From Brooklyn to Havana: the midwifery program delegation to Cuba.
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Cuba↗
Biomedical subjects
G Holmes
Publications and source records attributed to G Holmes.
Two N-terminal self-association domains are required for the dominant negative transcriptional activity of WT1 Denys-Drash mutant proteins.
Patients with Denys-Drash syndrome (DDS) have been shown to be constitutionally heterozygous for mutations of the WT1 gene. Almost all DDS mutations inactivate or remove the DNA-binding zinc finger region of WT1 and the resulting mutant proteins appear to act in a dominant negative manner. This may occur via WT1 self-association, which has been shown to involve the first 180 amino acids. By creating a series of N-terminal deletions, we have further investigated WT1 self-association using a yeast di-hybrid system and an in vitro protein binding assay. Our results suggest that there are two distinct domains within the N-terminal region facilitating self-association, residing from amino acids 1-45 and 157-253. Co-transfection of WT1 with progressively shorter N-terminal constructs demonstrates that both of these sites are required for a dominant negative activity as assessed by activation of a reporter construct.
Base Sequence↗
Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn's disease.
BACKGROUND: Tumour necrosis factor-alpha (TNF alpha) is thought to have a central role in the pathogenesis of Crohn's disease. We tested the hypothesis that CDP571, a genetically engineered human antibody to TNF alpha, is effective in modifying disease activity in patients with moderately active Crohn's disease. METHODS: In this double-blind, placebo-controlled study, 31 patients were randomly assigned to CDP571 (n = 21) or placebo (n = 10). The primary endpoint was change in Crohn's disease activity index 2 weeks after a single infusion of CDP571 (5 mg/kg), or human albumin as placebo. One patient who attended no follow-up assessments was excluded from the analyses (CDP571 group). FINDINGS: The median Crohn's disease activity index fell from 263 (IQR 186.5-323.5) at baseline to 167 (137.5-294.0) at 2 weeks in the CDP571-treated patients (p = 0.0003); the change in the placebo group (253 [240-334] to 247 [183-256]) was not significant. In the treated group, there were also significant differences between baseline and 2 weeks in Harvey-Bradshaw score (p = 0.0005), key symptom score (p = 0.049), alpha 1-glycoprotein concentration (p = 0.012), and erythrocyte sedimentation rate (p = 0.01); concentrations of C-reactive protein fell, but not significantly (p = 0.067). Six patients achieved remission (Crohn's disease activity index < or = 150) and three others had activity indices of 156 or lower. There were no significant changes in the placebo group. INTERPRETATION: A single 5 mg/kg infusion of CDP571 reduced disease activity in Crohn's disease at 2 weeks. These data suggest that antibody neutralisation of TNF alpha is a potentially effective strategy in the management of Crohn's disease. The use of CDP571 in Crohn's disease requires further study.
Adolescent↗
Three-dimensional reconstruction and surgical navigation in pediatric epilepsy surgery.
We have used MRI-based three-dimensional (3D) reconstruction and a real-time, frameless, stereotactic navigation device to facilitate the removal of seizure foci in children suffering from intractable epilepsy. Using this system, the location of subdural grid and strip electrodes is recorded on the 3D model to facilitate focus localization and resection. Ten operations were performed, including 2 girls and 8 boys ranging in age from 3 to 17, during which 3D reconstruction and surgical instrument tracking navigation was used. In all the cases, the patients tolerated the procedure well and showed no postoperative neurological deficits. We believe this to be a valuable tool for a complete and safe resection of seizure foci, thereby reducing the incidence of postoperative neurological deficits and significantly improving the overall quality of life of the patients.
Adolescent↗
Disseminated superficial actinic porokeratosis occurring in two members of an Asian family.
Disseminated superficial actinic porokeratosis (DSAP) is a genodermatosis which usually affects fair-skinned individuals at sites of chronic sun exposure, although the face is usually spared. We now report the occurrence of this condition in a Pakistani mother and her 13-year-old daughter, both predominantly with facial lesions.
Adolescent↗
A novel target for the Wilms' tumour suppressor protein (WT1) is bound by a unique combination of zinc fingers.
All isoforms of the Wilms' tumour suppressor protein, WT1, contain four consecutive zinc fingers which facilitate DNA binding. The predominant WT1 transcript contains a 9 base pair insertion resulting in an additional three amino acids, lysine-threonine-serine (KTS), between zinc fingers 3 and 4. WT1 zinc fingers 2, 3 and 4 are highly homologous to the zinc fingers of the early growth response gene, EGR1. However, only WT1--KTS is capable of binding an EGR1 consensus site. In contrast, the previously described genomic fragment, +P5 (D1S3309E), is bound by both WT1--KTS and WT1 + KTS. In this study, the region within + P5 to which both WT1 -- KTS and WT1 + KTS bind was defined as 5'-GGAGAGGGAGGATC-3'. EGR1 did not bind + P5. By creating zinc finger deletions, we demonstrate that zinc finger 1, but not zinc finger 4, is critical for + P5 binding; whereas zinc finger 4, but not 1, is necessary for the binding of WT1 target sites within EGR1, PDGF A chain and IGF2 promoters. Thus, zinc finger usage can vary with target and + P5 may represent a novel type of WT1 binding site, the physiological relevance of which must be investigated.
