bluuebunny/crossref_metadata_2025 huggingface dataset:
Are renal microgranulomas related to inflammatory tubular destruction?
Authors: Mahmood A , Poller D N , Ramage J K
Published: April 2004

Two cases of renal microgranuloma formation are reported, one in a patient with known Crohn’s disease and another in a case of acute renal allograft rejection. In both cases, the microgranulomas arose as a result of inflammatory tubular destruction, in a manner analogous to that seen in patients with ulcerative colitis arising adjacent to ruptured epithelial crypts in the large intestine. Microgranulomas may occur at multiple anatomical sites in Crohn’s disease, although renal microgranulomas are very rare. Non-specific inflammatory tubular destruction should be considered as a cause of renal microgranuloma formation, in addition to systemic granulomatous diseases, such as tuberculosis, sarcoid, or Crohn’s disease, when granulomas are seen in the presence of inflammatory tubular destruction in renal biopsies.
NOISE IN NEURAL NETWORKS — IN TERMS OF RELATIONS
Authors: LILJENSTRÖM HANS , HALNES GEIR
Published: April 2004

The issue of noise in biological systems is primarily a question of relations: between order and disorder, between stability and flexibility, and between processes at different temporal and spatial scales. In this paper, we use computational models of cortical structures to investigate relations between structure, dynamics, and function of such systems. In particular, we investigate the nature and role of noise at different organizational levels of the nervous system, emphasizing the neural network level. We show that microscopic noise can induce global network oscillations and pseudo-chaos, which make neural information processing more efficient. We find optimal noise levels for which the convergence to stored memory attractor states reaches a maximum, akin to stochastic resonance. We finally discuss the relation between neural and mental processes, and how computational models may relate to real neural systems.
Increased glucose sensitivity of both triggering and amplifying pathways of insulin secretion in rat islets cultured for 1 wk in high glucose
Authors: Khaldi M. Z. , Guiot Y. , Gilon P. , Henquin J. C. , Jonas J. C.
Published: April 2004

Chronic hyperglycemia has been shown to induce either a lack of response or an increased sensitivity to glucose in pancreatic β-cells. We reinvestigated this controversial issue in a single experimental model by culturing rat islets for 1 wk in 10 or 30 mmol/l glucose (G10, Controls; or G30, High-glucose islets) before testing the effect of stepwise glucose stimulation from G0.5 to G20 on key β-cell stimulus-secretion coupling events. Compared with Controls, the glucose sensitivity of High-glucose islets was markedly increased, leading to maximal stimulation of oxidative metabolism and both triggering and amplifying pathways of insulin secretion in G6 rather than G20, hence to loss of glucose effect above G6. This enhanced glucose sensitivity occurred despite an approximately twofold increase in islet uncoupling protein 2 mRNA expression. Besides this increased glucose sensitivity, the maximal glucose stimulation of insulin secretion in High-glucose islets was reduced by ∼50%, proportionally to the reduction of insulin content. In High-glucose islets, changes in45Ca2+influx induced by glucose and diazoxide were qualitatively similar but quantitatively smaller than in Control islets and, paradoxically, did not lead to detectable changes in the intracellular Ca2+concentration measured by microspectrofluorimetry (fura PE 3). In conclusion, after 1 wk of culture in G30, the loss of glucose stimulation of insulin secretion in the physiological range of glucose concentrations (G5–G10) results from the combination of an increased sensitivity to glucose of both triggering and amplifying pathways of insulin secretion and an ∼50% reduction in the maximal glucose stimulation of insulin secretion.
Novel role of phospholipase C-δ1: regulation of liver mitochondrial Ca2+uptake
Authors: Knox Clayton D. , Belous Andrey E. , Pierce Janene M. , Wakata Aya , Nicoud Ian B. , Anderson Christopher D. , Pinson C. Wright , Chari Ravi S.
Published: April 2004

Mitochondrial Ca2+(mCa2+) handling is an important regulator of liver cell function that controls events ranging from cellular respiration and signal transduction to apoptosis. Cytosolic Ca2+enters mitochondria through the ruthenium red-sensitive mCa2+uniporter, but the mechanisms governing uniporter activity are unknown. Activation of many Ca2+channels in the cell membrane requires PLC. This activation commonly occurs through phosphitidylinositol-4,5-biphosphate (PIP2) hydrolysis and the production of the second messengers inositol 1,4,5-trisphosphate [I(1,4,5)P3] and 1,2-diacylglycerol (DAG). PIP2was recently identified in mitochondria. We hypothesized that PLC exists in liver mitochondria and regulates mCa2+uptake through the uniporter. Western blot analysis with anti-PLC antibodies demonstrated the presence of PLC-δ1 in pure preparations of mitochondrial membranes isolated from rat liver. In addition, the selective PLC inhibitor U-73122 dose-dependently blocked mCa2+uptake when whole mitochondria were incubated at 37°C with45Ca2+. Increasing extra mCa2+concentration significantly stimulated mCa2+uptake, and U-73122 inhibited this effect. Spermine, a uniporter agonist, significantly increased mCa2+uptake, whereas U-73122 dose-dependently blocked this effect. The inactive analog of U-73122, U-73343, did not affect mCa2+uptake in any experimental condition. Membrane-permeable I(1,4,5)P3receptor antagonists 2-aminoethoxydiphenylborate and xestospongin C also inhibited mCa2+uptake. Although extra mitochondrial I(1,4,5)P3had no effect on mCa2+uptake, membrane-permeable DAG analogs 1-oleoyl-2-acetyl- sn-glycerol and DAG-lactone, which inhibit PLC activity, dose-dependently inhibited mCa2+uptake. These data indicate that PLC-δ1 exists in liver mitochondria and is involved in regulating mCa2+uptake through the uniporter.
Regular exercise is associated with a protective metabolic phenotype in the rat heart
Authors: Burelle Yan , Wambolt Richard B. , Grist Mark , Parsons Hannah L. , Chow Jeffrey C. F. , Antler Christine , Bonen Arend , Keller Angelica , Dunaway George A. , Popov Kirill M. , Hochachka Peter W. , Allard Michael F.
Published: April 2004

