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Biomedical subjects

C Small

Publications and source records attributed to C Small.

At least 19 recordsLinked to original sources
PubMed2005

Ghrelin increases food intake in obese as well as lean subjects.

OBJECTIVE: To investigate whether effects on food intake are seen in obese subjects receiving exogenous administration of ghrelin. DESIGN: Randomised, double-blind, placebo-controlled study of intravenous ghrelin at doses 1 pmol/kg/min and 5 pmol/kg/min. SUBJECTS: In all, 12 healthy lean subjects (mean body mass index (BMI) 20.5+/-0.17 kg/m(2)) and 12 healthy overweight and obese subjects (mean BMI 31.9+/-1.02 kg/m(2)). MEASUREMENTS: Food intake, appetite and palatability of food, ghrelin and other obesity-related hormones, growth hormone. RESULTS: Low-dose infusion of ghrelin increased ad libitum energy intake at a buffet meal in the obese group only (mean increase 36.6+/-9.4%, P<0.01.) High-dose ghrelin infusion increased energy intake in both groups (mean increase 20.1+/-10.6% in the lean and 70.1+/-15.5% in the obese, P<0.01 in both cases.) Ghrelin infusion increased palatability of food in the obese group. CONCLUSION: Ghrelin increases food intake in obese as well as lean subjects. Obese people are sensitive to the appetite-stimulating effects of ghrelin and inhibition of circulating ghrelin may be a useful therapeutic target in the treatment of obesity.

Adult↗
PubMed2004

The influence of ridge migration on the magmatic segmentation of mid-ocean ridges.

The Earth's mid-ocean ridges display systematic changes in depth and shape, which subdivide the ridges into discrete spreading segments bounded by transform faults and smaller non-transform offsets of the axis. These morphological changes have been attributed to spatial variations in the supply of magma from the mantle, although the origin of the variations is poorly understood. Here we show that magmatic segmentation of ridges with fast and intermediate spreading rates is directly related to the migration velocity of the spreading axis over the mantle. For over 9,500 km of mid-ocean ridge examined, leading ridge segments in the 'hotspot' reference frame coincide with the shallow magmatically robust segments across 86 per cent of all transform faults and 73 per cent of all second-order discontinuities. We attribute this relationship to asymmetric mantle upwelling and melt production due to ridge migration, with focusing of melt towards ridge segments across discontinuities. The model is consistent with variations in crustal structure across discontinuities of the East Pacific Rise, and may explain variations in depth of melting and the distribution of enriched lavas.

Journal Article↗
PubMed2001

Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women.

OBJECTIVE: To determine whether the presence of a single epsilon4 allele of the APOE gene is associated with an increased rate of hippocampal volume loss or decline in cognition in healthy women in their sixth decade of life. METHODS: Nine APOE-epsilon4 allele-negative (mean age +/- SD, 60.6 +/- 10.2 years) and 16 APOE-epsilon4 allele-positive (mean age +/- SD, 55.1 +/- 6.0 years) healthy women underwent neurocognitive testing and MRI at the time of entry into the study (baseline) and 2 years later. Neurocognitive testing consisted of the Buschke-Fuld Free Recall, verbal fluency tests, the Rey Figure Test, the Wechsler Memory Scale-Revised, and the Wechsler Adult Intelligence Survey-Revised Block Design. Hippocampal volume determinations were based on manual outlining of sagittal slices aided by axial, coronal, and three-dimensional views of high-resolution 124-slice whole-brain scans; the scans were obtained with a 1.5-tesla scanner using a T1-weighted three-dimensional gradient echo sequence with RF spoiling (TR/TE/flip angle, 24 msec/3 msec/30 degrees ). RESULTS: The percent change in hippocampal volume per year was greater in the APOE-epsilon4 allele-positive group (mean +/- SD, 2.32 +/- 1.75%) than in the APOE-epsilon4 allele-negative group (mean +/- SD, 0.77 +/- 1.02%; t = 2.41; p < 0.03, two-tailed test). There were no significant differences between the two groups in terms of any of the cognitive measures, and hippocampal volume loss was not correlated with changes in any of the above-mentioned cognitive measures. CONCLUSIONS: The presence of a single APOE-epsilon4 allele is associated with an increased rate of hippocampal volume loss in healthy women in their sixth decade of life that is not related to any detectable memory changes.

