable, it is fully agreed that early diagnosis and treatment are essential. We present an 86-year-old man in whom asymptomatic bilateral DDH was diagnosed incidentally. This is apparently the second such case reported in the orthopedic literature.
Explore the source record for details and available documents.
To elucidate the role of the CD3 eta subunit of the T cell receptor (TCR) in thymic development, a CD3 eta -/- mouse was generated by gene targeting. Insertion of a neomycin resistance gene into exon 9 of the CD3 zeta/eta/phi locus disrupted expression of CD3 eta and CD3 phi without affecting the expression of CD3 zeta. Little difference was observed between wild type and CD3 eta -/- mice with regard to cellularity or subset composition in thymus and peripheral lymphoid organs. Furthermore, neither alloproliferative responses nor cytotoxic T lymphocyte generation and effector function was affected by the mutation. The effect of the CD3 eta -/- mutation on thymic selection was examined by crossing the CD3 eta knockout animals with anti-HY TCR transgenic animals: the absence of the CD3 eta subunit altered neither positive nor negative selection. Thus, CD3 eta is not required for thymic selection. Of note, the birth rate of the CD3 eta -/- animals was significantly lower than that of wild type or heterozygous animals (P = 0.041-0.002). This unexpected result is probably the consequence of an alteration in mRNA expression of the Oct-1 nuclear transcription factor in CD3 eta -/- animals. The CD3 zeta/eta/phi locus partially overlaps the gene encoding Oct-1 whose transcription is dysregulated by the CD3 eta -/- mutation. Our results clearly underscore the value of characterizing all products of a genetic locus disrupted by gene targeting.
To determine the prevalence of short polymers of glucose and starch malabsorption caused by small intestinal glucoamylase deficiency in children with chronic diarrhea, we studied small bowel biopsy specimens from 511 children (aged 1 month to 9 years) with chronic diarrhea evaluated at 54 medical centers. Glucoamylase and disaccharidase (lactase, sucrase, maltase, and palatinase) enzyme assays were performed. Of the 511 children, 15 had glucoamylase deficiency. Six who had significant small intestinal mucosal injury and disaccharidase deficiencies were defined as having secondary glucoamylase deficiency; the other nine patients with normal mucosal morphologic features were defined as having primary glucoamylase deficiency. Secretin tests showed normal pancreatic amylase values for age in all seven children tested. Four of them had abnormal findings on tolerance tests for starch and short polymers of glucose (rise in blood glucose concentration: < 20 mg/dl) and reducing substances in stools, and three of these four had symptoms of intolerance (abdominal distention, flatulence, and diarrhea). All seven patients responded to a starch elimination diet. After reintroduction of a starch diet, diarrhea recurred in four patients; this was alleviated 48 hours after reelimination of starch. We conclude that intestinal glucoamylase deficiency is present in some patients with chronic diarrhea.
The immunological markers proposed to supplement intestinal biopsy for the diagnosis of coeliac disease are antigliadin, antireticulin and antiendomysial antibodies. These antibodies have been studied separately or compared as pairs, but no prospective comparison of all three antibodies in childhood coeliac disease exists. Thirty-four confirmed coeliacs were compared with nine non-coeliacs with pathological small intestines, and 32 children with a normal intestinal histology. Sera were examined for IgG- and IgA-antigliadin antibodies (AGA) by ELISA, and for IgA-antireticulin antibodies (ARA) and IgA endomysial antibodies (EMA) by indirect immunofluorescence. In active coeliac disease, IgA-EMA was the most sensitive (97%), while IgA-AGA the least sensitive antibody (52%). The specificity of IgA-AGA, IgG-AGA, IgA-ARA, IgA-EMA was 95%, 92%, 100% and 98%, respectively. Positive predicted values of ARA and EMA were comparable (97-100%), while EMA had the highest negative predicted value (98%). Compared with IgG-AGA, IgA-EMA titres better reflected variations in dietary gluten, and correlated best with intestinal pathology. Compared with AGA and ARA sensitivity, specificity and predictive values, EMA is the most reliable serological marker for the diagnosis of coeliac disease. It reflects dietary changes in gluten and correlates best with intestinal histopathology. Therefore, it should be considered the best of the three serological tests available for childhood coeliac disease.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
CD3 zeta and eta are signal-transducing components of the TCR and are derived from alternative splicing of transcripts from a single genetic locus that also encodes CD30 theta. We have isolated two murine cDNA clones that appear to result from antisense transcription through CD3 theta-specific exon 10 and CD3 eta-specific exon 9. The sequence of these clones shows no open reading frame. Northern analysis with single stranded probes confirms the existence of a ubiquitously expressed > 12-kb polyadenylated mRNA antisense to CD3 eta. A "genomic walk," which extended 32 kb distal to murine CD3 eta exon 9, provided genomic DNA containing a more 5' portion of the antisense transcript. This probe identified two murine thymic cDNA with 91% sequence homology to the human transcription factor Oct-1. Five exons of murine Oct-1 map in an antisense orientation to the CD3 zeta/eta/theta locus on the cloned genomic sequences. The murine Oct-1 cDNA and exon 9 of CD3 eta hybridize to the same > 12-kb mRNA. Similarly, human Oct-1 and previously characterized human genomic sequences homologous to murine CD3 eta exon 9 each hybridize to the same > 15-kb human mRNA. Thus, the CD3 zeta/eta/theta and Oct-1 gene loci are partially overlapping and transcribed in opposite directions. The potential functional implications of these findings are discussed.