Adaptation of myocardial energy substrate utilization may contribute to the cardioprotective effects of regular exercise, a possibility supported by evidence showing that pharmacological metabolic modulation is beneficial to ischemic hearts during reperfusion. Thus we tested the hypothesis that the beneficial effect of regular physical exercise on recovery from ischemia-reperfusion is associated with a protective metabolic phenotype. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured in isolated working hearts from sedentary control (C) and treadmill-trained (T: 10 wk, 4 days/wk) female Sprague-Dawley rats submitted to 20 min ischemia and 40 min reperfusion. Training resulted in myocardial hypertrophy (1.65 ± 0.05 vs. 1.30 ± 0.03 g heart wet wt, P < 0.001) and improved recovery of function after ischemia by nearly 50% ( P < 0.05). Glycolysis was 25–30% lower in T hearts before and after ischemia ( P < 0.05), whereas rates of glucose oxidation were 45% higher before ischemia ( P < 0.01). As a result, the fraction of glucose oxidized before and after ischemia was, respectively, twofold and 25% greater in T hearts ( P < 0.05). Palmitate oxidation was 50–65% greater in T than in C before and after ischemia ( P < 0.05), whereas lactate oxidation did not differ between groups. Alteration in content of selected enzymes and proteins, as assessed by immunoblot analysis, could not account for the reduction in glycolysis or increase in glucose and palmitate oxidation observed. Combined with the studies on the beneficial effect of pharmacological modulation of energy metabolism, the present results provide support for a role of metabolic adaptations in protecting the trained heart against ischemia-reperfusion injury.
Experience-Dependent Neural Integration of Taste and Smell in the Human Brain
Authors: Small Dana M. , Voss Joel , Mak Y. Erica , Simmons Katharine B. , Parrish Todd , Gitelman Darren
Published: April 2004

Flavor perception arises from the central integration of peripherally distinct sensory inputs (taste, smell, texture, temperature, sight, and even sound of foods). The results from psychophysical and neuroimaging studies in humans are converging with electrophysiological findings in animals and a picture of the neural correlates of flavor processing is beginning to emerge. Here we used event-related fMRI to evaluate brain response during perception of flavors (i.e., taste/odor liquid mixtures not differing in temperature or texture) compared with the sum of the independent presentation of their constituents (taste and/or odor). All stimuli were presented in liquid form so that olfactory stimulation was by the retronasal route. Mode of olfactory delivery is important because neural suppression has been observed in chemosensory regions during congruent taste–odor pairs when the odors are delivered by the orthonasal route and require subjects to sniff. There were 2 flavors. One contained a familiar/congruent taste–odor pair (vanilla/sweet) and the other an unfamiliar/incongruent taste–odor pair (vanilla/salty). Three unimodal stimuli, including 2 tastes (sweet and salty) and one odor (vanilla), as well as a tasteless/odorless liquid (baseline) were presented. Superadditive responses during the perception of the congruent flavor compared with the sum of its constituents were observed in the anterior cingulate cortex (ACC), dorsal insula, anterior ventral insula extending into the caudal orbitofrontal cortex (OFC), frontal operculum, ventral lateral prefrontal cortex, and posterior parietal cortex. These regions were not present in a similar analysis of the incongruent flavor compared with the sum of its constituents. All of these regions except the ventrolateral prefrontal cortex were also isolated in a direct contrast of congruent − incongruent. Additionally, the anterior cingulate, posterior parietal cortex, frontal operculum, and ventral insula/caudal OFC were also more active in vanilla + salty minus incongruent, suggesting that delivery of an unfamiliar taste–odor combination may lead to suppressed neural responses. Taken together with previous findings in the literature, these results suggest that the insula, OFC, and ACC are key components of the network underlying flavor perception and that taste–smell integration within these and other regions is dependent on 1) mode of olfactory delivery and 2) previous experience with taste/smell combinations.
Electric Low-Frequency Stimulation of the Tongue Induces Long-Term Depression of the Jaw-Opening Reflex in Anesthetized Mice
Authors: Ellrich Jens
Published: April 2004

Long-term depression (LTD) of somatosensory processing has been demonstrated in slice preparations of the spinal dorsal horn. Although LTD could be reliably induced in vitro, inconsistent results were encountered when the same types of experiments were conducted in adult animals in vivo. We addressed the hypothesis that LTD of orofacial sensorimotor processing can be induced in mice under general anesthesia. The effects of electric low- and high-frequency conditioning stimulation of the tongue on the sensorimotor jaw-opening reflex (JOR) elicited by electric tongue stimulation were investigated. Low-frequency stimulation induced a sustained decrease of the reflex integral for ≥1 h after the end of conditioning stimulation. After additional high-frequency stimulation, the reflex partly recovered from LTD. High-frequency stimulation alone induced a transient increase of the JOR integral for <10 min. The LTD of the sensorimotor jaw-opening reflex in anesthetized mice may be an appropriate model to investigate the central mechanisms and the pharmacology of synaptic plasticity in the orofacial region. The application of electrophysiological techniques in mice provides the opportunity to include adequate knock-out models to elucidate the neurobiology of LTD.
Patch Clamp Study of Serotonin‐Gated Currents via 5‐HT Type 3 Receptors by Using a Novel Approach SHAM forReceptor Channel Scanning
Authors: Kaneez Fatima-Shad , White M.
Published: April 2004

