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Biomedical subjects

F Connell

Publications and source records attributed to F Connell.

At least 19 recordsLinked to original sources
PubMed2001

Identification of ligand-binding site III on the immunoglobulin-like domain of the granulocyte colony-stimulating factor receptor.

The granulocyte colony-stimulating factor receptor (G-CSF-R) forms a tetrameric complex with G-CSF containing two ligand and two receptor molecules. The N-terminal Ig-like domain of the G-CSF-R is required for receptor dimerization, but it is not known whether it binds G-CSF or interacts elsewhere in the complex. Alanine scanning mutagenesis was used to show that residues in the Ig-like domain of the G-CSF-R (Phe(75), Gln(87), and Gln(91)) interact with G-CSF. This binding site for G-CSF overlapped with the binding site of a neutralizing anti-G-CSF-R antibody. A model of the Ig-like domain showed that the binding site is very similar to the viral interleukin-6 binding site (site III) on the Ig-like domain of gp130, a related receptor. To further characterize the G-CSF-R complex, exposed and inaccessible regions of monomeric and dimeric ligand-receptor complexes were mapped with monoclonal antibodies. The results showed that the E helix of G-CSF was inaccessible in the dimeric but exposed in the monomeric complex, suggesting that this region binds to the Ig-like domain of the G-CSF-R. In addition, the N terminus of G-CSF was exposed to antibody binding in both complexes. These data establish that the dimerization interface of the complete receptor complex is different from that in the x-ray structure of a partial complex. A model of the tetrameric G-CSF.G-CSF-R complex was prepared, based on the viral interleukin-6.gp130 complex, which explains these and previously published data.

Amino Acid Sequence↗
PubMed2001

Neuronal ceroid lipofuscinoses: classification and diagnosis.

The neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative disorders characterized by accumulation of ceroid lipopigment in lysosomes in various tissues and organs. The childhood forms of the NCLs represent the most common neurogenetic disorders of childhood and are inherited in an autosomal-recessive mode. The adult form of NCL is rare and shows either an autosomal-recessive or autosomal dominant mode of inheritance. Currently, five genes associated with various childhood forms of NCLs, designated CLN1, CLN2, CLN3, CLN5, and CLN8, have been isolated and characterized. Two of these genes, CLN1 and CLN2, encode lysosomal enzymes: palmitoyl protein thioesterase 1 (PPT1) and tripetidyl peptidase 1 (TPP1), respectively. CLN3, CLN5, and CLN8 encode proteins of predicted transmembrane topology, whose function has not been characterized yet. Two other genes, CLN6 and CLN7, have been assigned recently to small chromosomal regions. Gene(s) associated with the adult form of NCLs (CLN4) are at present unknown. This study summarizes the current classification and new diagnostic criteria of NCLs based on clinicopathological, biochemical, and molecular genetic data. Material includes 159 probands with NCL (37 CLNI, 72 classical CLN2, 10 variant LINCL, and 40 CLN3) collected at the New York State Institute for Basic Research in Developmental Disabilities (IBR) as well as a comprehensive review of the literature. The results of our study indicate that although only biochemical and molecular genetic studies allow for definitive diagnosis, ultrastructural studies of the biopsy material are still very useful. Thus, although treatments for NCLs are not available at present, the diagnosis has become better defined.

Adolescent↗
PubMed2000

Neuronal ceroid lipofuscinoses: research update.