Aged↗
PubMed2001

Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats.

The primary role of the orexins was originally believed to be appetite regulation, but is now believed to be the regulation of sleep, arousal and locomotor activity. Orexin A immunoreactivity (orexin A-IR) and prepro-orexin mRNA were measured in the CNS of obese and lean Zucker rats. There were no differences in orexin A-IR or prepro-orexin mRNA levels between obese and lean Zucker rats. The orexins are therefore unlikely to be important in this model of obesity. Levels of orexin A-IR and prepro-orexin mRNA were measured in the CNS of Wistar-Kyoto (WKY) rats, which are hypoactive and have abnormal sleep architecture. Compared to Wistar rats, WKY rats had significantly lower orexin A-IR (with differences of up to 100% in some brain regions) and prepro-orexin mRNA levels. These observations suggest that the sleep and activity phenotype of the WKY strain may be related to orexin deficiency and that this strain may be a useful model of partial orexin deficiency.

Animals↗
PubMed2001

Overlapping roles for granulocyte-macrophage colony-stimulating factor and interleukin-3 in eosinophil homeostasis and contact hypersensitivity.

Studies of mice rendered deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) have established unique roles for these cytokines in pulmonary homeostasis, resistance to infection, and antigen-specific T- and B-cell responses. In addition to these distinctive properties, however, GM-CSF and IL-3 also stimulate the development and activation of hematopoietic cells in many similar ways, raising the possibility that each factor might partially compensate for the other's absence in singly deficient mice. To test whether endogenous GM-CSF and IL-3 mediate redundant functions in vivo, we generated mice lacking both cytokines through sequential gene targeting experiments in embryonic stem (ES) cells. Surprisingly, doubly deficient animals, but not single knockouts, showed increased numbers of circulating eosinophils. Doubly deficient mice, moreover, developed weaker contact hypersensitivity reactions to haptens applied epicutaneously than mice deficient in either factor alone. Together, these findings delineate overlapping roles for GM-CSF and IL-3 in hematopoiesis and immunity. (Blood. 2001;97:922-928)

Animals↗
PubMed2001

Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb.

GDF11, a new member of the TGF-beta gene superfamily, regulates anterior/posterior patterning in the axial skeleton during mouse embryogenesis. Gdf11 null mice display skeletal abnormalities that appear to represent anterior homeotic transformations of vertebrae consistent with high levels of Gdf11 expression in the primitive streak, presomitic mesoderm, and tail bud. However, despite strong Gdf11 expression in the limb throughout development, this structure does not appear to be affected in the knockout mice. In order to understand this dichotomy of Gdf11 expression versus Gdf11 function, we identified the chicken Gdf11 gene and studied its role during limb formation. In the early limb bud, Gdf11 transcripts are detected in the subectodermal mesoderm at the distal tip, in a region overlapping the progress zone. At these stages, Gdf11 is excluded from the central core mesenchyme where precartilaginous condensations will form. Later in development, Gdf11 continues to be expressed in the distal most mesenchyme and can also be detected more proximally, in between the forming skeletal elements. When beads incubated in GDF11 protein were implanted into the early wing bud, GDF11 caused severe truncations of the limb that affected both the cartilage elements and the muscle. Limb shortening appeared to be the result of an inhibition of chondrogenesis and myogenesis and using an in vitro micromass assay, we confirmed the negative effects of GDF11 on both myogenic and chondrogenic cell differentiation. Analysis of molecular markers of skeletal patterning revealed that GDF11 induced ectopic expression of Hoxd-11 and Hoxd-13, but not of Hoxa-11, Hoxa-13, or the Msx genes. These data suggest that GDF11 may be involved in controlling the late distal expression of the Hoxd genes during limb development and that misregulation of these Hox genes by excess GDF11 may cause some of the observed alterations in skeletal element shape. In addition, GDF11 induced the expression of its own antagonist follistatin, indicating that the activity of GFD11 may be limited by a negative feedback mechanism. The data from our studies in the chick suggest that Gdf11 plays a role in the formation and development of the avian limb skeleton.