The choice of treatment for clomiphene-resistant anovulation associated with polycystic ovary syndrome (PCOS) is presently arbitrary and selection criteria are not available. A total of 144 women with anovulatory infertility associated with PCOS who failed to conceive on clomiphene were treated with either pure follicle stimulating hormone (FSH) (n = 29), or human menopausal gonadotrophin (HMG) (n = 60), or gonadotrophin-releasing hormone analogue (GnRHa) and HMG (n = 55). Analysis of 306 treatment cycles and 53 pregnancies revealed a cumulative conception rate at 4 months of 23% with FSH, 47% with HMG and 69% with GnRHa + HMG. The miscarriage rate was highest in the HMG group (44%) and consequently the cumulative live birth rate was superior when GnRHa was used in combination with HMG. There were no significant differences in the basal clinical and endocrinological features of those who conceived compared with those who did not, either in the whole group, or in the individual treatment groups. Thus, the choice of treatment for clomiphene-resistant women with PCOS cannot be guided by the basal clinical or endocrinological features of this heterogeneous syndrome with the present state or knowledge.
Explore the source record for details and available documents.
Carnitine is essential for muscle energy production and is required for the transport of long chain fatty acids and acyl co-enzyme A derivatives across the inner mitochondrial membrane. Recently, an absorptive transport mechanism was discovered at the small bowel level suggesting the possibility of a carnitine deficient state in patients with mucosal damage. Therefore, this study investigated carnitine concentrations in serum of patients with coeliac disease. Serum samples were obtained from 12 patients with active coeliac disease and seven with non-active disease, and compared with serum samples of 17 children with gastrointestinal symptoms but with a small bowel normal on biopsy examination and 33 normal controls. Total serum carnitine concentration was significantly lower in the patients with coeliac disease compared with the other two groups and to reference values. When the degree of atrophy of coeliac intestinal mucosa was numerically graded, serum carnitine concentrations did not correlate to the degree of the intestinal lesion but were significantly lower in the damaged intestine compared with the group with normal mucosa. It is suggested that coeliac disease should be considered as a potential cause of secondary carnitine deficiency.
The T-cell receptor (TCR) is a multisubunit complex consisting of the clonotypic Ti alpha and beta (or Ti gamma and delta) subunits and the invariant CD3 gamma, CD3 delta, CD3 epsilon, CD3 zeta, and CD3 eta subunits. Herein, we describe an additional product from the CD3 zeta/eta gene locus which we have termed CD3 theta. The cDNA derives from the first seven exons common to CD3 zeta and CD3 eta, 94 base pairs (bp) of the CD3 eta-specific exon 9 and an additional exon 10 encoding the carboxyl-terminal 15 amino acids and the 3'-untranslated region. The expression of CD3 theta is equivalent to that of CD3 eta in tissue distribution and level of expression as judged by RNase protection analysis. Despite the identity of the amino-terminal 121 amino acids of CD3 zeta, CD3 eta, and CD3 theta and an additional 31 amino acids shared between CD3 eta and CD3 theta, transfection of CD3 theta into the CD3 zeta- eta- T-cell hybridoma, MA5.8, failed to restore detectable surface TCR expression in contrast to transfection with CD3 zeta or CD3 eta. Analysis of the CD3 theta protein in transfectants indicated that CD3 theta is associated with the TCR intracellularly. However, unlike with CD3 zeta, Ti alpha-beta chains remain endoglycosidase H sensitive, suggesting a role for the unique COOH-terminal segment of CD3 theta in mediating TCR retention and/or degradation in a pre-Golgi compartment.
Explore the source record for details and available documents.
