Molecular characterization of a putative sodium/iodide symporter in the South African clawed frog, Xenopus laevis.
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Animals↗
Biomedical subjects
J A Carr
Publications and source records attributed to J A Carr.
The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo.
Oseltamivir carboxylate is a potent and specific inhibitor of influenza A and B neuraminidase (NA). Oseltamivir phosphate, the ethyl ester prodrug of oseltamivir carboxylate, is the first orally active NA inhibitor available for the prophylaxis and treatment of influenza A and B. It offers an improvement over amantadine and rimantadine which are active only against influenza A and rapidly generate resistant virus. The emergence of virus resistant to oseltamivir carboxylate in the treatment of naturally acquired influenza infection is low (about 1%). The types of NA mutation to arise are sub-type specific and largely predicted from in vitro drug selection studies. A substitution of the conserved histidine at position 274 for tyrosine in the NA active site has been selected via site directed mutagenesis, serial passage in culture under drug pressure in H1N1 and during the treatment of experimental H1N1 infection in man. Virus carrying H274Y NA enzyme selected in vivo has reduced sensitivity to oseltamivir carboxylate. The replicative ability in cell culture was reduced up to 3 logs, as was infectivity in animal models of influenza virus infection. Additionally, pathogenicity of the mutant virus is significantly compromised in ferret, compared to the corresponding wild type virus. Virus carrying a H274Y mutation is unlikely to be of clinical consequence in man.
Acetamides↗
Distribution of neuronal melanocortins in the spadefoot toad Spea multiplicata and effects of stress.
We examined the effects of an acute stressor on regional alpha-melanocyte-stimulating hormone (alphaMSH) content in the New Mexican spadefoot toad, Spea multiplicata. We first used immunocytochemistry along with radioimmunoassay (RIA) to examine the distribution of pro-opiomelanocortin (POMC) neurons in the brain of Spea. Neurons immunoreactive for alphaMSH, beta-endorphin, and corticotropin were observed in the preoptic nucleus and ventral infundibulum of the hypothalamus. Ascending immunoreactive fibers projected to the olfactory nucleus, nucleus accumbens, and striatum. Numerous immunoreactive fibers were also observed in the hypothalamus. The thalamus/hypothalamus (T/HT) contained the greatest concentrations of alphaMSH as determined by RIA followed by the preoptic area (PO). Levels in the telencephalon, brain stem, and optic tectum (OT) were 14-23 times lower than in the T/HT. Exposure to a brief stressor elevated alphaMSH levels in the PO and OT. We conclude that Spea possesses two distinct POMC neuronal cell groups, one located in the anterior preoptic area and one located in the ventral infundibulum. Ascending projections to the basal ganglia might play an indirect role in tectal regulation and the control of prey-catching behavior. Exposure to an acute stressor alters brain alphaMSH content in Spea, although there are regional and temporal differences in the response pattern compared to Bufo. These findings are consistent with the notion that neuronal melanocortins influence how frogs and toads gather information about their environment during stress.
Adrenocorticotropic Hormone↗
Primary venorrhaphy for traumatic inferior vena cava injuries.
Primary venorrhaphy for traumatic inferior vena cava (IVC) injury has been criticized because of the potential for stenosis, thrombosis, and embolism. A retrospective study was performed to evaluate the morbidity and outcome of this method. Thirty-eight patients at our institution had traumatic injuries to the IVC between 1994 and 1999. Thirty (79%) were from firearms, five (13%) from stab wounds, and three (8%) from blunt trauma. Six patients died in the emergency department. The remaining 32 patients underwent exploratory celiotomy with 23 survivors and nine intraoperative deaths for a mortality rate of 28 per cent (nine of 32). Vascular control was achieved by manual compression in 44 per cent and by local clamping directly above and below the injury in 38 per cent. All repairs were by primary venorrhaphy, and no patient was treated with patch angioplasty or venous reconstruction. Three patients had caval ligation. Follow-up IVC imaging in 11 patients revealed that the IVC was patent in eight, narrowed in two, and thrombosed below the renal veins in one. One patient developed a pulmonary embolus. The vast majority of traumatic injuries to the IVC can be managed by direct compression or local clamping and primary venorrhaphy. Direct repairs are associated with a low thrombosis and embolic complication rate.
