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Biomedical subjects

J D Smith

Publications and source records attributed to J D Smith.

At least 181 records · Page 10Linked to original sources
PubMed1993

3-Nitro-3,4-dihydro-2(1H)-quinolones. Excitatory amino acid antagonists acting at glycine-site NMDA and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.

3,4-Dihydro-2(1H)-quinolones, evolved from 2-carboxy-1,2,3,4,- tetrahydroquinolines and 3-carboxy-4-hydroxy-2(1H)-quinolones, have been synthesized and evaluated in vitro for antagonist activity at the glycine site on the NMDA receptor and for AMPA [(RS)-alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid] antagonist activity. Generally poor potency at the glycine site is observed when a variety of electron-withdrawing substituents are attached to the 3-position of 3,4-dihydro-2(1H)-quinolones. The analogues 5-9 (IC50 values > 100 microM, Table I) exist largely in the 3,4-dipseudoaxial conformation (as evidenced by 1H NMR spectra), whereas the 3-cyano derivative (10, IC50 = 12.0 microM) has a relatively high population of the 3-pseudoequatorial conformer. The 3-nitro analogue (4, IC50 = 1.32 microM) has a pKa approximately 5 and thus exists at physiological pH as an anion with the nitro group planar to the quinolone ring. The general requirement of acidity for high affinity binding at the glycine/NMDA site is supported with the good activity of the other 3-nitro derivatives (13-21), all of which are deprotonated at physiological pH. The 3-nitro-3,4-dihydro-2(1H)-quinolones and 2-carboxy-1,2,3,4-tetrahydroquinolines show quite different structure-activity relationships at the 4-position. The unselective excitatory amino acid activity of 21 is comparable with 6,7-dichloro-quinoxaline-2,3-dione and 6,7-dichloroquinoxalic acid and this suggests similarities in their modes of binding to excitatory amino acid receptors. The broad spectrum excitatory amino acid antagonist activity of the 4-unsubstituted analogue 21 (KbNMDA = 6.7 microM, KbAMPA = 9.2 microM) and the glycine/NMDA selectivity of the other 3-nitro derivatives allows the proposal of a model for AMPA receptor binding which differs from the glycine binding pharmacophore in that there is bulk intolerance adjacent to the 4-position. Compound 21 (L-698,544) is active (ED50 = 13.2 mg/kg) in the DBA/2 mouse anticonvulsant model and is the most potent combined glycine/NMDA-AMPA antagonist yet reported, in vivo, and may prove to be a useful pharmacological tool.

Amino Acids↗
PubMed1993

A population-based assessment of invasive disease due to group B Streptococcus in nonpregnant adults.

BACKGROUND: Group B streptococci (Streptococcus agalactiae) are a major cause of meningitis and septicemia in neonates and pregnant women, but the importance of group B streptococcal disease in nonpregnant adults has not been clearly defined. METHODS: We conducted a prospective surveillance of the pathogens responsible for meningitis for a period of 24 months in 35 hospitals and a referral laboratory in metropolitan Atlanta. We reviewed the clinical and laboratory records of all the nonpregnant adults identified as having invasive group B streptococcal disease during this period. RESULTS: During 1989 and 1990 there were 424 patients with invasive group B streptococcal disease (annual incidence, 9.2 cases per 100,000 population). Of these patients, 46 percent were 1 month of age or younger, 6 percent were older than 1 month but younger than 18 years of age, and 48 percent were 18 or older. Men and nonpregnant women accounted for 68 percent (n = 140) of all cases among adults (annual incidence, 4.4 per 100,000). Clinical and laboratory records were available for 137. In the nonpregnant adult patients (age, 18 to 99 years), the most common clinical diagnoses were skin, soft-tissue, or bone infection (in 36 percent); bacteremia with no identified source (30 percent); urosepsis (14 percent); pneumonia (9 percent); and peritonitis (7 percent). Risk factors included older age (> or = 60 years), the presence of diabetes mellitus, the presence of malignant neoplasms, and infection with the human immunodeficiency virus. The mortality rate in nonpregnant adults was 21 percent, accounting for 67 percent of all deaths related to group B streptococcal infection during the surveillance period. CONCLUSIONS: Invasive group B streptococcal infection is a major problem not only in pregnant women and neonates but also in nonpregnant adults, especially those who are elderly and those who have chronic diseases.

