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Biomedical subjects

B Thornhill

Publications and source records attributed to B Thornhill.

10 recordsLinked to original sources
PubMed2006

Distinct roles of Mac-1 and its counter-receptors in neonatal obstructive nephropathy.

Urinary tract obstruction during renal development leads to tubular atrophy and interstitial fibrosis. Inflammatory macrophages are crucial in this process, and beta2-integrins play a major role in leukocyte recruitment. We investigated the role of beta2-integrins and their major counter-receptors (intercellular adhesion molecule-1 (ICAM-1), receptor for advanced glycation endproducts (RAGE), junctional adhesion molecule (JAM)-C) in obstructive nephropathy in neonatal mice. Two-day-old beta2-integrin-deficient mice (Mac-1-/- and LFA-1-/-(deficient for leukocyte function-associated antigen-1)) and wild-type mice (C57BL/6) underwent unilateral ureteral obstruction (UUO) or sham operation. After 1, 5 or 12 days of obstruction, renal macrophage infiltration and tubulointerstitial damage were quantitated. Tissue abundance of Mac-1 and its ligands ICAM-1, RAGE and JAM-C was examined by Western blot and immunoprecipitation. Deficiency of either integrin was associated with reduced early macrophage invasion into the obstructed kidney. After 12 days of UUO, macrophage infiltration and tubulointerstitial injury were reduced only in Mac-1-/- but not in LFA-1-/- mice. Besides ICAM-1, an upregulation of two novel Mac-1 ligands, RAGE and JAM-C were observed, however, with distinct time courses. We conclude that beta2-integrins mediate macrophage infiltration in UUO. Mac-1 is the predominant leukocyte integrin involved in leukocyte recruitment after obstruction. ICAM-1 and its new ligands RAGE and JAM-C are sequentially activated in UUO. Blocking of Mac-1 and its ligands may confer synergistic renoprotective effects in neonatal obstructive nephropathy.

Animals↗
PubMed1999

Effect of peroxisome proliferator-activated receptor alpha activators on tumor necrosis factor expression in mice during endotoxemia.

Inflammatory mediators orchestrate the host immune and metabolic response to acute bacterial infections and mediate the events leading to septic shock. Tumor necrosis factor (TNF) has long been identified as one of the proximal mediators of endotoxin action. Recent studies have implicated peroxisome proliferator-activated receptor alpha (PPARalpha) as a potential target to modulate regulation of the immune response. Since PPARalpha activators, which are hypolipidemic drugs, are being prescribed for a significant population of older patients, it is important to determine the impact of these drugs on the host response to acute inflammation. Therefore, we examined the role of PPARalpha activators on the regulation of TNF expression in a mouse model of endotoxemia. CD-1 mice treated with dietary fenofibrate or Wy-14,643 had fivefold-higher lipopolysaccharide (LPS)-induced TNF plasma levels than LPS-treated control-fed animals. Higher LPS-induced TNF levels in drug-fed animals were reflected physiologically in significantly lower glucose levels in plasma and a significantly lower 50% lethal dose than those in LPS-treated control-fed animals. Utilizing PPARalpha wild-type (WT) and knockout (KO) mice, we showed that the effect of fenofibrate on LPS-induced TNF expression was indeed mediated by PPARalpha. PPARalpha WT mice fed fenofibrate also had a fivefold increase in LPS-induced TNF levels in plasma compared to control-fed animals. However, LPS-induced TNF levels were significantly decreased and glucose levels in plasma were significantly increased in PPARalpha KO mice fed fenofibrate compared to those in control-fed animals. Data from peritoneal macrophage studies indicate that Wy-14,643 modestly decreased TNF expression in vitro. Similarly, overexpression of PPARalpha in 293T cells decreased activity of a human TNF promoter-luciferase construct. The results from these studies suggest that any anti-inflammatory activity of PPARalpha in vivo can be masked by other systemic effects of PPARalpha activators.

Animals↗
PubMed1997

K+ channel subunit isoforms with divergent carboxy-terminal sequences carry distinct membrane targeting signals.