Adolescent↗
The association of HER-2/neu amplification with breast cancer recurrence.
HYPOTHESIS: Amplification of the HER-2/neu oncogene in 25% of breast cancers is associated with a shortened disease-free survival. DESIGN: Retrospective analysis of a patient population referred to a tertiary care facility for HER-2/neu testing. The mean follow-up was 56 months. SETTING: Large, urban, tertiary care hospital. PATIENTS: From 1995 to 1999, a consecutive sample of 190 patients with breast cancer had tissue samples tested for overexpression of the cell surface oncoprotein by immunostaining (IM) or amplification of the HER-2/neu oncogene by fluorescence in situ hybridization or both. Forty-nine subjects were excluded because they had tissue samples tested at our institution but received their treatment elsewhere. All patients tested for HER-2/neu after diagnosis with breast cancer in 1999 (n = 47) were excluded from analysis because of short follow-up time. One patient was excluded who had in situ ductal carcinoma. The remaining 93 patients were analyzed. RESULTS: Of 93 patients, 40 (43%) had gene amplification. Overall, patients with oncogene amplification had a shorter median disease-free interval (22 months) compared with controls (40 months) (P =.003). Analysis by the Cox regression model showed that the HER-2/neu status remained significantly associated with time to relapse even after adjusting for age and tumor grade (P =.002; adjusted relative risk, 2.4; 95% confidence interval, 1.4-4.4). No association was found between gene amplification and tumor grade (P =.98), estrogen/progesterone receptor status (P = .29 and P = .43, respectively), or lymph node status (P = .98). Seventy-two patients (77%) eventually had disease recurrence, with 18 (25%) of these recurring locally. CONCLUSIONS: The HER-2/neu oncogene is an independent prognostic indicator of a subset of breast cancers that are at high risk of early recurrence, regardless of tumor grade, estrogen/progesterone receptor status, and lymph node status. Patients amplifying the HER-2/neu oncogene have a shorter disease-free survival than patients without the oncogene.
Breast Neoplasms↗
Secondary aortoenteric fistula.
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Aortic Diseases↗
Mu and delta opioid receptor regulation of pro-opiomelanocortin peptide secretion from the rat neurointermediate pituitary in vitro.
We investigated the ability of selective opioid agonists and antagonists to influence pro-opiomelanocortin peptide secretion from the rat neurointermediate lobe in vitro. The mu-opioid agonist DAMGO ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]enkephalin) significantly stimulated beta-endorphin and alpha-melanocyte-stimulating hormone release relative to controls early (30 min) in the incubation period. Similar effects on beta-endorphin secretion were observed with the selective mu-opioid agonist dermorphin. The delta-opioid receptor agonist DPDPE ([D-Pen(2,5)]enkephalin) weakly inhibited beta-endorphin secretion relative to controls while the kappa-opioid receptor agonist U50488 had no effect. The mu-opioid selective antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2)) inhibited basal beta-endorphin secretion while kappa- and delta-opioid receptor antagonists had no effect. Our data support a role for local mu-opioid receptor control of intermediate lobe pro-opiomelanocortin peptide secretion. Peptide secretion from melanotropes appears to be tonically stimulated by activation of mu-opioid receptors in the absence of intact neuronal innervation to the intermediate lobe.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Visceral pseudoaneurysms due to pancreatic pseudocysts: rare but lethal complications of pancreatitis.