AIDS-Related Opportunistic Infections↗
PubMed1993

Mammalian heterogeneous ribonucleoprotein A1 and its constituent domains. Nucleic acid interaction, structural stability and self-association.

With a view toward further understanding the structure-function relationships of the eukaryotic heterogeneous ribonucleoprotein (hnRNP) A1, and in particular its multiplicity of nucleic acid-interactive domains, we have studied the nucleic acid binding properties of the globular N-domain (UP1) and sequence-repetitive, flexible C-domain, the thermal denaturation of UP1 and the concomitant effects of binding polynucleotide, and the self-associative properties of the full-length protein. Utilizing protein tryptophan fluorescence as a probe, polynucleotide binding was shown to stabilize UP1 against thermal unfolding. The denaturation profile of UP1-poly(thymidylic acid) complexes was biphasic, suggesting that unfolding of the two subdomains of UP1 can occur independently. This is in agreement with a previously proposed structure in which only one of the two UP1 subdomains binds the nucleic acid. The subdomains of UP1 can be prepared by controlled proteolysis of A1, further indicating that these two globular segments within A1 are connected by an exposed, flexible linkage. Circular dichroism measurements on UP1 confirm previous data that this portion of A1 binds single-stranded nucleic acids non-co-operatively. UP1 clearly shows a preference for single-stranded nucleic acids with a 2'-OH, since its affinity for poly(U) is three times higher than for poly(dU), and five times higher than its affinity for poly(2'-OCH3U). The nucleic acid-interactive properties of the C-domain were further examined by preparing a synthetic peptide polymer (M(r) approximately 12,000) containing about seven repeats of a 16-residue sequence, GNFGGGRGGNYGGSRG, which in turn comprises two copies of the C-terminal consensus, GN(F/Y)GG(G/S)RG. The polymer of this sequence exhibited significant affinity for the fluorescent polyribonucleotide, poly(ethenoadenylic acid), binding stoichiometrically at < or = 0.2 M-Na+. Complex formation was accompanied by an increase in aggregate formation, as indicated by the appearance of scattering. For purposes of comparison, the data were analyzed via the linear co-operative model of McGhee and von Hippel, though this model may not be fully descriptive of the protein-nucleic acid complex(es) formed in this case. In contrast to the non-co-operative binding mode of the UP1 domain, the C-polymer exhibited moderate co-operativity, comparable to that seen with full-length A1. Although addition of sufficient NaCl reversed the interaction, a sigmoidal binding isotherm could still be observed (with sufficient added polymer) at 0.8 M-NaCl. This suggests that non-electrostatic interactions contribute significantly to the free energy of binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1993

Phospholipid biosynthesis in protozoa.

Because of the diverse nature of the organisms which are all classed as 'protozoa' (and because of the lack of detailed information on phospholipid metabolism about most of them), it will probably never be possible to generalize phospholipid metabolism to the degree that it has been possible to characterize a mammalian metabolism. Nonetheless, patterns have begun to emerge (i.e. the similarities among the ciliates Entodinium, Paramecium and Tetrahymena) and will not doubt be expanded upon in the future.

Animals↗
PubMed1993

Clozapine-induced agranulocytosis and colony-stimulating cytokines.

A case of clozapine-induced agranulocytosis that was treated with a granulocyte colony-stimulating cytokine is presented. The hematological status normalized. Two colony-stimulating factors are marketed for activating bone marrow function. Their utility in clozapine a granulocytoses is not clear, but they offer a potential new therapeutic option.