This study describes the phenotype/genotype analysis of 159 probands with neuronal ceroid lipofuscinosis (37 CLN1, 72 classic CLN2, 10 variant LINCL, and 40 CLN3) collected at the New York State Institute for Basic Research in Developmental Disabilities (IBR). Phenotype/genotype comparison showed that mutations in the CLN1 gene were associated with different phenotypes: infantile, late infantile, and juvenile. Two common mutations (223A-->C and 451C-->T) were found in 26 of 37 CLN1 subjects (64% of alleles examined). A nonsense point mutation, 451C-->T, was the most common in CLN1 subjects with infantile onset at 0-2 years, accounting for 50% of alleles studied. A missense point mutation, 223A-->C, was the most common among CLN1 subjects with juvenile onset older than 4 years, accounting for 45% of alleles examined. Twenty-one other CLN1 mutations were identified in 4 of 37 subjects with infantile onset, 6 of 37 with late-infantile onset, and 6 of 37 with juvenile onset. All CLN1 probands were palmitoyl-protein thioesterase (PPT)-deficient and showed granular osmiophilic deposits (GROD) at the electron microscopic (EM) level. In the group of classic CLN2 (72 probands), two common mutations were found: an intronic 3556G-->C transversion in the invariant AG of 3' splice junction in 55% of probands, and a nonsense mutation 3670C-->T in 30% of probands. Classic late-infantile onset (2-4 years) was found in 68 of 72 (95%) cases, whereas juvenile onset (> 4 years) occurred only in 4 of 72 (5%) cases. All probands had deficiency of tripeptidyl-peptidase I (TPP1) activity and, at the EM level, curvilinear profiles. Ten probands with late-infantile onset did not show mutations in the CLN2 gene, had normal TPP1 activity, and at the EM level had mixed profiles. Further studies are in progress to identify genetic defect(s) in these subjects. The CLN3 group (40 probands) was divided into two categories: classic or typical presentation, and delayed classic or atypical presentation. All CLN3 patients had onset of symptoms after 4 years of age. In 40 probands, the 1.02-kb common deletion was found in one or two alleles of the CLN3 gene. Homozygotes for the common CLN3 deletion showed the classic phenotype. The phenotype in compound heterozygotes was either the classic or the delayed classic or atypical form. Thus, our study indicates that some mutations in the CLN1 and CLN2 genes may be associated with juvenile onset of the disease process and a more benign clinical course. Interfamilial and intrafamilial variations also were found, especially in the speed of becoming blind and neurologically disabled.

Aminopeptidases↗
PubMed1999

Reevaluation of neuronal ceroid lipofuscinoses: atypical juvenile onset may be the result of CLN2 mutations.

This study describes the phenotype/genotype analyses of 56 probands with a juvenile onset, some of which had atypical features of neuronal ceroid lipofuscinosis, collected at the New York State Institute for Basic Research (IBR). In this group, we found probands with abundant curvilinear profiles in lysosomal storage material, deficiency of pepstatin-insensitive peptidase, and mutations in the CLN2 gene, as well as patients with a predominance of granular osmiophilic deposits in the lysosomal storage material, deficiency of palmitoyl-protein thioesterase, and mutations in the CLN1 gene. We have divided the probands into two categories: typical (or classic) and atypical. Most of the typical and atypical probands had onset of symptoms about or after 4 years of age. Interfamiliar and intrafamiliar variations were found, especially in the speed of becoming practically blind. Thus, our study indicates that some mutations in the CLN1, CLN2, and CLN3 genes may be associated with late onset of the disease process, may have a more benign clinical course, and clinic overlap with other forms of neuronal ceroid lipofuscinosis.

Adolescent↗
PubMed1998

Palmitoyl-protein thioesterase deficiency in a novel granular variant of LINCL.

Typically, late infantile neuronal ceroid-lipofuscinosis (LINCL) patients present between the ages of 2 and 4 years with progressive dementia, blindness, seizures, and motor dysfunction. Curvilinear profiles are seen on electron microscopic examination of tissues derived from those patients. Data were collected on 122 LINCL cases, representing 81 independent families, diagnosed on the basis of age of onset, clinical symptomatology, and pathologic findings. Careful analysis of our data has revealed that 20% of these cases (24 of 122) show either an atypical clinical course or atypical pathologic findings and may represent variants of LINCL. Recent progress in the biochemistry and molecular genetics of NCL has led us to reevaluate these atypical cases. Five atypical LINCL cases (representing three independent families) manifested granular inclusions when examined by electron microscopy, a finding normally associated with the infantile form of NCL. In addition, these five cases did not show elevated subunit c levels in urine (typically seen in LINCL). In these five cases, palmitoyl-protein thioesterase activity was found to be deficient (less than 10% normal activity), suggesting that these cases represent INCL, presenting at a later age of onset. These findings suggest that palmitoyl-protein thioesterase deficiency is not restricted to infantile onset cases, and they raise the possibility that milder forms of INCL may result from less deleterious mutations.

Age of Onset↗
PubMed1997

Atypical late infantile and juvenile forms of neuronal ceroid lipofuscinosis and their diagnostic difficulties.