We studied 5‐hydroxy tryptamine type 3 (5‐HT 3) receptors
transfected in tsA‐201 cell line to examine serotonin‐induced
whole cell currents. Using the site‐directed mutagenesis
technique, we individually mutated each residue in the
membrane‐spanning M2 segment to histidine. A high proportion of
tsA‐201 cells cotransfected with the cDNAs of 5‐HT 3R and CD8
produced large amplitude responses (0.5–7.0 nA) to
serotonin. The dose‐response curve of wild‐type (WT) receptor
ranging from 0.5 to 500 μmole increases its K d
values, and Imax

of 5‐HT 3R falls at low external pH as if
protonation of an acid group is enough to block the channel.
Lysine at position 281, a basic residue, is more susceptible to
acidification‐induced blockade of the 5‐HT 3R channel.
Dose‐response curves of K281S (replacing lysine at the 281
position with serine) at different pH are not significantly
modulated, and histidine substitutions at the three consecutive
positions 293, 294, and 296 eliminate the pH block of the channel.
Adhesion to Vitronectin and Collagen I Promotes Osteogenic Differentiation of Human Mesenchymal Stem Cells
Authors: Salasznyk Roman M. , Williams William A. , Boskey Adele , Batorsky Anna , Plopper George E.
Published: April 2004

The mechanisms controlling human mesenchymal stem
cells (hMSC) differentiation are not entirely understood. We
hypothesized that the contact with extracellular matrix (ECM)
proteins normally found in bone marrow would promote osteogenic
differentiation of hMSC in vitro. To test this hypothesis, we
cultured hMSC on purified ECM proteins in the presence or absence
of soluble osteogenic supplements, and assayed for the presence of
well‐established differentiation markers (production of
mineralized matrix, osteopontin, osteocalcin, collagen I, and
alkaline phosphatase expression) over a 16‐day time course. We
found that hMSC adhere to ECM proteins with varying affinity
(fibronectin > collagen I ≥ collagen
IV ≥ vitronectin > laminin‐1) and through distinct integrin receptors.
Importantly, the greatest osteogenic differentiation occurred in
cells plated on vitronectin and collagen I and almost no
differentiation took place on fibronectin or uncoated plates. We
conclude that the contact with vitronectin and collagen I promotes
the osteogenic differentiation of hMSC, and that ECM contact
alone may be sufficient to induce differentiation in these cells.
Attenuation of Oxidative Stress and Remodeling by Cardiac Inhibitor of Metalloproteinase Protein Transfer
Authors: Cox Michael J. , Hawkins Urseline A. , Hoit Brian D. , Tyagi Suresh C.
Published: April 2004

Background—

Matrix metalloproteinase (MMP) and cardiac inhibitor of metalloproteinase (CIMP) are coexpressed in the heart. Although it is known that oxidative stress activates MMP and CIMP inhibits MMP, it is unclear whether CIMP administration attenuates oxidative stress and MMP-mediated cardiac dilatation.

Methods and Results—

Arteriovenous fistula (AVF) was created in C57BL/J6 mice, and CIMP was administered to AVF and sham mice by protein transfer into peritoneal cavity by minipump for 4 weeks. Mice were grouped as follows: sham; sham+CIMP; AVF; and AVF+CIMP (n=6). In vivo left ventricular (LV) pressure was measured. Plasma and LV tissue levels of CIMP were measured by Western analysis. LV levels of NADPH oxidase activity, marker of oxidative stress, were increased in AVF mice and decreased in AVF mice treated with CIMP. Compared with sham, CIMP was decreased in AVF mice, and CIMP protein transfer increased plasma and LV tissue levels of CIMP in AVF mice; there was no increase in sham animals. In situ zymography demonstrated a robust increase in MMP activity in the hearts from AVF mice compared with sham, and treatment with CIMP decreased MMP activity. In AVF mice, the cardiac pressure-length relationship was similar to that observed in sham mice after administration of CIMP. Contractile responses of normal LV rings were measured in the presence and absence of CIMP. CIMP shifted the pressure-length relationship to the left, attenuated LV dilatation, and had no effect on CaCl
2
-mediated contraction.

Conclusions—

Treatment of AVF mice with CIMP significantly abrogated the contractile dysfunction and decreased the oxidative stress in volume overload–induced heart failure.
Detection of Acutely Impaired Microvascular Reperfusion After Infarct Angioplasty With Magnetic Resonance Imaging
Authors: Taylor Andrew J. , Al-Saadi Nidal , Abdel-Aty Hassan , Schulz-Menger Jeanette , Messroghli Daniel R. , Friedrich Matthias G.
Published: April 2004

Background—

Despite the reopening of the infarct-related artery (IRA) with infarct angioplasty, complete microvascular reperfusion does not always ensue.

Methods and Results—

We performed cardiovascular MRI (CMR) in 20 acute myocardial infarction (AMI) patients within 24 hours of successful infarct angioplasty and 10 control patients without obstructive coronary artery disease on a clinical 1.5-T CMR scanner. Three-month follow-up CMR in AMI patients evaluated the impact of abnormal reperfusion on recovery of function. Infarction was localized by delayed contrast hyperenhancement and impaired systolic thickening. Microvascular perfusion was assessed at rest by first-pass perfusion CMR after a bolus of gadolinium-DTPA by use of the time to 50% maximum myocardial enhancement. Whereas contrast wash-in was homogeneous in control patients, AMI patients exhibited delays in the hypokinetic region subtended by the IRA compared with remote segments in 19 of 20 patients, with a mean contrast delay of 0.9±0.1 seconds (95% CI, 0.6 to 1.2 seconds). At follow-up, the mean recovery of systolic thickening was lower in segments with a contrast delay of 2 seconds or more (10±7% versus 39±4%,
P
<0.001). A contrast delay ≥2 seconds and infarction >75% transmurally were independent predictors of impaired left ventricular systolic thickening at 3 months (
P
=0.002 for severe contrast delay,
P
=0.048 for >75% for transmural infarction).