Animals↗
PubMed2000

Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors.

The epidermal growth factor receptor (EGFR) is often amplified and rearranged structurally in tumors of the brain, breast, lung, and ovary. The most common mutation, EGFRvIII, is characterized by an in-frame deletion of 801 base pairs, resulting in the generation of a novel tumor-specific epitope at the fusion junction. A murine homologue of the human EGFRvIII mutation was created, and an IgG2a murine mAb, Y10, was generated that recognizes the human and murine equivalents of this tumor-specific antigen. In vitro, Y10 was found to inhibit DNA synthesis and cellular proliferation and to induce autonomous, complement-mediated, and antibody-dependent cell-mediated cytotoxicity. Systemic treatment with i.p. Y10 of s.c. B16 melanomas transfected to express stably the murine EGFRvIII led to long-term survival in all mice treated (n = 20; P < 0.001). Similar therapy with i.p. Y10 failed to increase median survival of mice with EGFRvIII-expressing B16 melanomas in the brain; however, treatment with a single intratumoral injection of Y10 increased median survival by an average 286%, with 26% long-term survivors (n = 117; P < 0.001). The mechanism of action of Y10 in vivo was shown to be independent of complement, granulocytes, natural killer cells, and T lymphocytes through in vivo complement and cell subset depletions. Treatment with Y10 in Fc receptor knockout mice demonstrated the mechanism of Y10 to be Fc receptor-dependent. These data indicate that an unarmed, tumor-specific mAb may be an effective immunotherapy against human tumors and potentially other pathologic processes in the "immunologically privileged" central nervous system.

Animals↗
PubMed2000

Altered fetal pituitary-adrenal function in the ovine fetus treated with RU486 and meloxicam, an inhibitor of prostaglandin synthase-II.

Term and preterm labor are associated with increased fetal hypothalamic-pituitary-adrenal (HPA) activation and synthesis of prostaglandins (PGs) generated through the increased expression of prostaglandin H synthase-II (PGHS-II) in the placenta. Inhibition of PGHS-II has been advocated as a means of producing uterine tocolysis, but the effects of such treatment on fetal endocrine functions have not been thoroughly examined. Because PGE(2) is known to activate the fetal HPA axis, we hypothesized that administration of meloxicam, a PGHS-II inhibitor, to sheep in induced labor would suppress fetal HPA function. Chronically catheterized pregnant ewes were treated with RU486, a progesterone receptor antagonist, to produce active labor, and then treated with either high-maintenance-dose meloxicam, graded-maintenance-dose meloxicam, or a saline infusion. Maternal uterine contraction frequency increased 24 h after the RU486 injection and the animals were in active labor by 48 +/- 4 h. RU486 injection led to increased concentrations of PGE(2), ACTH, and cortisol in the fetal circulation, and increased concentrations of 13,14 dihydro 15-ketoprostaglandin F(2 alpha) (PGFM) in the maternal circulation. Uterine activity was inhibited within 12 h of beginning meloxicam infusion at both infusion regimes. During meloxicam infusion there were significant decreases in fetal plasma PGE(2), ACTH, and cortisol concentrations, and PGFM concentrations in maternal plasma. In control animals, frequency of uterine contractions, maternal plasma PGFM, fetal plasma PGE(2), ACTH, and cortisol concentrations increased after RU486 administration, and continued to rise during saline infusion until delivery occurred. We conclude that RU486-provoked labor in sheep is associated with activation of fetal HPA function, and that this is attenuated during meloxicam treatment to a level considered compatible with pregnancy maintenance.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Cathepsin S required for normal MHC class II peptide loading and germinal center development.

Major histocompatibility complex (MHC) class II molecules acquire antigenic peptides after degradation of the invariant chain (Ii), an MHC class II-associated protein that otherwise blocks peptide binding. Antigen-presenting cells of mice that lack the protease cathepsin S fail to process Ii beyond a 10 kDa fragment, resulting in delayed peptide loading and accumulation of cell surface MHC class II/10 kDa Ii complexes. Although cathepsin S-deficient mice have normal numbers of B and T cells and normal IgE responses, they show markedly impaired antibody class switching to IgG2a and IgG3. These results indicate cathepsin S is a major Ii-processing enzyme in splenocytes and dendritic cells. Its role in humoral immunity critically depends on how antigens access the immune system.