OBJECTIVE: Erosion of pancreatic pseudocysts into adjacent vessels is a rare but highly lethal cause of intra-abdominal hemorrhage. Percutaneous angiographic embolization (PAE) of the bleeding artery has recently been advocated as the preferred therapy. This study was undertaken to survey the outcome after treatment of this complication and to make recommendations for its management. METHODS: An 11-year retrospective analysis was performed of all patients treated at a large tertiary care referral center for visceral artery pseudoaneurysms associated with pancreatic pseudocysts. RESULTS: From 1988 to 1998, 256 patients were admitted for complications of pancreatic pseudocysts. Sixteen patients (11 men and 5 women) were identified in whom a pseudocyst had eroded into a major blood vessel with hemorrhage or development of a false aneurysm. The mean age was 45 years (range, 23-67 years). Active bleeding was present in 13 patients, whereas three had evidence of recent hemorrhage. Ten of 16 patients initially underwent operative therapy, four elective and six emergency, whereas six stable patients were initially treated with PAE. Technical failures of the initial treatment or secondary complications required both therapeutic modalities in six patients, which resulted in 13 total surgical interventions and 10 PAEs. The surgical morbidity rate was 62% (8 of 13), whereas that of PAE was 50% (5 of 10). Three deaths occurred after emergency operations, two of which failed to stop the bleeding, accounting for all of the deaths in the series (3 [19%] of 16). A trend was noted toward increased death with necrotizing pancreatitis (P =.07) and emergency surgery (P =.06). Ranson's criteria were not found to be predictive of death in this series. Surgical drainage procedures were required in seven (44%) of 16 patients for infections (n = 3) or mass effect of the pseudoaneurysm (n = 3). The mean size of pseudoaneurysms that required operative intervention for secondary complications was 13.9 cm, compared with 7.7 cm for all others in the series (P =.046). Long-term follow-up was available in all 13 survivors at a mean of 44 months (range, 1-108 months). CONCLUSIONS: The management of pancreatic pseudocyst-associated pseudoaneurysms remains a challenging problem with high morbidity and death rates. Operation and PAE play complementary management roles. PAE is recommended as the initial therapy for hemodynamically stable patients. Surgery should be reserved for actively bleeding, hemodynamically unstable patients; for failed embolization; and for other secondary complications such as infection or extrinsic compression.
Adult↗
alpha-melanocyte-stimulating hormone and habituation of prey-catching behavior in the Texas toad, Bufo speciosus.
We investigated dose-dependent effects of alpha-melanocyte-stimulating hormone (alpha-MSH) on habituation in the Texas toad, Bufo speciosus. Additionally, we determined changes in plasma and brain levels of alpha-MSH following peripheral administration of the peptide or following exposure to an ether stressor. The ability of alpha-MSH to facilitate acquisition of habituation was dose dependent. Plasma alpha-MSH concentrations were elevated within 5 min of dorsal lymph sac injection and remained elevated up to 600% over controls after 30 min. Administration of 50 microgram alpha-MSH had no effect on plasma corticosterone levels. Radiolabeled alpha-MSH was detected in cerebrospinal fluid microdialysates within minutes of peripheral injection. Concentrations of alpha-MSH in the telencephalon and preoptic area were significantly lowered after ether exposure, whereas levels in the optic tectum, thalamus/hypothalamus, brainstem, and plasma were unchanged. We conclude that alpha-MSH administered peripherally facilitates habituation in a dose-dependent fashion. Our results confirm that the effects of alpha-MSH are independent of corticosterone secretion. The peptide is cleared rapidly into the bloodstream and enters the cerebrospinal fluid after dorsal lymph sac injection. Neuronal alpha-MSH may help toads gather information about their environment when exposed to certain stressors.
Animals↗
Errors made by animals in memory paradigms are not always due to failure of memory.
It is commonly assumed that errors in animal memory paradigms such as delayed matching to sample, radial mazes, and food-cache recovery are due to failures in memory for information necessary to perform the task successfully. A body of research, reviewed here, suggests that this is not always the case: animals sometimes make errors despite apparently being able to remember the appropriate information. In this paper a case study of this phenomenon is described, along with a demonstration of a simple procedural modification that successfully reduced these non-memory errors, thereby producing a better measure of memory.
Animals↗
The role of endogenous interleukin-12 in resistance to murine cytomegalovirus (MCMV) infection and a novel action for endogenous IL-12 p40.