We have collected 122 late-infantile neuronal ceroid lipofuscinosis (LINCL, CLN2) and 191 juvenile NCL (JNCL, CLN3) cases, diagnosed on the basis of age-at-onset, clinical symptomatology, and pathological findings and representing the most common forms of NCL in the United States, and Europe. However, careful analysis of available data revealed that about 80% of cases show typical and 20% show atypical clinical course and/or pathological findings and thus, may represent variants of LINCL and JNCL, respectively. Recent progress in the biochemistry and molecular genetics of NCL inclined us to reevaluate these atypical NCL cases. The gene responsible for LINCL has not yet been identified, except for the Finnish variant. Accumulation of subunit c of mitochondrial ATP synthase, to curvilinear profiles, is found in LINCL cases. A novel variant of LINCL, with predominantly granular profiles in the lysosomal storage, as well as normal excretion of subunit c in urine samples, was found in five cases. When the palmitoyle-protein thioesterase (PPT) was studied in these five cases, it was found that the level was deficient, suggesting that they are not LINCL, but the infantile form of neuronal ceroid lipofuscinosis (INCL). Using molecular genetic techniques in the typical JNCL cases, common 1.02 kb deletion to CLN3 was found in 23/27 (homozygotes) and in one allele 4/27 (heterozygotes) in affected pedigrees. In atypical JNCL pedigrees, it was found in 5/16 heterozygotes, while in 1/5 pedigrees, a novel mutation of one atypical JNCL where a single amino acid substitution at 295 E-->K was found in one allele. None of the atypical JNCL cases was homozygote. In atypical JNCL cases where mutation in CLN3 has not been identified (11/16 probands), several possibilities may exist. The phenotype may be caused by a yet undefined mutation in CLN3 or may be due to phenotypically overlapping with other forms of NCL. Pheno/genotypic correlation and the diagnostic difficulties are discussed.

Adolescent↗
PubMed1995

Topographic variabilities of immunoreactivity to subunit c of mitochondrial ATP synthase and lectin binding in late infantile neuronal ceroid-lipofuscinosis.

A subset of lipophilic neurons in the brain tissue of late infantile neuronal ceroid lipofuscinosis (LINCL) cases shows in addition to finely granular storage lipopigment, larger spheroidal lysosomal inclusions, so called protein-type myoclonus bodies. Their incidence, significance, and biochemical composition have not been determined. To further characterize this type of lysosomal storage material, immunocytochemistry to subunit c of mitochondrial ATP synthase at the light and electron microscopy level, electron microscopy, and lectin histochemistry were applied. The majority of spheroidal inclusions were nonreactive to subunit c, the main protein component of the storage material in LINCL. These inclusions also showed no binding sites for the eight lectins examined, although six of the lectins used labeled finely granular storage material. According to electron and immunoelectron microscopy, spheroidal inclusions were composed of more homogeneous and more densely arranged material than typical curvilinear profiles, with shorter membranous profiles and sometime filamentous structures. The dissimilarities disclosed between finely granular lipopigment with curvilinear profiles and spheroidal inclusions in LINCL brain tissue suggest that either protein(s) other than subunit c are present in spheroidal inclusions, or subunit c in these sites undergoes conformational or proteolytic changes. These changes require further biochemical evaluations.

Brain↗
PubMed1995

Parents' attitudes toward firearm injury prevention counseling in urban pediatric clinics.

OBJECTIVES: To examine characteristics and experiences associated with gun ownership among parents of pediatric patients who attend urban pediatric clinics and to determine the receptivity of these parents to firearm injury prevention counseling. DESIGN: A focus group discussion was followed by a cross-sectional survey. SETTING: Four public pediatric clinics in a large metropolitan area were included. PARTICIPANTS: A focus group discussion was held with parents and was used to develop the questionnaire, which was then distributed over a 6-week period to parents accompanying children to the clinic. The anonymous, self-administered questionnaire was completed by 510 parents or guardians, with an 88% response rate. RESULTS: Twenty percent of respondents reported that they had a firearm in the home. Twenty-seven percent of respondents had experienced having a family member shot. Eighty-two percent of all respondents indicated that they would find information about the safest way to store a gun helpful or very helpful. Of all respondents, 47% would follow and an additional 37% would think over a provider's advice not to keep guns in the home. Gun owners were less inclined to report that they would follow this advice (19%), but 55% of the gun owners would think over this advice. Only 6% of all respondents reported that they would ignore or be offended by such advice. CONCLUSIONS: Children attending public urban pediatric clinics are exposed to guns in their homes, and their parents appear to be receptive to firearm injury prevention counseling from their child's health care providers.

Ambulatory Care Facilities↗
PubMed1993

StORQS: Washington's Statewide Obstetrical Review and Quality System: overview and provider evaluation.

The Foundation for Health Care Quality (Washington) used three administrative public databases and indicators recommended by the Joint Commission and the American College of Obstetrics and Gynecology to build algorithms to measure quality of obstetric care in the state of Washington. Analyses demonstrated a high degree of variability across hospitals for major processes of care such as cesarean section, vaginal birth after cesarean section, and forceps deliveries. Eighty-five percent of the participating hospitals concluded that important aspects of care were being measured. Ninety-four percent found the information useful in describing their performance compared with other hospitals. Sixty-two percent believed the information was useful for initiating quality improvement projects. Of the 25 indicators tested in the project, indicators rated as most useful were the same 10 obstetric indicators chosen by the Joint Commission after alpha testing.