Binding Sites↗
RNA binding by the Wilms tumor suppressor zinc finger proteins.
The Wilms tumor suppressor gene WT1 is implicated in the ontogeny of genito-urinary abnormalities, including Denys-Drash syndrome and Wilms tumor of the kidney. WT1 encodes Kruppel-type zinc finger proteins that can regulate the expression of several growth-related genes, apparently by binding to specific DNA sites located within 5' untranslated leader regions as well as 5' promoter sequences. Both WT1 and a closely related early growth response factor, EGR1, can bind the same DNA sequences from the mouse gene encoding insulin-like growth factor 2 (Igf-2). We report that WT1, but not EGR1, can bind specific Igf-2 exonic RNA sequences, and that the zinc fingers are required for this interaction. WT1 zinc finger 1, which is not represented in EGR1, plays a more significant role in RNA binding than zinc finger 4, which does have a counterpart in EGR1. Furthermore, the normal subnuclear localization of WT1 proteins is shown to be RNase, but not DNase, sensitive. Therefore, WT1 might, like the Kruppel-type zinc finger protein TFIIIA, regulate gene expression by both transcriptional and posttranscriptional mechanisms.
Animals↗
Clinicians' hypotheses regarding clients' problems: are they less likely to hypothesize sexual abuse in male compared to female clients?
Sixty-one clinical psychologists completed a questionnaire about a detailed case summary of an adult client which incorporated a number of indicators that the client may have been sexually abused. The gender of the client was manipulated. Significantly more clinicians hypothesized that the female client (compared to the male client) had been sexually abused in childhood. Clinicians who were more recently qualified, and clinicians who identified their predominant theoretical orientation as psychodynamic (rather than cognitive-behavioral), were more likely to hypothesize sexual abuse, although these effects were only statistically significant for the female clients. The majority of clinicians hypothesizing sexual abuse in the female client rated the abuse as the most important issue to address in therapy; this was not the case for the male client. These findings are discussed in relation to the literature suggesting that the apparent low number of male victims of sexual abuse currently being seen by the helping professions may in part be accounted for by a lack of awareness in clinicians as to the possibility that males, including their male clients, are sexually abused.
Adolescent↗
Efficacy of gabapentin therapy in children with refractory partial seizures.
Thirty-two children with refractory partial epilepsy received open-label gabapentin as an additional medication to their antiepileptic drug regimen. Gabapentin was given in a dose ranging from 10 to 50 mg/kg per day (mean dose, 26.7 mg/kg daily). All patients had partial seizures with or without secondary generalization. Compared with baseline, 11 patients (34.4%) had a greater than 50% decrease in seizure frequency, and 4 (12.5%) had a 25% to 50% decrease in seizure frequency. Of the seven children who received the medication for 6 months or longer, two were seizure free and four were almost seizure free (having one seizure every few months). Mean gabapentin concentration was 4.8 micrograms/ml, and mean apparent clearance was 372 ml/kg per hour. The major reported side effects were behavioral. These consisted of hyperactivity, irritability, and agitation that occurred in patients with baseline mental retardation with attention deficit. We conclude that gabapentin can be a useful adjunctive medication in the treatment of refractory partial epilepsy in children.
Acetates↗
Ictal and interictal technetium-99m-bicisate brain SPECT in children with refractory epilepsy.