Biologically active interleukin-12 (IL-12), comprising a 40 kDa subunit (p40) covalently linked to a 35 kDa subunit (p35), is produced in response to a range of infectious stimuli. Here, we demonstrate that mice deficient in either IL-12 p40 (p40-/-) or IL-12 p35 (p35-/-) are susceptible to murine cytomegalovirus (MCMV) infection in terms of survival (Balb/c p35-/-) and viral clearance (Balb/c p35-/- and Balb/c p40-/-), and this susceptibility may be correlated to a deficiency in serum interferon-gamma (IFN-gamma) levels. These data support a role for endogenous IL-12 in controlling MCMV infection. The IL-12 p40 subunit is produced in excess of IL-12 p35, and to date the function of the excess endogenous p40 has been assumed to be one of IL-12 antagonism, as demonstrated by experiments with exogenous p40 both in vivo and in vitro. We show that Balb/c p35-/- alone are significantly compromised in survival of a sublethal infection and in clearance of virus from the spleen. These mice produce a very early IFN-gamma spike (8 h after infection) and an aberrant tumor necrosis factor-alpha (TNF-alpha) spike (day 2 after infection). MCMV infection has revealed an altered Balb/c p35-/- phenotype compared with Balb/c p40-/-, and this indicates that endogenous p40 may have an activity independent of and additional to IL-12 antagonism in vivo.
Animals↗
The heparin-protamine interaction. A review.
The heparin-protamine interaction is a topic of intense scrutiny due to its mandatory use during cardiopulmonary bypass. It can be estimated that over 2,000,000 patients are exposed to the heparin-protamine interaction each year. From clinical and experimental observation it is known that protamine neutralization of heparin causes increased pulmonary artery pressures and decreased systolic and diastolic blood pressure, myocardial oxygen consumption, cardiac output, heart rate, and systemic vascular resistance. These multiple cardiovascular effects are mediated via complement activation, histamine release, thromboxane and nitric oxide production, and antibody formation. This article reviews the current understanding of the heparin-protamine interaction from the world's literature.
Animals↗
Adenocarcinoma of the head of the pancreas: effects of surgical and nonsurgical therapy on survival--a ten-year experience.
A retrospective analysis of all patients treated for adenocarcinoma of the head of the pancreas from 1989 to 1998 was performed. Excluded were cancers in the body and tail, cystic neoplasms, ampullary tumors, and cancers of the duodenum and bile ducts. One hundred forty-five patients were reviewed, and 43 patients underwent pancreaticoduodenectomy. Data collected included the stage, lymph node status, surgical margins, adjuvant therapies, and survival. Statistical analysis was performed with Cox's Proportional Hazards Analysis and Log-Rank Life Table Analysis. The surgical population had a 21 per cent 3-year survival rate and a 7 per cent operative mortality rate. Median survival was: 1) the resection group versus no resection was 13.5 versus 3.1 months; 2) adjuvant therapy versus no therapy after resection was 16.1 versus 5.1 months; and 3) chemoradiation therapy versus no therapy for unresectable disease was 5.3 versus 1.8 months. The presence of positive surgical margins was found in 33 per cent of the surgical specimens and carried an increased mortality hazard ratio of 3.1. Patients with negative lymph nodes had a 15 per cent 5-year survival, versus 0 per cent with positive nodes. Seventy-three per cent of those resected had a T2 lesion, and 46 per cent of patients presented with metastatic disease. Surgical resection and adjuvant therapy significantly improves survival in patients with adenocarcinoma of the head of the pancreas. All patients who underwent resection as part of their therapy showed extended survival compared with chemoradiation therapy alone. Adjuvant chemoradiation improved survival when compared with surgery alone. Multimodality treatment in carcinoma of the head of the pancreas provides the best treatment option. However, better adjuvant therapies are needed.
Adenocarcinoma↗
Characterization of [125I]beta-endorphin binding sites in the rat caudal dorsomedial medulla.