Cesarean Section↗
PubMed1993

New subform of the late infantile form of neuronal ceroid lipofuscinosis.

Clinicopathological studies of a series of nine children with a new subform of Jansky-Bielschowsky disease or late infantile neuronal ceroid lipofuscinosis (LINCL) is presented. The onset of this subform is between 2.5-3.5 years of age with initial neurological symptoms of abnormal motor skills caused by cerebellar and extrapyramidal signs. Soon after dementia, myoclonic seizures are followed. Visual impairment is more clearly seen after the age of 5 or 6 years. The ultrastructural studies of the skin and/or buffy coat showed abundant lysosomal storage of curvilinear profiles, rarely intermixed with fingerprint profiles. The MRI of the head performed in seven cases, showed initially enlargement of the ventricles that is secondary to basal ganglia atrophy and presence of cerebellar and cerebral atrophy. In 4 of 7 cases (Cases 1, 5, 6, 8) abnormalities in the deep white matter showing increased signals of T2-weighted imaging in the periventricular areas of the fronto-parietal region, internal capsule, tracks of the brainstem, and white matter of cerebellum were seen. These abnormalities were also observed by post-mortem neuropathological studies in three cases (nos. 7-9). The MRI in Cases 7 and 9 was not performed. The electrophysiological abnormalities (EEG, ERG, VER) are similar as described in the classical LINCL. Neuropathological studies done in 3 of 9 cases showed generalized brain atrophy and unique type of neuronal cytoplasmic inclusion body in the basal ganglia, brainstem, dentate nuclei, and rarely, cerebral cortex. These large, round neuronal cytoplasmic inclusions were pink in hematoxylin (HE), violet in cresyl violet, and dark blue with Klüver-Barrera method.(ABSTRACT TRUNCATED AT 250 WORDS)

Basal Ganglia↗
PubMed1992

Variability in the clinical and pathological findings in the neuronal ceroid lipofuscinoses: review of data and observations.

We reviewed the clinical and pathological data on 319 neuronal ceroid lipofuscinosis (NCL) cases to determine the degree of variability within the different forms and among and within families. Thirty-six cases (11.3%) were the infantile form; 116 cases (36.3%), late infantile; 163 cases (51.1%), juvenile; and four cases (1.3%), the adult form (Kufs disease). Clinical variability was found in all forms studied, but was most striking in the juvenile and late infantile forms of NCL. The expected initial findings of seizures, dementia, blindness, or motor impairment were evident in 255 cases (80%), and rarer, less typical initial neurological symptoms were seen mainly in the 64 cases (20%) of the juvenile form: behavior abnormalities (18/64), psychoses (12/64), neuropathy (2/64), involuntary movements (15/64), ataxia (9/64). Six juvenile and two adult cases had no detectable impairment of vision. All 319 NCL cases had skin or conjunctive biopsies or buffy coats that showed the characteristic ultrastructural abnormalities of NCL. Variability was evident in 16.7% in that a combination of fingerprint, curvilinear, and membranous profile inclusion bodies was observed in storage lysosomes, although one type of inclusion was distinctly predominant for each form. Postmortem examination of brains of 19 NCL cases (three with the infantile form, six with the late infantile form, nine with the juvenile form, and one with the adult form) revealed characteristic changes. Sixteen of the 19 NCL brains (84%) showed pathological variability in that they contained more than one kind of characteristic inclusion body in the neuronal lysosomal storage compartment. In all 19 NCL brains, small amounts of aging lipofuscin were also found.(ABSTRACT TRUNCATED AT 250 WORDS)

Amyloid beta-Protein Precursor↗
PubMed1991

Referral keeping in homeless women.

We examined factors associated with referral keeping among 118 homeless women screened for health care needs in Seattle. Referral keeping for medical conditions among the homeless was comparable to rates found in general low-income populations (62 percent vs. 65 percent), but their proportion of kept referrals for preventive care was much lower (22 percent vs. 44-51 percent). Referral keeping varied directly with symptom severity. Consistent with this finding was that among interviewed subjects who did not keep the index referral, 37 percent kept other referrals for more severe problems or if the condition worsened. Personal stresses and competing priorities, weighted against perceived medical urgency, were the major factors influencing referral keeping. Screener encouragement and communication of medical urgency were indicated by one-third of the subjects who kept referrals as providing important motivation for treatment.