UNLABELLED: Identification of epileptogenic foci in patients with refractory epilepsy remains a significant diagnostic challenge. Magnetic resonance imaging studies frequently fail to reveal an anatomic origin for the seizures, and scalp electroencephalography is often limited to identification of the involved hemisphere. Functional imaging modalities such as PET and SPECT are more promising tools for this application because they reflect the functional pathology associated with the seizure. These changes are more pronounced ictally, but until recently, no radiopharmaceutical was available that could be used routinely for ictal SPECT. The present study was therefore undertaken to determine whether 99mTc-bicisate could be used in ictal SPECT in pediatric patients with refractory epilepsy, to compare the patterns of ictal and interictal blood flow in these patients and to compare the localization information provided by ictal SPECT with that available from other techniques. METHODS: Technetium-99m-bicisate/SPECT was compared prospectively with scalp EEG for its ability to identify a possible seizure focus in pediatric patients with refractory epilepsy. Ictal and interictal SPECT studies were performed in 10 patients (3-19 yr old, mean age 10.9 +/- 4.3 yr; 7 female, 3 male) in whom MRI scans revealed no lesions that might be responsible for the seizures. RESULTS: Ictal SPECT was performed in all patients, and all ictal studies revealed focal perfusion abnormalities. By comparison, four of the interictal SPECT studies showed regional hypoperfusion that corresponded to the regions of hyperperfusion in the ictal studies, and three showed regional hyperperfusion corresponding to the hyperperfused regions in the ictal studies. Three interictal studies revealed no abnormal perfusion. Scalp EEG provided localization information in five patients. CONCLUSION: These initial results suggest that ictal SPECT with 99mTc-bicisate is a more promising tool for the identification of epileptogenic foci than interictal SPECT or scalp EEG in patients without focal abnormalities on MRI.
Brain↗
ECT in Parkinson's disease: neuropsychological response.
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Electroconvulsive Therapy↗
Maturational differences in coronary flow and interstitial transudate adenosine during alteration of perfusate oxygenation in isolated rabbit hearts.
This study was designed to investigate effects of perfusate oxygenation and maturation on coronary flow (CF), interstitial transudate adenosine (ITA) and coronary effluent adenosine (CEA) in isolated rabbit hearts. Hearts were paced at a fixed rate and were perfused under constant pressure at two different levels of perfusate oxygenation: baseline (B) (pO2 = 408 +/- 7 mmHg, O2 content = 1.28 +/- 0.03 ml O2/dl) and a lower level (L) (pO2 = 189 +/- 4 mmHg, O2 content = 0.59 +/- 0.02 ml O2/dl). CF was higher in immature (I, age 5 weeks) compared with mature (M, age 12 weeks) hearts at both levels of perfusate oxygenation (9.7 +/- 0.4 vs. 7.7 +/- 0.3 and 12.9 +/- 0.4 vs. 9.2 +/- 0.3 ml/min/g). I hearts had correspondingly higher values for myocardial oxygen consumption (MVO2) (53 +/- 3 vs. 49 +/- 2 and 39 +/- 3 vs. 35 +/- 2 microL O2/min/g), but similar values for venous oxygen tensions (nuO2) (240 +/- 9 vs. 219 +/- 10 and 74 +/- 4 vs. 62 +/- 3 mmHg), compared with M hearts at B and L. Although interstitial transudate adenosine (ITA) concentration was similar in I and M hearts at B (409 +/- 75 vs. 254 +/- 39 nM), it was lower in I than M hearts at L (2500 +/- 770 vs. 4210 +/- 1000 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine↗
DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations.
Constitutional point mutations in the zinc finger (ZF) region of the Wilms' tumour suppressor gene 1 (WT1) lead to Denys-Drash syndrome (DDS). Patients with this syndrome display renal failure, Wilms' tumour (WT) and pseudohermaphroditism. DDS WT1 mutations fall into three major categories: (a) missense mutations altering amino acids which directly interact with the DNA target; (b) substitution of amino acids involved in zinc complexing; and (c) nonsense mutations leading to the removal of at least two zinc fingers. We have expressed the WT1 zinc fingers as glutathione-S-transferase fusion proteins, with the lysine-threonine-serine (KTS) alternate splice between ZF3 and ZF4 either present or absent. WT1 fusion constructs with all three classes of DDS mutation were also created. Wild-type and mutant fusion proteins were assayed for their DNA-binding affinity using four previously identified WT1 DNA targets: an EGR1 consensus site; murine insulin-like growth factor 2 promoter 2 (IGF2P2); a (TCC)n motif from the PDGFA-chain promoter; and +P5, a genomic fragment isolated by its affinity for WT1 + KTS. WT1-KTS bound all four targets, but WT1 + KTS only bound +P5. All three classes of DDS mutation investigated, with or without KTS, abolished binding to all four targets. This provides evidence that DDS mutations act either as dominant-negative antimorphs, or elicit their effect through disturbed isoform dosage balance.
Abnormalities, Multiple↗
A national survey of admissions criteria and processes in selected allied health professions.
A national survey of admissions criteria and procedures was conducted for allied health programs in diagnostic medical imaging, health information management, nurse-midwifery, occupational therapy, physical therapy, and physician assistant education. From a sample of 462, 63.2% responded. The survey canvassed general program information, prerequisites, admissions procedures, and demographic trends. Respondents were primarily from public institutions with faculty actively involved in admissions. The most common prerequisites were anatomy/physiology, physics, biology, chemistry, and psychology; and the most frequently required admissions criteria were GPA, references, interviews, science GPA, and writing sample. Standardized tests were rarely utilized. The following were the major prerequisite characteristics and skills considered: academic skills, communication skills, problem-solving abilities, maturity/confidence, motivation, and work/study habits. Changing demographics were reported, including an increase in second-career, older, and ethnically diverse applicants. Also discussed were nontraditional and minority applicant admissions issues. Future research suggestions include use of noncognitive variables, and academic and clinical outcome studies. The utility of this information for validation/revision of admissions criteria are presented.