Animals↗
PubMed1998

Hypsographic demography: the distribution of human population by altitude.

The global distribution of the human population by elevation is quantified here. As of 1994, an estimated 1.88 x 10(9) people, or 33. 5% of the world's population, lived within 100 vertical meters of sea level, but only 15.6% of all inhabited land lies below 100 m elevation. The median person lived at an elevation of 194 m above sea level. Numbers of people decreased faster than exponentially with increasing elevation. The integrated population density (IPD, the number of people divided by the land area) within 100 vertical meters of sea level was significantly larger than that of any other range of elevations and represented far more people. A significant percentage of the low-elevation population lived at moderate population densities rather than at the highest densities of central large cities. Assessments of coastal hazards that focus only on large cities may substantially underestimate the number of people who could be affected.

Altitude↗
PubMed1998

Involvement of interleukin-3 in delayed-type hypersensitivity.

The in vivo functions of interleukin-3 (IL-3) were investigated by generating IL-3-deficient mice. Although hematopoiesis was unimpaired in homozygous mutant animals, contact hypersensitivity reactions were compromised. IL-3 was required for efficient priming of hapten-specific contact hypersensitivity responses, but was dispensable for T-cell-dependent sensitization to tumor cells. These findings reveal a critical role for IL-3 in some forms of delayed-type hypersensitivity.

Animals↗
PubMed1997

Leptin interacts with glucagon-like peptide-1 neurons to reduce food intake and body weight in rodents.

The adipose tissue hormone, leptin, and the neuropeptide glucagon-like peptide-1 (7-36) amide (GLP-1) both reduce food intake and body weight in rodents. Using dual in situ hybridization, long isoform leptin receptor (OB-Rb) was localized to GLP-1 neurons originating in the nucleus of the solitary tract. ICV injection of the specific GLP-1 receptor antagonist, exendin(9-39), at the onset of dark phase, did not affect feeding in saline pre-treated controls, but blocked the reduction in food intake and body weight of leptin pre-treated rats. These findings suggest that GLP-1 neurons are a potential target for leptin in its control of feeding.

Animals↗
PubMed1995

Neuroprotective properties of lifarizine compared with those of other agents in a mouse model of focal cerebral ischaemia.

1. Changes in the peripheral type benzodiazepine binding site density following middle cerebral artery occlusion in the mouse, have been used as a marker of neuronal damage. These sites can be identified using the selective ligand [3H]-PK 11195 located on non neuronal cells, macrophages and astroglia, within the CNS. Glial cell proliferation and macrophage invasion is an unvoidable sequelae to cerebral ischaemic injury, secondary to neuronal loss. Following occlusion of the left middle cerebral artery (left MCA) a reproducible lesion was found in the parietal cortex within 7 days which gave rise to a significant increase in [3H]-PK 11195 binding. 2. Treatment of animals with the sodium channel blocker, lifarizine, significantly reduced the ischaemia-induced increase in [3H]-PK 11195 binding when given either 30 min pre-ischaemia and three times daily for 7 days at 0.5 mg kg-1, i.p. (P < 0.01) or delayed until 15 min post-ischaemia and three times daily for 7 days at 0.5 mg kg-1, i.p. (P < 0.001). Lifarizine was an effective neuroprotective agent in this model of focal ischaemia in the mouse. 3. Lifarizine also showed a dose-related protection against the ischaemia-induced increase in [3H]-PK 11195 binding with significant protection at doses of 0.1 mg kg-1, i.p. (P < 0.05), 0.25 mg kg-1, i.p. (P < 0.01) or 0.5 mg kg-1, i.p. (P < 0.01) 15 min post-ischaemia and b.i.d. for 7 days. No significant change is seen in the Kd for [3H]-PK 11195. The first dose could be delayed for up to 4 h after cerebralartery cauterization and protection was maintained.4. Phenytoin (28 mg kg-1, i.v. 15 min and 24 h post-ischaemia) was also neuroprotective in this model(P<0.01). This agent is thought to interact with voltage-dependent sodium channels to effect its anticonvulsantactions and this mechanism may also underlie its neuroprotective actions in focal cerebralischaemia.5. Agents with other mechanisms of action were also shown to have significant neuroprotection in this model. The non-competitive NMDA antagonist, MK 801, showed significant neuroprotection in the model when given at 0.5 mg kg-1, i.p. 30 min pre-ischaemia with t.i.d. dosing for 7 days (P< 0.001). The dihydropyridine calcium antagonist, nimodipine was not protective when given using the same dosing protocol as MK 801, 0.5 mg kg-1 30 min pre-occlusion and three times daily for 7 days but showed significant protection when given at 0.05 mg kg-1 15 min post-ischaemia and three times daily for 7days. The lipid peroxidation inhibitor, tirilazad (single dose 1 mg kg-1, i.v.) showed significant neuroprotection when given 5 min post-ischaemia but not when the first dose was delayed for 4 h.