Conclusions—

CMR detects impaired microvascular reperfusion in AMI patients despite successful infarct angioplasty, which when severe is associated with a lack of recovery of wall motion.
Folate Intake and Risk of Stroke Among Women
Authors: Al-Delaimy Wael K. , Rexrode Kathryn M. , Hu Frank B. , Albert Christine M. , Stampfer Meir J. , Willett Walter C. , Manson JoAnn E.
Published: April 2004

Background and Purpose—

Few studies have examined the association between folate intake and risk of stroke, although numerous studies have suggested that high levels of homocysteine are positively related to stroke. We aim to assess the relation between folate intake and stroke incidence among women participating in the Nurses’ Health Study.

Methods—

83 272 female nurses aged 34 to 59 years in 1980 and residing in 11 US states were followed-up for 18 years. Follow-up questionnaires were sent biennially to update information on diet and to identify newly diagnosed cases of stroke and other illnesses.

Results—

During 1 379 614 person-years of follow-up from 1980 to 1998, we identified 1140 incident cases of stroke. Using age-adjusted and multivariable-adjusted models, no appreciable association between the intake of folate and total incidence of stroke was observed [relative risk in the multivariable-adjusted model for the highest quintile of folate intake (median=696 μg/d) compared with the lowest quintile (median=158 μg/d) was 1.01 (95% confidence interval [CI]: 0.79 to 1.29),
P
for trend=0.8]. Similar null results were found in secondary analyses on stroke subtypes (ischemic, thrombotic, embolic, subarachnoid hemorrhage, intraparenchymal hemorrhage) and in analyses that separately assessed dietary folate (excluding supplement users) and folate supplement intake.

Conclusions—

Folate intake was not associated with incident stroke among women participating in the Nurses’ Health Study.
Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA)
Authors:   The SSYLVIA Study Investigators
Published: April 2004

Background and Purpose—

Stroke rates in patients with symptomatic intracranial stenosis may be as high as 10% to 24% per year on medical therapy. This multicenter, nonrandomized, prospective feasibility study evaluated the NEUROLINK System for treatment of vertebral or intracranial artery stenosis.

Methods—

Patients were 18 to 80 years old with symptoms attributed to a single target lesion of ≥50% stenosis. Patients received 5 neurological examinations before and in the year after the procedure, and another angiogram at 6 months.

Results—

In 61 patients enrolled, 43 (70.5%) intracranial arteries (15 internal carotid, 5 middle cerebral, 1 posterior cerebral, 17 basilar, 5 vertebral) and 18 (29.5%) extracranial vertebral arteries (6 ostia, 12 proximal to the posterior inferior cerebellar artery [PICA]) were treated. In the first 30 days, 4 patients (6.6%) had strokes and no deaths occurred. Successful stent placement was achieved in 58/61 cases (95%). At 6 months, stenosis of >50% occurred in 12/37 (32.4%) intracranial arteries and 6/14 (42.9%) extracranial vertebrals, 4 in the vertebral ostia. Seven (39%) recurrent stenoses were symptomatic. Four of 55 patients (7.3%) had strokes later than 30 days, 1 of which was in the only patient not stented.

Conclusions—

The NEUROLINK System is associated with a high rate of successful stent deployment. Strokes occurred in 6.6% of patients within 30 days and in 7.3% between 30 days and 1 year. Although restenoses occurred in 35% of patients, 61% were asymptomatic. Further trials involving the NEUROLINK System are warranted.
Matters of Life and Death: The Story of Elijah and the Widow's Son in Comparative Perspective
Authors: Lasine Stuart
Published: April 2004

This paper examines the concept of death projected by 1 Kgs 17:17-24 and other accounts of miraculous resuscitation. Viewed as a medical case history, Elijah's reviving of the widow's son raises difficult questions. Was the boy really dead, "only mostly dead," or merely gravely ill? Scholars often answer such questions by claiming that ancient Israelites did not consider corpses "to be 'totally' dead for a couple of days," and regarded death as "an enfeebled form of life." This paper challenges these claims by comparing Elijah's actions to those of other biblical and ancient Greek healers, as well as to Mesopotamian and shamanic healing practices. Why do healers like Elijah end up getting into bed with their patients? Examples in modern stories by Flaubert and Kafka reveal the kinship between the healer and the scapegoat, and suggest that miraculous healers tend to display narcissistic personality traits. Analysis of Greek sources and the Mount Horeb episode (1 Kings 19) indicates that this may also be the case for ancient healers like Elijah, Empedocles, and Asclepius, and that narcissism is itself a defense against death.
Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome
Authors: Markert M. Louise , Alexieff Marilyn J. , Li Jie , Sarzotti Marcella , Ozaki Daniel A. , Devlin Blythe H. , Sedlak Debra A. , Sempowski Gregory D. , Hale Laura P. , Rice Henry E. , Mahaffey Samuel M. , Skinner Michael A.
Published: April 2004

Complete DiGeorge syndrome is a fatal congenital disorder characterized by athymia, hypoparathyroidism, and heart defects. Less than half of patients are 22q11 hemizygous. The goal of this study was to assess if immune suppression followed by postnatal thymus transplantation would lead to T-cell function in 6 infant patients who had host T cells at the time of transplantation. All infants had fewer than 50 recent thymic emigrants (CD3+CD45RA+CD62L+) per cubic millimeter (mm3) and all had some proliferative response to the mitogen phytohemagglutinin. Four infants had rash, lymphadenopathy, and oligoclonal populations of T cells in the periphery. Five of 6 patients are alive at the follow-up interval of 15 months to 30 months. The 5 surviving patients developed a mean of 983 host CD3+ T cells/mm3 (range, 536/mm3-1574/mm3), a mean of 437 recent thymic emigrants/mm3 (range, 196/mm3-785/mm3), and normal proliferative responses to phytohemaglutinin (follow-up from day 376 to day 873). The TCR repertoire became polyclonal in patients who presented with oligoclonal T cells. All patients had thymopoiesis on allograft biopsy. Postnatal thymus transplantation after treatment with Thymoglobulin shows promise as therapy for infants with complete DiGeorge syndrome who have significant proliferative responses to mitogens or who develop rash, lymphadenopathy, and oligoclonal T cells.
A TREM family member, TLT-1, is found exclusively in the α-granules of megakaryocytes and platelets
Authors: Washington A. Valance , Schubert Rebecca L. , Quigley Laura , Disipio Theresa , Feltz Robert , Cho Edward H. , McVicar Daniel W.
Published: April 2004