Adult↗
PubMed1990

What is too much variation? The null hypothesis in small-area analysis.

A small-area analysis (SAA) in health services research often calculates surgery rates for several small areas, compares the largest rate to the smallest, notes that the difference is large, and attempts to explain this discrepancy as a function of service availability, physician practice styles, or other factors. SAAs are often difficult to interpret because there is little theoretical basis for determining how much variation would be expected under the null hypothesis that all of the small areas have similar underlying surgery rates and that the observed variation is due to chance. We developed a computer program to simulate the distribution of several commonly used descriptive statistics under the null hypothesis, and used it to examine the variability in rates among the counties of the state of Washington. The expected variability when the null hypothesis is true is surprisingly large, and becomes worse for procedures with low incidence, for smaller populations, when there is variability among the populations of the counties, and when readmissions are possible. The characteristics of four descriptive statistics were studied and compared. None was uniformly good, but the chi-square statistic had better performance than the others. When we reanalyzed five journal articles that presented sufficient data, the results were usually statistically significant. Since SAA research today is tending to deal with low-incidence events, smaller populations, and measures where readmissions are possible, more research is needed on the distribution of small-area statistics under the null hypothesis. New standards are proposed for the presentation of SAA results.

Age Factors↗
PubMed1987

Phospholipid metabolism in mouse sciatic nerve in vivo.

To probe the activities of various pathways of lipid metabolism in peripheral nerve, six phospholipid-directed precursors were individually injected into the exposed sciatic nerves of adult mice, and their incorporation into phospholipids and proteins was studied over a 2-week period. Tritiated choline, inositol, ethanolamine, serine, and glycerol were mainly used in phospholipid synthesis; in contrast, methyl-labeled methionine was primarily incorporated into protein. Phosphatidylcholine was the main lipid formed from tritiated choline, glycerol, and methionine precursors. Phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol were the main lipids formed from serine, ethanolamine, and inositol, respectively. With time there was a shift in label among phospholipids, with higher proportions of choline appearing in sphingomyelin, glycerol in phosphatidylserine, ethanolamine in phosphatidylethanolamine (plasmalogen), and inositol in polyphosphoinositides, especially phosphatidylinositol 4,5-bisphosphate. We suggest that the delay in formation of these phospholipids, which are concentrated in peripheral nerve myelin, may, at least in part, be due to their formation at a site(s) distant from the sites where the bulk of Schwann cell lipids are made. We propose that separating the synthesis of these myelin-destined lipids to near the Schwann cell's plasma membrane would facilitate their concentration in peripheral nerve myelin sheaths. At earlier labeling times, ethanolamine and glycerol were more actively incorporated into phosphatidylcholine and phosphatidylinositol, respectively, than later. The transient labeling of these phospholipids may reflect some unique role in peripheral nerve function.

Animals↗
PubMed1985

Adult fragile X syndrome. Clinico-neuropathologic findings.

Fragile X syndrome [fra (X)] is currently accepted as the second most frequent chromosomal disorder associated with developmental disability. Although next to Down syndrome in frequency, no postmortem studies of confirmed adult cases had been reported. The autopsy examination of a 62-year-old, moderately retarded man with the fra (X) syndrome confirmed the preferential involvement of cerebral and testicular structures in this disorder. Dendritic spine abnormalities of the type observed in trisomic chromosomal disorders were associated with synaptic immaturity. Severe testicular hypogonadism accompanied bilateral macro-orchidism, normal penis, and unilateral hydrocele. Valvular, articular, and testicular interstitial compartments showed normal histochemical staining characteristics for glycoproteins and lipids.

Brain↗
PubMed1979

Remyelination in multiple sclerosis.

Chronic plaques in central nervous system tissue fixed by in situ perfusion for electron microscopy were examined for evidence of remyelination in 2 patients with multiple sclerosis (MS). Fibers with abnormal central myelin sheaths of several types were found at the margins of most of the plaques studied. The most common of these were: (1) the presence of bare stretches of axon between contiguous internodes, (2) the presence of thin paranodes, (3) internodes which changed markedly in thickness along their length due to premature termination of superficial or deep myelin lamellae that ended as hypertrophic lateral loops, and (4) abnormally thin internodes which were of uniform thickness along their length, which were shorter than normal, and which terminated in the form of normal nodal complexes. The finding of internodes of the last type at the edges of many plaques indicates that remyelination by oligodendrocytes can occur in the adult human CNS and that it is common in some cases of MS, although limited in its extent.

Central Nervous System↗