Animals↗
PubMed1995

Self-measurement of blood pressure: assessment of equipment. Canadian Coalition for High Blood Pressure Prevention and Control.

Equipment for the self-measurement of blood pressure is readily available to consumers. These devices use one or more surrogate (indirect) measures of pressure to estimate systolic and diastolic blood pressure. Manual auscultatory devices using stethoscope and sphygmomanometer have been adapted for home use, but a variety of automated devices based on auscultation, oscillometry, and other techniques are available and may be more suitable for individuals who have limited vision, hearing or dexterity. Despite the existence of voluntary evaluation protocols and mandatory manufacturing standards, blood pressure readings from some automatic devices may not be accurate. Some devices are packaged with insufficient information to ensure proper use, and most individuals need some form of guidance in their use and calibration testing. If self-measurement of blood pressure is to be of benefit, the health care professional must recommend only those devices that are accurate and suitable to the patient or client. The Canadian Coalition for High Blood Pressure Prevention and Control will endeavour to develop a regular means by which health care professionals can keep informed of available devices for blood pressure self-measurement.

Blood Pressure Determination↗
PubMed1994

Comparison of two methods for measuring hamstring reaction time using the Kin-Com isokinetic dynamometer.

Methods for quantifying deficits in proprioceptive feedback need to be examined. The purpose of this study was to compare two protocols measuring hamstring reaction time. Forty subjects, 13 males and 27 females, between 21 and 31 years of age (means = 24.3, SD = 2.04) were tested bilaterally on the Kin-Com isokinetic dynamometer with simultaneous use of the KC-EMG electromyograph. Subjects were instructed to maximally contract their hamstring musculature in response to a sudden lever arm movement. The peak torque time (PTT) protocol quantified the time lapse between initial lever arm movement and the generation of maximum torque. The electromyograph time (EMGT) protocol measured the time lapse between initial lever arm movement and initial myoelectrical activity of the hamstring musculature. Both PTT and EMGT were found to be reliable (Cronbach alpha 0.823-0.896), with no significant difference (p < .05) between dominant and nondominant limbs. These results indicate that PTT and EMGT are effective for quantifying hamstring reaction time and that the uninvolved lower extremity may be used as a control.

Adult↗
PubMed1993

The pharmacology of RS-15385-197, a potent and selective alpha 2-adrenoceptor antagonist.