The triggering receptors expressed on myeloid cells (TREMs) have drawn considerable attention due to their ability to activate multiple cell types within the innate immune system, including neutrophils, monocyte/macrophages, and dendritic cells, via their association with DAP12. TLT-1 (TREM-like transcript-1) lies within the TREM gene cluster and contains the characteristic single V-set immunoglobulin (Ig) domain of the family, but its longer cytoplasmic tail is composed of both a proline-rich region and an immune receptor tyrosine-based inhibitory motif, the latter known to be used for interactions with protein tyrosine phosphatases. Here we report that TLT-1 is expressed exclusively in platelets and megakaryocytes (MKs) and that TLT-1 expression is up-regulated dramatically upon platelet activation. Consistent with this observation, confocal microscopy demonstrates that TLT-1 is prepackaged, along with CD62P, into both MK and platelet α-granules. Differences in thrombin-induced redistribution of CD62P and TLT-1 indicate that TLT-1 is not simply cargo of α-granules but may instead regulate granule construction or dispersal. Together these data show that that TLT-1 does not function to inhibit members of the TREM family but instead may play a role in maintaining vascular hemostasis and regulating coagulation and inflammation at sites of injury.
HCMV activates PI(3)K in monocytes and promotes monocyte motility and transendothelial migration in a PI(3)K-dependent manner
Authors: Smith M Shane , Bentz Gretchen L , Smith Patrick M , Bivins Elizabeth R , Yurochko Andrew D
Published: April 2004

Human cytomegalovirus (HCMV) is a leading cause of morbidity and mortality in immunocompromised hosts. In immunocompetent hosts, HCMV is associated with chronic inflammatory diseases including atherosclerosis. Monocytes and macrophages are proposed to play key roles in HCMV dissemination to host tissue, and their infection provides a biological link between the lifecycle of HCMV and disease pathology. We hypothesize that viral spread occurs via a mechanism in which infected peripheral blood monocytes, which are nonpermissive for viral replication, extravasate into host tissue and subsequently differentiate into permissive macrophages. Supporting this hypothesis, we recently showed that HCMV specifically induced the differentiation of monocytes into macrophages that become permissive for viral replication. To expand our understanding of HCMV pathogenesis, we next examined monocyte activation and migration, the first events in viral pathogenesis. We show here that HCMV up-regulates phosphatidylinositol 3,4,5 triphosphate kinase [PI(3)K] activity and that this increased PI(3)K activity is essential for infected monocyte-transendothelial migration. This increase in migration occurs through the up-regulation of cell motility in a PI(3)K-dependent process. Last, we show that these activated monocytes express a number of inflammatory mediators via PI(3)K signaling. We propose that the up-regulation of monocyte migration and immune mediators by HCMV infection is required for the hematogenous dissemination of the virus and as a consequence, could promote chronic inflammatory diseases associated with HCMV infection.
A Critical Role for the Evolutionarily Conserved Gonadotropin-Releasing Hormone II: Mediation of Energy Status and Female Sexual Behavior
Authors: Kauffman Alexander S. , Rissman Emilie F.
Published: April 2004

GnRH is an evolutionarily conserved neuropeptide, of which there are multiple structural variants; the function of the most widespread variant, GnRH-II, remains undefined. GnRH-II may affect reproductive behavior; GnRH-II administration to female musk shrews reinstates mating behavior previously inhibited by food restriction. To determine whether this action of GnRH-II is universal, we conducted the following studies in mice. Ovariectomized mice were primed with estradiol benzoate and progesterone once a week and tested for sexual behavior. Females showing a lordosis quotient (LQ) of 50 or higher on the fourth trial underwent food deprivation (FD) for either 24 or 48 h before an additional behavior test. FD for 48 h significantly reduced LQ compared with ad libitum-fed females. Next, females were FD for 48 h or maintained on ad libitum feeding and retested for sexual behavior after an intracerebroventricular infusion of either GnRH-I, GnRH-II, or saline. GnRH-II, but not GnRH-I, significantly increased LQ in FD females compared with FD females treated with saline. Lordosis was unaffected by GnRH-II in females maintained on ad libitum feeding. To assess whether the GnRH-I receptor mediates GnRH-II’s behavioral effects, underfed females were pretreated with the type 1 GnRH receptor antagonist Antide and retested for sexual behavior. Antide pretreatment did not prevent GnRH-II from promoting mating behavior, suggesting that GnRH-II’s behavioral actions are mediated through the type 2 GnRH receptor. We speculate that GnRH-II acts via its own receptor as a regulatory signal in mammals to ensure that reproduction is synchronized with energetically favorable conditions.
Compositional and structural requirements for laminin and basement membranes during mouse embryo implantation and gastrulation
Authors: Miner Jeffrey H. , Li Cong , Mudd Jacqueline L. , Go Gloriosa , Sutherland Ann E.
Published: April 2004