Kv3 K+ channel genes encode multiple products by alternative splicing of 3' ends resulting in the expression of K+ channel proteins that differ only in their C-termini. This divergence does not affect the electrophysiological properties of the channels expressed by these proteins. A similar alternative splicing with unknown function is seen in K+ channel genes of other families. We have investigated the possibility that the alternative splicing serves to generate channel subunits with different membrane targeting signals by examining the sorting behavior of three alternatively-spliced Kv3.2 isoforms when expressed in polarized MDCK cells. Two Kv3.2 proteins, Kv3.2b and Kv3.2c were expressed predominantly in the apical membrane, while Kv3.2a was localized mainly to the basolateral side (thought to be equivalent to the axonal and somatodendritic compartments in neurons, respectively). The Kv3.2 mRNA transcripts used in these studies are identical except for their 3' sequence, encoding the extreme C-terminal domain of the protein and the 3'UTR of the mRNA. However, the proteins achieve the same localizations in MDCK cells when expressed from constructs containing or lacking the 3'UTR, indicating that the differential localization is due to targeting signals present in the C' terminal domain of the protein. These results suggest that the alternative splicing of Kv3 genes is involved in channel localization. Since the precise localization of any given ion channel on the neuronal surface has significant functional implications, the results shown here suggest an important function for the alternative splicing of 3' ends seen in many K+ channel genes.

Alternative Splicing↗
PubMed1990

Role of atrial natriuretic peptide in the response to blood volume expansion in the weanling rat.

After acute blood volume expansion (BVE) in the rat, diuresis and natriuresis are reported to be minimal in rats 20 to 30 d of age, but increase to mature levels by 40 d of age. To evaluate the role of atrial natriuretic peptide (ANP) and its renal action in BVE, anesthetized Sprague-Dawley rats were studied at 25 to 30 (group I) and 45 to 50 d of age (group II). Hematocrit, mean arterial pressure, glomerular filtration rate, urine flow rate, urine sodium excretion, urine cyclic GMP excretion, and plasma ANP concentration [( ANP]) were measured before and after infusion of donor littermate whole blood, 2.5% body wt (BVE), and in time controls (no BVE) in each group. Baseline hematocrit, mean arterial pressure, and glomerular filtration rate were greater in group II than group I, but urine flow rate, urine sodium excretion, urine cyclic GMP excretion, and [ANP] did not differ. BVE caused a prompt increase in urine flow rate, urine sodium excretion, and [ANP], but not urine cyclic GMP excretion, in both groups, but there was no difference in the response between groups. Additional groups of rats of the same ages as groups I and II studied using a protocol similar to that of a previous report also showed the "mature" diuretic and natriuretic response even in the younger animals. We conclude that there is no further maturation of the renal response to acute BVE in the euvolemic rat after 25 d of age. The increase in [ANP] after acute BVE in the immature weanling rat is consistent with a role for ANP in mediation of the renal response.

Aging↗
PubMed1987

Radiographic abnormalities in coagulation factor VII deficiency.

We report the plain film findings as knees and elbows in two patients with congenital coagulation factor VII deficiency. The radiographic features resemble hemophilia, although the joint manifestations are milder, appear later in life, and occur in both men and women.

Adolescent↗
PubMed1981

Prediction of amputation wound healing. Roles of Doppler ultrasound and digit photoplethysmography.

Segmental limb blood pressures (BPs) measured by Doppler ultrasound and digit photoplethysmography were used to define hemodynamic correlates of wound healing in 122 lower-extremity amputations for ischemia. Healing of digit or transmetatarsal amputations were influenced by the presence of diabetes and correlated better with digit pulsation and BP than with ankle pressure. Healing of below-knee amputation did not correlate with segmental limb BPs. In the absence of an absolute threshold to predict wound healing or failure, caution is urged in using hemodynamic indices to select the level of amputation of arterial insufficiency.

Aged↗
PubMed1979

Noninvasive determination of carotid artery operability by Doppler ultrasound.

Indirect periorbital screening techniques may detect obstruction of the extracranial internal carotid artery, but they do not distinguish operable stenosis from inoperable occlusion. In an attempt to overcome this limitation, direct interrogation of carotid artery flow velocity by Doppler ultrasound was added to periorbital screening of 97 arteries in 53 patients. Analysis of results suggests that this assessment can improve diagnostic accuracy and distinguish stenosis from occlusion of the internal carotid arteries in stroke-prone patients.

Aged↗