1. RS-15385-197 ((8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro- 3-methoxy-12-(methylsulphonyl)-6H-isoquino [2,1-g][1,6]-naphthyridine) was evaluated in a series of in vitro and in vivo tests as an antagonist at alpha 2-adrenoceptors. 2. RS-15385-197 had a pKi of 9.45 for alpha 2-adrenoceptors in the rat cortex (pA2 in the guinea-pig ileum of 9.72), whereas the 8aS, 12aR, 13aR enantiomer, RS-15385-198, had a pKi of only 6.32 (pA2 6.47) indicating a high degree of stereoselectivity. The racemate RS-15385-196 had a pKi of 9.18. 3. RS-15385-197 showed unprecedented alpha 2 vs. alpha 1 adrenoceptor selectivity in vitro. In the rat cortex, RS-15385-197 had a pKi of 9.45 in displacing [3H]-yohimbine and 5.29 in displacing [3H]-prazosin (alpha 2/alpha 1 selectivity ratio in binding experiments > 14000). The compound had a pA2 of 9.72 as a competitive antagonist of the inhibitory effects of UK-14,304 in transmurally-stimulated guinea-pig ileum and 10.0 against BHT-920-induced contractions in dog saphenous vein (DSV); this latter value was unaltered by phenoxybenzamine. An apparent pKB of 5.9 was obtained against cirazoline-induced contractions in DSV, whilst a pA2 of 6.05 was obtained against phenylephrine-induced contractions in the rabbit aorta (alpha 2/alpha 1 selectivity ratio in functional experiments > 4000). 4. RS-15385-197 was highly selective for alpha 2-adrenoceptors over other receptors: the compound showed low affinity for 5-HT1A (pKi 6.50) and 5-HT1D (pKi 7.00) receptor subtypes, and even lower affinity (pKi < or = 5) for other 5-HT receptor subtypes, dopamine receptors, muscarinic cholinoceptors, beta-adrenoceptors and dihydropyridine binding sites. RS-15385-197 was devoid of affinity for the non-adrenoceptor imidazoline binding site, labelled by [3H]-idazoxan, which provides further evidence that these sites are not related to alpha 2-adrenoceptors. In the DSV, contractile responses to 5-hydroxytryptamine (5-HT) were unaffected by a concentration of 1 microM RS-15385-197. 5. RS-15385-197 was non-selective for the alpha 2A- and alpha 2B-adrenoceptor subtypes in that the pKi for the alpha 2A-adrenoceptor in human platelets was 9.90 and the pKi for the alpha 2B-adrenoceptor in rat neonate lung was 9.70. However, RS-15385-197 showed lower affinity for the alpha 2-adrenoceptor subtype in hamster adipocytes (pKi 8.38). 6. In anaesthetized rats, RS-15385-197 was a potent antagonist of the mydriasis response induced by UK-14,304 or clonidine (AD50 5 and 7 microg kg-1, i.v., respectively; 96 microg kg-1, p.o.) and of UK-14,304-induced pressor responses in pithed rats (AD50 7 microg kg-1, i.v.); the compound therefore is both centrally and orally active. Even at a high dose (10 mg kg-1, i.v.), RS-15385-197 did not antagonize pressor responses to cirazoline in pithed rats, indicating that the selectivity for alpha2 vs. alpha1-adrenoceptors was maintained in vivo.8 RS-15385-197 is therefore a very potent, selective, competitive alpha2-adrenoceptor antagonist, both in vitro and in vivo, is orally active and readily penetrates the brain. It will thus be a powerful pharmacological tool for exploring the various physiological roles of alpha2-adrenoceptors.

Administration, Oral↗
PubMed1992

Haemophilus influenzae type b bacteremia in adults with AIDS and at risk for AIDS.

PURPOSE: Our objective was to determine the number of cases of Haemophilus influenzae type b bacteremia in patients with and at risk for acquired immunodeficiency syndrome (AIDS) from January 1983 to June 1991 at a municipal hospital in Bronx, New York. PATIENTS AND METHODS: We reviewed blood culture records of adult patients admitted to North Central Bronx Hospital from January 1983 to June 1991 to identify cases of bacteremic H. influenzae type b disease. The hospital charts and admission chest radiographs of bacteremic patients were then reviewed. RESULTS: Ten of 15 cases of adult H. influenzae type b bacteremia occurred in patients with AIDS or who were at risk for AIDS. Seven had AIDS at presentation. Nine were active or former intravenous drug users (IVDUs). All 10 cases were associated with a respiratory source, and five of the 10 patients also had H. influenzae type b isolated from sputum. All H. influenzae type b strains were negative for beta-lactamase. CONCLUSIONS: Human immunodeficiency virus-positive IVDUs may be at increased risk for bacteremic H. influenzae type b infections. Empiric antibiotic regimens for community-acquired pneumonia in these patients should include appropriate antibiotics for the treatment of H. influenzae type b. In addition, these patients may be candidates for conjugate H. influenzae type b vaccine trials.

Acquired Immunodeficiency Syndrome↗