We have cloned and sequenced human genomic DNA homologous to exons 9 and 10 of the CD3 zeta/eta/theta locus. Although there are open reading frames within the human sequences corresponding to the translated portions of murine exons 9 and 10, we find no evidence of conservation of the encoded polypeptide product. Furthermore, using oligonucleotides derived from these homologous sequences, we are unable to detect human CD3 eta- or CD3 theta-like transcripts by polymerase chain reaction amplification of reverse-transcribed RNA from a variety of human lymphoid tissues. Despite the absence of evidence for conservation of human CD3 eta and CD3 theta, there is a surprising degree of similarity between human and murine nucleotide sequences, not only for exons 9 and 10 (78% and 70%, respectively), but also for the 9/10 intron (71%). A possible mechanism for this conservation is discussed.
[3H]Dopamine (DA) uptake by platelet storage granules was determined in 26 schizophrenic male patients, paranoid type (14 acute stage; 12 in remission) and 20 age-matched, normal controls. Maximum velocity (Vmax) of DA uptake was significantly higher in acute patients, than patients in remission or controls (p less than 0.05). The apparent Michaelis constant (Km) of DA uptake in acute patients was also significantly different from chronic patients (p less than 0.05). Preincubation with reserpine (10(-4), 10(-5) M) produced a substantial diminution of DA uptake, while haloperidol (10(-4), 10(-5) M) did not affect the assay. Considering that a DA dysequilibrium in schizophrenia may be expressed not only in the brain, but also in the periphery and that an increased amount of DA accumulated in the vesicles, implies that an increased quantity of catecholamine is available for release, our findings suggest additional evidence for the role of DA overactivity in the pathophysiology of this disorder.
PURPOSE: A phase II study of etoposide, doxorubicin, and cisplatin (EAP) therapy in patients with advanced gastric carcinoma was performed in an attempt to confirm encouraging results reported by German investigators using an identical EAP regimen. PATIENTS AND METHODS: Thirty-six consecutive, previously untreated patients with surgically unresectable, measurable gastric carcinoma were treated every 28 days with etoposide (120 mg/m2, days 4, 5, and 6), doxorubicin (20 mg/m2, days 1 and 7), and cisplatin (40 mg/m2, days 2 and 8). A total of 108 courses of treatment was given. RESULTS: Therapy was associated with myelosuppression (median granulocyte nadir, 239/microL; median platelet nadir, 81,000/microL), which reached its maximum 14 days after the start of therapy and necessitated hospitalization after 24 of 108 (22%) treatment courses. Four of 36 (11%) patients died of treatment-related toxicity: three from sepsis and one from hemorrhage. Objective responses were observed in 12 of 36 (33%) patients; three (8%) patients experienced a clinical complete response. The median time to progression was 4 months for all 36 patients and 8 months for the 12 responding patients. Of the 13 patients with localized but unresectable disease, five subsequently underwent surgical resection; only one of these five was rendered disease-free. CONCLUSION: The EAP regimen is highly toxic and results in response rates and survival times no better than those of more easily tolerated treatment programs.
Early work on T-cell hybridomas lacking the T-cell-receptor (TCR) sub-unit CD3 eta had suggested a correlation between the presence of CD3 zeta-eta heterodimers and signalling leading to phosphatidyl-inositol (PI) turnover as well as activation-induced cell death. The cloning of CD3 eta has now allowed thorough and direct analysis of the signal transduction properties of CD3 zeta-zeta-, CD3 zeta-eta- and CD3 eta-eta-containing TCRs. We have found that all forms of the TCR are capable of transducing signals leading to PI turnover, Ca2+ mobilization, IL-2 production and cell-cycle arrest. CD3 zeta and CD3 eta utilize the same promoter which yields coordinate expression of both products, so that restricted CD3 eta expression in a sub-population of thymocytes is unlikely. Immunohistochemical methods employing an anti-CD3 eta-specific monoclonal antibody (MAb) show no detectable staining of thymic sections from adult mice, implying at best a low level of constitutive CD3 eta expression. In contrast, CD3 eta expression is readily detected in the majority of cortical thymocytes of CD3 eta transgenic mice using a Thy-1 promoter construct. However, over-expression of CD3 eta in mice transgenic for this polypeptide does not result in increased negative selection in vivo, consistent with the in vitro findings that induction of cell death is not strictly dependent on CD3 eta. Despite earlier reports of the detection of human CD3 eta protein, we find no CD3 eta message in human thymus or T cells. Cloning of the human CD zeta-eta genomic locus has demonstrated approximately 70% homology between the mouse and human genomic sequence, corresponding to the mouse CD3 eta-specific exon. However, translation of the DNA sequence does not result in a homologous amino acid sequence. Thus, there does not appear to be a CD3 eta protein in humans.
Explore the source record for details and available documents.