bluuebunny/crossref_metadata_2025 huggingface dataset:
A fatal case of disseminated aspergillosis caused by a non-sporulating strain ofAspergillus fumigatus: Figure 1
Authors: Callister M E , Griffiths M J , Nicholson A G , Leonard A , Johnson E M , Polkey M I , Kerr J R
Published: August 2004

This report describes the case of a 38 year old pregnant woman with fatal disseminated aspergillosis and multiorgan failure, which was preceded by a long history of allergic bronchopulmonary aspergillosis. Postmortem revealed massive infarction and abscess formation in both lungs. Histology revealed a focal granulomatous response. Fungal infiltration with areas of necrosis were also seen in the liver, spleen, and paratracheal, mediastinal, para-aortic, and hilar lymph nodes. Culture of tissue samples produced a non-sporulating, beige coloured fungus that developed green pigmentation only after three weeks of incubation. Nucleotide sequencing of the D1–D2 region of the large ribosomal subunit revealed 100% homology withAspergillus fumigatus. Minimum inhibitory concentrations for amphotericin B and itraconazole were both 0.25 mg/litre (susceptible). Further work is urgently required to determine the prevalence of such non-sporulating strains and their relevance to clinical infection.
Myelofibrosis and angiodysplasia of the colon: another manifestation of portal hypertension and massive splenomegaly?: Figure 1
Authors: Biss T , Hamilton P
Published: August 2004

Bleeding owing to portal hypertensive colopathy, a form of large bowel angiodysplasia, as a cause of increased blood transfusion requirement is described in a 74 year old man with idiopathic myelofibrosis. The proposed mechanism and the potential therapeutic options for this rare complication of myelofibrosis are discussed.
Statin precipitated lactic acidosis?
Authors: Neale R , Reynolds T M , Saweirs W
Published: August 2004

An 82 year old woman was admitted with worsening dyspnoea. Arterial blood gases were taken on air and revealed a pH of 7.39, with a partial pressure of CO2(pCO2) of 1.2 kPa, pO2of 19.3 kPa, HCO3of 13.8 mmol/litre, and base excess of −16.3 mmol/litre: a compensated metabolic acidosis with hyperventilation induced hypocapnia, which is known to be a feature of lactic acidosis. There was also an increased anion gap ((Na140 + K4.0) – (Cl 106 + HCO313.8)  =  24.2 mEq/litre (reference range, 7–16)), consistent with unmeasured cation. Lactate was measured and found to be raised at 3.33 mmol/litre (reference range, 0.9–1.7). After exclusion of common causes of lactic acidosis Atorvastatin was stopped and her acid–base balance returned to normal. Subsequently, thiamine was also shown to be deficient. The acidosis was thought to have been the result of a mitochondrial defect caused by a deficiency of two cofactors, namely: ubiquinone (as a result of inhibition by statin) and thiamine (as a result of dietary deficiency).
A primary amelanotic melanoma of the vagina, diagnosed by immunohistochemical staining with HMB-45, which recurred as a pigmented melanoma
Authors: Oguri H , Izumiya C , Maeda N , Fukaya T , Moriki T
Published: August 2004

Usually, malignant melanoma is readily diagnosed by the presence of melanin granules. Although amelanotic melanoma contains a few melanin granules, it is often difficult to differentiate from non-epithelial malignant tumours. This report describes a case of amelanotic melanoma of the vagina, which was originally suspected to be a non-epithelial malignant tumour, but was subsequently correctly diagnosed by immunohistochemical staining with the HMB-45 antibody and for the S-100 protein. A light grey tumour with superficial ulceration was located in the upper third of the vagina. The patient was treated with irradiation followed by chemotherapy. Subsequently, the tumour disappeared and cytology was negative; thus, she achieved complete remission. However, 20 months after complete remission, the tumour recurred locally: the site had a grossly black appearance, which was pathognomonic for a malignant melanoma. Thus, HMB-45 and S-100 protein immunohistochemistry confirmed the diagnosis of amelanotic melanoma.
Discrepancies between clinical and postmortem diagnoses in Jamaica: a study from the University Hospital of the West Indies
Authors: Gibson T N , Shirley S E , Escoffery C T , Reid M
Published: August 2004

Aims:It has previously been shown that the low necropsy request rate at the University Hospital of the West Indies (UHWI) in Jamaica (35.3%) results primarily from clinicians’ confidence in clinical diagnoses and laboratory investigations. This study aimed to determine the rates of discrepancy between clinical and necropsy diagnoses at the UHWI, because many previous studies from other institutions have shown persistent high rates of discrepancy, despite advances in medical investigative technology over the past several years.

Methods:Data were extracted retrospectively from consecutive necropsies performed at the UHWI over a two year period. The data were analysed to determine the categories and rates of discrepancy, and to determine the relation between discrepancy rates and age, sex, type and number of diagnoses for each patient, hospital service, and length of hospitalisation.