Laminins are components of all basement membranes and have well demonstrated roles in diverse developmental processes, from the peri-implantation period onwards. Laminin 1 (α1β1γ1) is a major laminin found at early stages of embryogenesis in both embryonic and extraembryonic basement membranes. The laminin γ1 chain has been shown by targeted mutation to be required for endodermal differentiation and formation of basement membranes; Lamc1-/- embryos die within a day of implantation. We report the generation of mice lacking lamininα1 and laminin β1, the remaining two laminin 1 chains. Mutagenic insertions in both Lama1 and Lamb1 were obtained in a secretory gene trap screen. Lamb1-/- embryos are similar to Lamc1-/- embryos in that they lack basement membranes and do not survive beyond embryonic day (E) 5.5. However, in Lama1-/- embryos, the embryonic basement membrane forms,the embryonic ectoderm cavitates and the parietal endoderm differentiates,apparently because laminin 10 (α5β1γ1) partially compensates for the absent laminin 1. However, such compensation did not occur for Reichert's membrane, which was absent, and the embryos died by E7. Overexpression of laminin α5 from a transgene improved the phenotype of Lama1-/- embryos to the point that they initiated gastrulation, but this overexpression did not rescue Reichert's membrane, and trophoblast cells did not form blood sinuses. These data suggest that both the molecular composition and the integrity of basement membranes are crucial for early developmental events.
Treatment of Vancomycin-Resistant Enterococcus with Quinupristin/Dalfopristin and High-Dose Ampicillin
Authors: Bethea J Audis , Walko Christine M , Targos Patricia A
Published: April 2004

OBJECTIVE:

To report the successful treatment of vancomycin-resistant Enterococcus (VRE) bacteremia using the combination of quinupristin/dalfopristin and high-dose ampicillin.

CASE SUMMARY:

A 38-year-old African American woman with relapsed acute myeloid leukemia and neutropenic fever developed VRE bacteremia following 3 successive courses of vancomycin for methicillin-resistant staphylococcal infections. Treatment with linezolid was initiated; however, after 9 days of therapy, blood cultures continued to reveal VRE and the patient became febrile. The patient was subsequently switched to quinupristin/dalfopristin and high-dose ampicillin. The fever resolved and all subsequent blood cultures were negative after the initiation of combination therapy.

DISCUSSION:

The emergence of VRE infections presents a treatment challenge in immunocompromised patients. When treating VRE infections in this patient population, the effectiveness of linezolid and quinupristin/dalfopristin is limited by their bacteriostatic activity when used as monotherapy. Recent in vitro data suggest synergistic activity with quinupristin/dalfopristin when used in combination with other antimicrobials in selected isolates of VRE.

CONCLUSIONS:

Persistent VRE bacteremia was successfully treated in this neutropenic patient using the combination of high-dose ampicillin and quinupristin/dalfopristin. Case reports and in vitro data suggest that concomitant therapy with high-dose ampicillin may be an effective treatment alternative for VRE infections not responding to standard therapy.
Indinavir‐Associated Maculopapular Eruption
Authors: Fung Horatio B. , Pecini Raymond A. , Brown Sheldon T. , Gropper Charles A.
Published: April 2004

Indinavir‐associated adverse dermatologic reactions are rare but do occur. A 39‐year‐old man who was positive for the human immunodeficiency virus and had no known allergy, developed an erythematous, maculopapular eruption several hours after switching to a new triple‐drug regimen consisting of stavudine, didanosine, and indinavir. The eruption completely resolved 2 weeks after he discontinued the antiretroviral combination. To preserve future treatment options, the patient was sequentially rechallenged with each agent and confirmed indinavir as the cause. The patient tolerated and responded to a new combination of stavudine, didanosine, and nelfinavir. The rapid onset of the adverse reaction suggested that it might have been immunoglobulin‐E mediated. No cross‐sensitivity between indinavir and nelfinavir was apparent.
Vitamins for the Management of Cardiovascular Disease: A Simple Solution to a Complex Problem?
Authors: Lenhart Susan E. , Nappi Jean M.
Published: April 2004

Attention is focusing on the relationship between homocysteine and cardiovascular disease and the role of vitamins in the management of this prevalent ailment. Epidemiologic studies have shown that a relationship between elevated homocysteine concentrations and cardiovascular disease may exist; however, a cause‐and‐effect relationship has not been proven. The B vitamins are key components of homocysteine metabolism, and the trend is toward their being increasingly prescribed for cardiovascular disease. Prescribing of antioxidant vitamins, vitamin E in particular, has increased as well. Vitamin E may decrease the risk of nonfatal myocardial infarction in patients with coronary artery disease, but its benefit in preventing fatal myocardial infarction has not been shown. Vitamin supplements are not warranted in all patients with cardiovascular disease but may have a place in therapy for selected patients.
A Pilot Study of Estrogen's Effects on Bronchial Myocyte Adhesion Molecule Expression
Authors: Dickens George R. , Matheny Christopher J. , Morris Peter E. , Clifton G. Dennis , Ensom Mary H. H.
Published: April 2004

We examined the effects of estrogen on tumor necrosis factor α (TNF‐α)‐induced expression of intracellular adhesion molecule (ICAM‐1) and vascular adhesion molecule (VCAM‐1) in cultured human bronchial smooth muscle cells (BSMC). Experiments were performed in triplicate in T‐75 tissue culture flasks containing normal human BSMC. Four experiments were carried out: untreated BSMC cells (control); TNF‐α 1000 U/ml stimulation of BSMC; forskolin 5 μM before TNF‐α stimulation of BSMC; and estradiol 30 μM before TNF‐α stimulation of BSMC. Cyclic adenosine monophosphate was measured by a commercially available radioimmunoassay kit. Cell expression of ICAM‐1 and VCAM‐1 was quantified by flow cytometry. Incubation of cells with TNF‐α 1000 U/ml for 24 hours elicited a 27‐fold increase in basal expression of ICAM‐1 and a 2‐fold increase in VCAM‐1 (p>0.05). Incubation of BSMC with forskolin 5 μM, for 1 hour before TNF‐α, decreased TNF‐α‐induced expression of ICAM‐1 by 62% and VCAM‐1 slightly by 17%. The BSMC incubated with estradiol 30 μM, 1 hour before TNF‐α, decreased TNF‐α‐induced expression of ICAM‐1 by 21%; VCAM‐1 remained unchanged (p>0.05). We found a trend toward inhibition of TNF‐α‐stimulated ICAM‐1 expression in cultured BSMC with pretreatment with estradiol. However, due to large variability within the cell culture model, statistical significance was not reached.
Newer Strategies for the Treatment of Heparin‐Induced Thrombocytopenia
Authors: Warkentin Theodore E. , Barkin Robert L.
Published: April 2004