[125I]beta-endorphin bound to high affinity (Kd = 0.25 nM) receptors in the caudal dorsomedial medulla of rats with a Bmax of 97 fmol/mg protein. The relative potency for displacement of [125I]beta-endorphin binding was: beta-endorphin(1-31) > beta-endorphin(1-27) > DAMGO > naloxone > N-acetyl-beta-endorphin(1-31) > U50488 > DPDPE. The Bmax for [3H]DAMGO binding was 81 fmol/mg protein, indicating that most [125I]beta-endorphin binding corresponds to mu-opioid receptors. [3H]DAMGO binding was not influenced by lesioning noradrenergic nerve terminals in the caudal dorsomedial medulla. Our findings indicate that beta-endorphin interacts primarily with mu-opioid receptors in the caudal dorsomedial medulla. These receptors are not affected by noradrenergic denervation.
Animals↗
Alterations in brain and pituitary beta-endorphin content in genetically epilepsy-prone rats.
We measured beta-endorphin concentrations in the anterior and neurointermediate lobes of the pituitary gland and in microdissected brain regions of moderate-seizure genetically epilepsy-prone rats (GEPR-3), severe-seizure GEPR-9s and Sprague-Dawley non-epileptic control rats. Plasma concentrations of beta-endorphin and beta-melanocyte-stimulating hormone (alpha-MSH) were also measured as indicators of pituitary POMC-peptide secretion. Concentrations of beta-endorphin in the anterior lobe of GEPR-3s were 53% higher compared to controls and 57% higher compared to GEPR-9s. There were no differences in neurointermediate lobe beta-endorphin concentrations between control and either GEPR strain. Plasma beta-endorphin concentrations were significantly lower in GEPR-9s than controls. Plasma levels of alpha-MSH did not differ between control and GEPRs. In the hypothalamus of GEPR-9s beta-endorphin concentrations in the arcuate nucleus were significantly greater than in GEPR-3s. Concentrations of beta-endorphin in the central amygdala of GEPR-9s were two- to threefold greater than in control or GEPR-3s. Beta-Endorphin concentrations in the central gray of GEPR-3s were 58% lower than control or GEPR-9s. These data suggest that anterior lobe beta-endorphin secretion is reduced in GEPR-9s. Furthermore, brain endorphinergic pathways appear to be differentially altered in GEPR-3s and GEPR-9s. Alterations in pituitary beta-endorphin secretion and brain endorphinergic systems may contribute to seizure susceptibility in GEPRs and to differences in seizure severity between GEPR-3s and GEPR-9s.
Animals↗
Spigelian hernia with Crohn's appendicitis.
We present a case report of a young man found to have Crohn's appendicitis in an incarcerated spigelian hernia, initially diagnosed via laparoscopy. We have found two published cases of incarcerated appendicitis in spigelian hernias; however, only one of them also showed histologic evidence of Crohn's disease, and neither was discovered during laparoscopy. Therefore, we submit this rare case presentation and discuss the advantages of laparoscopy as an aid in diagnosing the cause of chronic abdominal pain.
Adult↗
Interactions of androgens and estradiol on sex accessory ducts of larval tiger salamanders, Ambystoma tigrinum.
Immature tiger salamander larvae were treated with 12.5 or 25 micrograms of estradiol, testosterone, or dihydrotestosterone (DHT), or 12.5 micrograms of estradiol combined with 12.5 micrograms of either testosterone or DHT. Müllerian duct epithelium was more stimulated by combined steroid treatment than by any steroid alone. Estradiol antagonized the action of DHT in the Wolffian duct. Both of the androgens and estradiol when administered alone at the higher dose stimulated enlargement of connective tissue surrounding the ducts, but the combined 12.5 micrograms androgen/12.5 micrograms estrogen treatment was more effective even though the total steroid administered was the same. The effectiveness of DHT on müllerian cells of this species is evidence against a required aromatization of androgens to explain paradoxical steroid effects and suggests that fundamental differences may exist in steroid receptors of müllerian ducts, connective tissue, and Wolffian ducts. A possible role for the urodele duct system for assessing estrogenic activity of environmental contaminants is discussed.
Ambystoma↗