Agranulocytosis↗
PubMed1993

The effect of panel reactive antibodies and the donor specific crossmatch on graft survival after heart and heart-lung transplantation.

Data from 699 cardiac and 290 heart-lung transplants has been analysed to determine the importance of the lymphocytotoxic crossmatch result and panel reactive antibody (PRA) status on graft survival. Donor reactive crossmatching was performed for 636 cardiac transplants. One year actuarial survival for a negative crossmatch (n = 580) was 73% compared to 56% for the positive crossmatch recipients (n = 56) p = 0.0014. Where crossmatches were performed on separated T and B cells, the T cell directed crossmatch was found to be highly predictive of graft failure in 289 cardiac transplants. One year survival for a negative crossmatch was 73% (n = 258), for B cell positive crossmatch recipients 62% (n = 24), and for a positive T cell crossmatch 28% (n = 7) (p = 0.001). Patients' PRA status were grouped into those with negative, medium and high frequencies. There was a trend (not statistically significant) for patients with PRA above 50% to have poor graft survival. Patients with PRA above 50% were significantly more likely to have a positive lymphocytotoxic crossmatch against donor lymphocytes. Donor reactive crossmatching was performed for 283 heart-lung transplants. One year actuarial survival for a negative crossmatch was 61% (n = 251) and for a positive result was 50% (n = 32), p = 0.02.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody Specificity↗
PubMed1993

Depression and category learning.

This article explores the relationship between depression and category learning. We predicted that depression would impair categorization performance on criteria-attribute tasks, which require systematic hypothesis testing, but not on family-resemblance tasks, which allow processing strategies that are likely preserved in depression. These predictions were confirmed in 2 experiments using different stimuli, tasks, and S populations. We discuss some implications of the empirical connections among depression, the use of less sophisticated cognitive strategies, and category learning.

Adult↗
PubMed1993

Bedside polysomnography as an adjunct in the management of infants with Robin sequence.

Objective indications for tongue-lip adhesion in infants with Robin sequence have been lacking because of the difficulty in assessing the clinical significance of airway obstruction. In 1988, we began to use 20-hour, four-channel polysomnography to assist us in the management of infants with Robin sequence. The four channels included electrocardiogram, respiratory motion, airflow, and oxygen saturation. Infants demonstrating significant episodes of airway obstruction during sleep were recommended for tongue-lip adhesion. Fifteen infants with Robin sequence were evaluated during a 3-year period. Two babies were having severe, clinically obvious events on admission and underwent tongue-lip adhesion without polysomnography. Polysomnography was done on the other 13 infants. No significant events were seen in 7 infants, and they were discharged after a mean hospitalization of 8 days. Six studies documented significant airway obstruction, and tongue-lip adhesion was recommended. Follow-up polysomnography performed after successful tongue-lip adhesion failed to show any significant events, and the infants only required hospitalization for a mean of 12 days. We conclude that polysomnography is a useful adjunct in the management of infants with Robin sequence, providing objective indications for surgical intervention and shortening hospitalization.

Humans↗
PubMed1993

Localization of a liver-specific enhancer in the apolipoprotein E/C-I/C-II gene locus.

The sequences necessary for liver-specific expression of the apolipoprotein (apo) E gene have been shown to reside 3' to the gene, within the apoE/C-I/C-II gene cluster, but have not been precisely characterized. Utilizing a transient transfection reporter gene assay based on the apoC-II promoter, we have localized a liver-specific enhancer to its approximate limit dimension of 154 base pairs. This enhancer directed liver-specific expression of an apoE gene construction in transgenic mice. A DNaseI protection assay revealed two footprints over an inverted repeat of a known transcriptionally active motif, TGACCT. DNaseI-sensitive sites were present in three of six repeats of a motif (consensus GCAAACA) which has been postulated to represent the recognition sequence of a hepatic transcriptional activity, HNF-5. This region of DNA may function as a liver-specific enhancer for the entire apoE/C-I/C-II gene cluster.