Treatment with heparin is associated with two types of thrombocytopenia. One is a mild, transient, nonimmune disorder, generally without adverse clinical consequence. The other, known as heparin‐induced thrombocytopenia (HIT), is a potentially serious, immunoglobulin‐mediated reaction with a paradoxic high risk of thromboembolic events. Various treatment options for HIT are discussed, with emphasis on pharmacologic approaches that control the increased thrombin generation characteristic of this disorder.
Increased Risk of Erythema Multiforme Major with Combination Anticonvulsant and Radiation Therapies
Authors: Micali Giuseppe , Linthicum Karin , Han Nina , West Dennis P.
Published: April 2004

Erythema multiforme major (EMM; Stevens‐Johnson syndrome) is a cutaneous disorder associated with a wide variety of factors including ingestion of drugs such as phenytoin and exposure to intracranial radiation therapy. Based on observations of a 47‐year‐old black man with brain metastases who developed EMM after combined phenytoin and radiation therapy, we conducted a MEDLINE literature search for articles on similar cases from 1966 to the present. Twenty cases were identified that support the hypothesis that EMM is associated with combined phenytoin and radiation therapy. The reaction, or its severity, has no relationship to the phenytoin or radiation therapy dosage, or to the histologic type of brain tumor. Also, EMM has no apparent age or gender predisposition in association with phenytoin‐radiation therapy. Thus this is a clinical phenomenon that occurs with unusual frequency in patients with brain tumor who undergo radiation therapy while taking phenytoin. Phenytoin and other anticonvulsants such as phenobarbital and carbamazepine induce cytochrome P450 3A and produce oxidative reactive intermediates that may be implicated in hypersensitivity reactions such as EMM. Both carbamazepine and barbiturates have shown cross‐sensitivity with phenytoin; furthermore, a case of EMM in a patient receiving carbamazepine and whole brain radiation therapy has been reported. As carbamazepine, valproate, and barbiturates have been associated with EMM, gabapentin may be considered as alternative anticonvulsant therapy when appropriate.
Outcome Assessment of Minimizing Vancomycin Monitoring and Dosing Adjustments
Authors: Karam Christine M. , McKinnon Peggy S. , Neuhauser Melinda M. , Rybak Michael J.
Published: April 2004

An approach to minimize monitoring of vancomycin therapy was evaluated in 120 patients, and results were compared with data from 120 patients in whom vancomycin therapy was monitored and adjusted based on serum peak and trough concentrations and traditional pharmacokinetic methods. Patients dosed by the nomogram (NM) had regimens adjusted based on actual body weight, estimated creatinine clearance, and a targeted trough concentration of 5–20 μg/ml. A single trough serum concentration was drawn only after 5 or more days of therapy. Overall, the average length of therapy was similar between groups (9.9 ± 9.4 days NM and 8.6 ± 7.2 days pharmacokinetic). The most common regimen for both groups was 1 g every 12 hours, although NM patients received significantly fewer grams/day (1.9 ± 0.7g/day) than the pharmacokinetic group (2.2 ± 1.0 g/day, p<0.04). Patients dosed by NM also had significantly fewer regimen changes (0.63 ± 0.96 vs pharmacokinetic 0.92 ± 0.97, p=0.02) as well as significantly fewer serum concentrations measured/patient (1.08 ± 1.9 vs 1.96 ± 2.0, p = 0.001). In addition, serum concentrations for NM patients were drawn later in therapy (5.4 ± 2.5 vs 3.8 ± 3.4 days, p = 0.004). Of patients dosed by NM guidelines, 77 had trough concentrations drawn; these data were used to validate the nomogram. Seventy‐two patients (94%) had trough concentrations in the target range of 5–20 μg/ml. No differences were found between groups with respect to cure, improvement, failure, or days to eradication, or with respect to nephrotoxicity. Finally, total drug cost/patient was not different between groups. A considerable cost savings to our institution was noted for patients dosed by NM compared with pharmacokinetics ($232.5 ± 50.74 vs $403.75 ± 70.97/mo, p = 0.009) based on levels saved. Caution should be applied when generalizing our results to other patient populations.
Nonchemotherapy Drug‐Induced Agranulocytosis: A Review of 118 Patients Treated with Colony‐Stimulating Factors
Authors: Beauchesne Marie‐France , Shalansky Stephen J.
Published: April 2004

To determine the role of growth factors in nonchemotherapy drug‐induced agranulocytosis, we reviewed 118 published reports of administration of colony‐stimulating factors for the disorder. Main outcomes were total duration of neutropenia and mortality. The mean time to neutrophil recovery was 4.6 ± 3.2 days and 7.7 ± 5.1 days in patients with a granulocyte count at diagnosis of 0.1‐0.5 × 103/mm3 and less than 0.1 × 103/mm3, respectively. The mortality rate was 4.2%. Without therapy with growth factors, the mean time to neutrophil recovery after discontinuation of the offending agent was reported to be 10 ± 8 days. The mortality rate was 16% in one study. We conclude that hematopoietic growth factors may shorten the duration of neutropenia and reduce mortality in patients with severe drug‐induced agranulocytosis.
Lipid‐Based Amphotericin B for the Treatment of Fungal Infections
Authors: Slain Douglas
Published: April 2004