Allied Health Personnel↗
Seizures in children with supratentorial astroglial neoplasms.
We reviewed the records of 98 consecutive patients, 18 years of age or younger, with pathologically confirmed supratentorial astroglial neoplasms at the Children's Hospital, Boston, to evaluate the importance of seizures in their presentation and natural history. Tumors were diagnosed using the WHO criteria as pilocytic astrocytomas, astrocytomas, anaplastic astrocytomas, glioblastomas, giant cell glioblastomas, oligoastrocytomas and gangliogliomas. Our results were as follows. (1) Fifty percent of children had seizures as part of their presentation and 30% had seizures as their only presenting phenomenon. (2) The seizures varied in nature, but complex (55%) or simple (28%) partial seizures were by far the most common types, occurring in 77% of cases. (3) Preoperative electroencephalography (EEG) accurately lateralized to the tumor side in 88% of the cases and localized to the correct lobe in 56%. (4) Tumors involving cerebral cortex significantly correlated with seizures at presentation as compared to noncortical locations; 59% of patients with cortical tumors presented with seizures, and only 15% of patients with noncortical tumors experienced seizures. Lesions in the temporal and frontal lobes had the highest incidence of seizures. (5) Patients with gangliogliomas and oligoastrocytomas had the highest incidence of seizures, 88 and 86%, respectively, whereas patients with anaplastic astrocytoma had the lowest incidence, 21%. (6) Histopathologic calcification was associated with seizures at presentation approaching significance (p = 0.06). (7) Seizures at presentation were significantly associated with good prognosis (p = 0.02).
Adolescent↗
Early hypercyanotic spells unrelated to ductal constriction in tricuspid atresia with infundibular stenosis.
Clinical, echocardiographic, hemodynamic, and angiographic findings were reviewed in 16 consecutive patients with tricuspid atresia (TA) and normally related great arteries, seen at the University of Florida between 1984 and 1990, to determine when and in which hypercyanotic spells (HS), unrelated to ductal constriction, occurred. Such spells developed in six patients (38%) and were life-threatening and refractory to medical management in three patients. Most HS (five of six) occurred in the first 2 months of life. Angiography done at the time of diagnosis revealed similar morphological features in all patients subsequently experiencing HS; infundibular stenosis due to anterior malalignment in the conal septum. These findings suggest a predisposition for development of early HS in TA patients with apparent infundibular stenosis due to anterior malalignment of the conal septum. Further study and a heightened clinical awareness are needed in such patients.
Angiography↗
Perforation from endoscopic small bowel biopsy.
Two patients, having undergone an apparently straightforward endoscopy with small bowel biopsy, developed a perforation. One, who proved to have normal small bowel mucosa, needed laparotomy and suturing of the duodenal perforation. The other, who had coeliac disease, settled with conservative management.
Adult↗
Effect of growth and maturation in a hypoxic environment on maximum coronary flow rates of isolated rabbit hearts.
This study was designed to determine the effect of growth and maturation of rabbits in a hypoxic (H) environment on the ability to perfuse myocardium. Rabbits were raised in either a normoxic (N) (PO2 = 19.7 kPa or 149 torr) or an H environment (PO2 = 8.6 kPa or 65 +/- 3 mm Hg) and were studied at ages 5 wk (immature) and 12 wk (mature). Coronary flow (CF) was measured at baseline, during infusion of a maximally dilating concentration of adenosine (A), and at peak reactive hyperemic response to transient inflow occlusion in an isolated, non-blood-perfused heart preparation. Hearts were unloaded, paced at a constant rate (200 beats/min), and perfused at a constant inflow pressure (50 mm Hg). Regional CF was measured, using microspheres, in right ventricular, left ventricular, and atrial cardiac segments during vasodilation with A. H rabbits developed right ventricular but not left ventricular segment hypertrophy/hyperplasia. CF was greater in immature than mature hearts and higher in H than N hearts during baseline, vasodilation with A, and at peak reactive hyperemia (two-way analysis of variance, p < or = 0.05). Regional CF during vasodilation with A was greater in immature than mature hearts, in both right and left ventricular segments, and higher in H than N hearts in all cardiac segments (two-way analysis of variance, p < or = 0.05). Differences in total and regional CF between H and N hearts were present at both study ages (t test, p < or = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Age Factors↗