Animals↗
PubMed1993

Institutionalization, involuntary sterilization, and mental retardation: profiles from the history of the practice.

For much of the 20th century, the practice of sterilization was a common accompaniment to institutionalization for individuals with mental retardation. Following the Supreme Court's decision in Buck v. Bell (1927) supporting the practice, numerous states passed legislation and, consequently, over 60,000 individuals with mental retardation were sterilized in this country. In the present study we analyzed data on 212 individuals in Virginia who were sterilized. Our focus included gender, age at and date of sterilization, level of mental retardation, and location of subsequent discharge. The nature of these findings within the general context of the practice of sterilization was discussed.

Adolescent↗
PubMed1992

Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.

apoE-deficient mice have been created by homologous recombination in ES cells. On a low fat, low cholesterol chow diet these animals have plasma cholesterol levels of 494 mg/dl compared with 60 mg/dl in control animals, and when challenged with a high fat Western-type diet, these animals have plasma cholesterol levels of 1821 mg/dl compared with 132 mg/dl in controls. This marked hypercholesterolemia is primarily due to elevated levels of very low and intermediate density lipoproteins. At 10 weeks of age, apoE-deficient mice have already developed atherosclerotic lesions in the aorta and coronary and pulmonary arteries. apoE-deficient mice are a promising small animal model to help understand the role of apoE in vivo and the genetic and environmental determinants of atherosclerosis.

Animals↗
PubMed1992

Extensive peptide ligand exchange by surface class I major histocompatibility complex molecules independent of exogenous beta 2-microglobulin.

Certain class I major histocompatibility complex molecules expressed on live cells have been shown to bind exogenous peptide ligands. However, it remains controversial whether this binding occurs by peptide exchange or to empty surface class I molecules. In this report we compare the surface binding and dissociation of two virus-derived ligands of the Ld class I molecule of the mouse. The peptide ligands were previously identified in immune responses to cytomegalovirus or lymphochoriomeningitis virus as immunodominant, optimally sized, and Ld restricted. Ligand dissociation was monitored on live cells indirectly by measuring the surface turnover of Ld-peptide complexes or directly by using labeled peptides. The cytomegalovirus-derived and lymphochoriomeningitis virus-derived peptides appeared to dissociate relatively rapidly; however, the cytomegalovirus-derived peptide had a more rapid off-rate than the lymphochoriomeningitis-derived peptide. Furthermore, these rates of dissociation appear to span that seen with endogenous Ld-associated peptides expressed by cells at 37 degrees C. Exploiting the extraordinary accessibility of the surface Ld ligand binding site we developed an assay to quantitate peptide ligand exchange. Cells were precoated with saturating amounts of unlabeled peptide by overnight incubation and were then tested for secondary binding of labeled peptides in a 4-h assay. Our results unequivocally demonstrate the potential for surface class I molecules to undergo peptide exchange. Furthermore, peptide exchange was found to be largely independent of exogenous beta 2-microglobulin. This result implies that beta 2-microglobulin association and not beta 2-microglobulin exchange is the critical factor in peptide exchange by surface class I molecules. Because of the exquisite ability of T cells to discriminate different amounts of ligand bound to class I, the binding of exogenous peptides could play a critical role in normal or aberrant immune responses.