The frequency of life‐threatening fungal infections has increased dramatically over the past few decades. For more than 30 years amphotericin B has been the standard treatment for systemic and deep‐seated fungal infections, primarily because of its broad spectrum of activity. Its usefulness is limited by a relatively high frequency of significant adverse events including infusion‐related reactions and nephrotoxicity. In an effort to overcome these side effects, a number of lipid‐based formulations were developed, each with its own composition and pharmacokinetic behavior. The clinical significance of these differences is unknown. Available clinical data suggest the formulations have a reduced propensity for causing nephrotoxicity. However, considering limited efficacy data, they should be reserved as second‐line therapy for patients who cannot tolerate or fail an adequate trial of conventional amphotericin B or cannot benefit from other antifungal agents.
Pharmacokinetics of Eprosartan in Healthy Subjects, Patients with Hypertension, and Special Populations
Authors: Bottorff Michael B. , Tenero David M.
Published: April 2004

After oral administration of eprosartan to healthy volunteers, bioavailability is approximately 13%, with peak plasma concentrations occurring 1–2 hours after an oral dose in the fasted state. Food slows the rate of absorption and changes the overall extent by less than 25%, which is unlikely to be of clinical consequence. Plasma concentrations increase in a slightly less than dose‐proportional manner from 100–800 mg. There is no evidence of significant accumulation of eprosartan with long‐term therapy. The drug's terminal elimination half‐life is typically 5–9 hours after oral administration. The agent is highly protein bound (∼ 98%), with low plasma clearance (∼ 130 ml/minute) and small volume of distribution (∼ 13 L). It is primarily unmetabolized by the liver, with less than 2% of an oral dose recovered in the urine as a glucuronide. Biliary (primary) and renal excretion contribute to its elimination. No dosage adjustment is required in patients with mild to moderate renal impairment. Although an increase in systemic exposure to eprosartan was observed in the elderly, in patients with hepatic impairment, and in those with severe renal disease, this finding is unlikely to be of clinical consequence, based on the drug's excellent safety and tolerability profile (doses up to 1200 mg) in phase III clinical trials in hypertensive patients. Eprosartan can be safely administered to these special populations without an initial dosage adjustment, with subsequent dosing individualized based on tolerability and response.
The Renal Profile of Eprosartan
Authors: Sica Domenic A. , Hollenberg Norman K.
Published: April 2004

The angiotensin II (AII) receptor antagonist eprosartan is a highly selective, nonpeptide drug specific for the AT1 receptor subtype that completely inhibits pressor, aldosterone secretory, and renal vasoconstrictive effects produced by AII infusions in healthy humans. It increases effective renal plasma flow in both salt‐replete and salt‐restricted healthy men, and maintains glomerular filtration rates in patients with essential hypertension and those with renal insufficiency after either single or multiple doses. In healthy salt‐restricted men, the drug suppresses and stimulates aldosterone and renin, respectively, in the initial few hours after administration. This feedback inhibition for renin release and suppression of aldosterone is reduced with normal sodium intake. Eprosartan is natriuretic in salt‐restricted subjects and does not induce sodium retention even when it reduces blood pressure. These properties, in addition to antagonism of AII effect at the AT1 receptor, no doubt contribute to the agent's antihypertensive effect in patients with essential hypertension. Pharmacodynamic studies predict that doses of up to 400 mg are safe. Additional preliminary studies suggest that doses as high as 1200 mg are safe and well tolerated, while producing meaningful hemodynamic and neurohumoral effects in patients with essential hypertension.
Catalytic Asymmetric Synthesis of Nitroaldols Using a Lanthanum‐Lithium‐BINOL Complex: (2S,3S)‐2‐Nitro‐5‐Phenyl‐1,3‐Pentanediol
Authors: Sasai Hiroaki , Watanabe Shizue , Suzuki Takeyuki , Shibasaki Masakatsu
Published: April 2004

(2S, 3S)‐2‐Nitro‐5‐phenyl‐1, 3‐pentanediol

R 3‐Phenylpropanal

Nitroethanol

P (2S, 3S)‐2‐Nitro‐5‐phenyl‐1, 3‐pentanediol
Palladium‐Catalyzed Amination of Aryl Halides and Aryl Triflates: N‐Hexyl‐2‐Methyl‐4‐Methoxyaniline and N‐Methyl‐N‐(4‐Chlorophenyl)Aniline
Authors: Wolfe John P. , Buchwald Stephen L.
Published: April 2004

N‐Hexyl‐2‐methyl‐4‐methoxylanaline

R 4‐Bromo‐3‐methylanisole

m‐Hexylamine

P N‐Hexyl‐2‐methyl‐4‐methoxylaniline

N‐Methyl‐N‐(4‐chlorophenyl) aniline

R 4‐chlorophenyl trifluoromethanesulfonate

N‐Methylaniline

P N‐Methyl‐N‐(4‐chlorophenyl) aniline
Synthesis of 4‐, 5‐, and 6‐Methyl‐2,2′‐Bipyridine by a
N
egishi Cross‐Coupling Strategy: 5‐Methyl‐2,2′‐Bipyridine
Authors: Smith Adam P. , Savage Scott A. , Love J. Christopher , Fraser Cassandra L.
Published: April 2004

5‐Methyl‐2, 2′‐bipyridine

R 2‐Amino‐5‐methylpyridine

I 2‐Hydroxy‐5‐methylpyridine 1

5‐Methyl‐2(trifluoromethanesulfonyl) oxypyridine 2

R 2‐Bromopyridine

P 5‐Methyl‐2, 2′‐bipyridine 3