Animals↗
PubMed1992

4-Amido-2-carboxytetrahydroquinolines. Structure-activity relationships for antagonism at the glycine site of the NMDA receptor.

trans-2-Carboxy-5,7-dichloro-4-amidotetrahydroquinolines, evolved from the lead 5,7-dichlorokynurenic acid, have been synthesized and tested for in vitro antagonist activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Optimization of the 4-substituent has provided antagonists having nanomolar affinity, including the urea trans-2-carboxy-5,7-dichloro-4[[(phenylamino)carbonyl]amino]-1,2,3, 4-tetrahydroquinoline (35; IC50 = 7.4 nM vs [3H]glycine binding; Kb = 130 nM for block of NMDA responses in the rat cortical slice), which is one of the most potent NMDA antagonists yet found. The absolute stereochemical requirements for binding were found to be 2S,4R, showing that, in common with other glycine-site NMDA receptor ligands, the unnatural configuration at the alpha-amino acid center is required. The preferred conformation of the trans-2,4-disubstituted tetrahydroquinoline system, as shown by X-ray crystallography and 1H NMR studies, places the 2-carboxyl pseudoequatorial and the 4-substituent pseudoaxial. Modifications of the 4-amide show that bulky substituents are tolerated and reveal the critical importance for activity of correct positioning of the carbonyl group. The high affinity of trans-2-carboxy-5,7-dichloro-4-[1-(3-phenyl-2-oxoimidazolidinyl)]- 1,2,3,4-tetrahydroquinoline (55; IC50 = 6 nM) suggests that the Z,Z conformer of the phenyl urea moiety in 35 is recognized by the receptor. Molecular modeling studies show that the 4-carbonyl groups of the kynurenic acids, the tetrahydroquinolines, and related antagonists based on N-(chlorophenyl)glycine, can interact with a single putative H-bond donor on the receptor. The results allow the establishment of a three-dimensional pharmacophore of the glycine receptor antagonist site, incorporating a newly defined bulk tolerance/hydrophobic region.

Aminoquinolines↗
PubMed1992

Invasive Haemophilus influenzae disease in adults. A prospective, population-based surveillance. CDC Meningitis Surveillance Group.

OBJECTIVE: To define the incidence of and possible risk factors for invasive Haemophilus influenzae disease in adults. DESIGN: Prospective, population-based surveillance of hospital and referral bacteriology laboratories. SETTING: Metropolitan Atlanta, Georgia community. PATIENTS: All patients with H. influenzae isolated from normally sterile sites (blood, cerebrospinal fluid, joint, pleura) from 1 December 1988 through 31 May 1990. MEASUREMENTS: Isolates of H. influenzae were analyzed for serotype and biotype status, outer membrane proteins, lipooligosaccharide phenotypes, ribotyping patterns and beta-lactamase production. RESULTS: A total of 194 cases of invasive H. influenzae occurred (annual incidence of 5.6 cases/100,000 population), of which 47 (24%) were in adults 18 years old or older (annual incidence 1.7 cases/100,000 adults). Adults with invasive H. influenzae ranged from 18 to 96 years; 79% were women. Bacteremic pneumonia accounted for 70% of the adult cases. Other sources for invasive H. influenzae in adults were obstetric infections, epiglottitis, and tracheobronchitis; one patient had meningitis. Underlying conditions were noted in 92% of the patients. Chronic lung disease was the most common risk factor, but pregnancy (annual incidence, 4.9/100,000 pregnant women), HIV infection (annual incidence, 41/100,000 known HIV-infected adults), and malignancy were also important. Overall mortality was 28% in adults, and over half of pregnancy-related infections resulted in fetal death. Fifty percent of the 40 isolates available for testing were serotype b; 47.5%, nontypable; and 2.5%, serotype f. Sixteen of the 45 isolates (36%) were ampicillin-resistant. Based on biotypes, outer membrane protein profiles, lipooligosaccharide phenotypes, and ribotyping patterns, the type b isolates showed less heterogeneity than the nontypable isolates but were distinguishable from one another. CONCLUSIONS: Adult cases currently represent one quarter of all cases of invasive H. influenzae disease. Half of the reported adult cases were caused by type b H. influenzae, and the rate of ampicillin resistance in H. influenzae isolates from adults was higher than previously reported. Haemophilus influenzae is an important cause of bacteremia in compromised adults.

Adolescent↗
PubMed1992

Disparate interaction of peptide ligand with nascent versus mature class I major histocompatibility complex molecules: comparisons of peptide binding to alternative forms of Ld in cell lysates and the cell surface.

To determine the mechanism and structural consequences of peptide binding to class I molecules, we have studied the Ld molecule of the mouse. Previous studies have shown that a significant proportion of surface and intracellular Ld molecules can be detected in an alternative conformation designated Ldalt. Ldalt molecules are non-ligand associated and show weak if any beta 2-microglobulin (beta 2m) association. We report here that Ld molecules have a relatively rapid surface turnover compared with other class I molecules and that exogenous peptide dramatically prolongs Ld surface half-life. By contrast, Ldalt molecules are stably expressed on the surface and their half-life is unaffected by exogenous peptide. To study the surface interaction of peptide with Ld, live cells were incubated with iodinated peptides and Ld molecules were precipitated from cells precoated with monoclonal antibody before lysis. Using this assay, peptide binding to surface Ld molecules was found not to depend upon exchange with exogenous beta 2m, but did correlate with the level of beta 2m association. To study the intracellular interaction of peptide with Ld, cell lysates were used. In cell lysates, peptide was found to convert Ldalt molecules to properly folded Ld. This peptide-induced folding was almost complete at earlier but not later time points in pulse-chase analyses. Furthermore, conversion of Ldalt to Ld was found to affect almost exclusively immature (Endo Hs) class I molecules. Thus intrinsic properties of immature Ldalt molecules or their associated chaperonins are maintained in cell lysates that allow them to undergo de novo folding in vitro. These combined results demonstrate that immature Ldalt molecules are precursors awaiting constituents such as peptide and beta 2m that influence folding, whereas surface Ldalt molecules appear refractory to association with peptide, beta 2m, and consequent folding.

Animals↗
PubMed1992

Reversible renal failure in the nephrotic syndrome.

Acute, usually reversible, renal failure has been observed in patients with normal or minimally altered glomeruli on renal biopsy. This review aims to examine the clinical features of acute renal failure in these patients and to evaluate factors that may contribute to the reduction in glomerular filtration rate (GFR). In an analysis of 79 cases affecting 75 patients reported in the English literature since 1966, with acute renal failure associated with minimal change disease or mild histopathological changes in glomeruli, the average age was 58 +/- 2 years (mean +/- 5 SEM), urine protein excretion 11.6 +/- 0.6 g/d, and serum albumin level 19 +/- 1 g/L (1.9 +/- 0.1 g/dL). Acute renal failure was documented an average of 29 +/- 5 days after onset of nephrotic syndrome, and persisted for 7 weeks in 62 episodes in the 58 patients in whom recovery of renal function occurred. Fourteen patients died of uremia or required chronic dialysis, and 3 were lost to follow-up. Although plasma volume depletion was sometimes cited as the cause of renal failure, objective signs of hypovolemia were not documented and most patients did not improve after treatment designed to correct volume deficits. In contrast, histopathological changes consistent with acute tubular necrosis (ATN) were observed in at least 60% of cases. Since the pathogenesis of acute renal failure in minimal change nephrotic syndrome is unknown, we evaluated hemodynamic determinants of GFR in patients with minimal change disease with normal or near-normal renal function, and in relevant animal models, to obtain insights into the effect of nephrotic syndrome on GFR. Although acute renal failure is uncommon, GFR is reduced concurrently with nephrotic syndrome in approximately 30% of children and adults. Absolute and effective blood volume and renal plasma flow are relatively well preserved. However, clinical and experimental observations suggest that the glomerular ultrafiltration coefficient may be reduced by as much as 50%. These findings, together with renal biopsy changes in cases with acute renal failure, suggest that severe reductions in GFR in some patients with minimal change nephrotic syndrome may result from an interaction between acute ischemic tissue injury and preexisting intrinsic renal abnormalities.

Acute Kidney Injury↗