Results:Necropsies were performed on 446 patients; 348 were suitable for further analysis. The overall discrepancy rate was 48.4% and the diagnoses with the highest individual discrepancy rates were pneumonia (73.5%), pulmonary thromboembolism (68.3%), and myocardial infarction (66.7%). Males and older patients were more likely to have discrepant diagnoses. There was a high frequency of discrepancies in patients who died within 24 hours of admission, but there was no consistent relation between length of hospitalisation and discrepancy rate.

Conclusions:The high discrepancy rates documented at the UHWI are similar to those reported globally. This study supports previous attestations that the necropsy remains a vital tool for determining diagnostic accuracy, despite modern modalities of clinical investigation and diagnosis.
Prognostic significance of tenascin-C expression in superficial and invasive bladder cancer
Authors: Brunner A , Mayerl C , Tzankov A , Verdorfer I , Tschörner I , Rogatsch H , Mikuz G
Published: August 2004

Aims:Tenascin-C (Tn-C) is an extracellular matrix glycoprotein that is upregulated in malignant tumours. Tn-C promotes cell growth, cell migration, and angiogenesis. It has been suggested to be a prognostic factor in various types of malignant tumours, but there is little information on its significance in bladder cancer with regard to overall survival (OS) and recurrence free survival (RFS).

Methods:Tn-C expression was studied in 106 patients with bladder cancer diagnosed between 1994 and 1997. Immunohistochemistry was performed using a monoclonal antibody against Tn-C. RFS and OS were estimated by the Kaplan–Meier method and compared by the log rank test in univariate analysis and by the Cox multistep regression method in multivariate analysis.

Results:Within the mean follow up period of 126 months, patients with diffuse Tn-C staining in the tumour stroma had a significantly worse OS than those with negative staining or only moderate Tn-C expression (p  =  0.025). Patients with cytoplasmic expression of Tn-C had a significantly better OS than those without (p  =  0.001). Multivariate analysis, taking into consideration age, grade, stage, tumour associated carcinoma in situ, progression, and Tn-C staining in tumour stroma, showed that only expression of Tn-C in invasive tumour cells was an independent positive prognostic factor for OS (p  =  0.049).

Conclusions:Tn-C may provide important prognostic information in bladder cancer depending on the expression pattern in the tumour stroma or cytoplasm of the tumour cells.
Presence of vascular adventitial fibroblastic cells in diffuse-type gastric carcinomas
Authors: Nakayama H , Enzan H , Miyazaki E , Kuroda N , Toi M , Hiroi M , Yasui W
Published: August 2004

Aim:To investigate morphological changes in the tumour vessel adventitia, particularly the distribution of vascular adventitial fibroblastic cells (VAFCs)—namely, CD34 positive fibroblastic cells just outside the vascular media—in diffuse-type gastric carcinomas.

Method:In total, 18 surgically resected advanced typical diffuse-type gastric carcinomas and their normal tissues were examined. Immunostaining for CD34, CD31, high molecular weight caldesmon (HCD), and cytokeratin 8 (CAM5.2) was performed to detect VAFCs. VAFCs are positive for CD34 but negative for CD31, and are located just outside the vascular media (HCD positive vascular smooth muscle bundle). The areas just outside the vascular media in the whole maximum tumour cut surface were assessed, except the tumour growing edge, which was confirmed by immunostaining with CAM5.2. CD34 positive and CD31 negative cells just outside the vascular media were defined as VAFCs.

Results:VAFC containing vessels were seen in 17 of the 18 diffuse carcinoma tissues. Vessels lacking VAFCs were also detected in these 17 tumours. In contrast, all of the vessels lacked VAFCs in the remaining tumour. In the 18 samples of normal tissue, all of the vessels contained VAFCs.

Conclusions:These results suggest that the presence of VAFCs is associated with the infiltration of diffuse scattered gastric carcinoma cells.
A case of 49,XXXXX in which the extra X chromosomes were maternal in origin
Authors: Cho Y G , Kim D S , Lee H S , Cho S C , Choi S I
Published: August 2004

This report describes an 11 month old female baby with features of pentasomy X. A molecular and cytogenetic evaluation revealed that her karyotype was 49,XXXXX and her extra X chromosomes were of maternal origin. She has muscular hypotonia, mental retardation, a cleft palate, mild hydrocephalus as a result of dilatation of both lateral ventricles, hyperextensible elbow joints, proximal radioulnar synostosis, clinodactyly of the fifth finger, valgus of the feet, and small hands and feet. In addition, she has a persistent pupillary membrane and congenital chorioretinal atrophy. The pathogenesis of pentasomy X is not clear at present, but it is thought to be caused by successive maternal non-dysjunctions.
Ki-ras gene mutations, LOH of the APC and DCC genes, and microsatellite instability in primary colorectal carcinoma are not associated with micrometastases in pericolonic lymph nodes or with patients’ survival
Authors: Zauber N P , Wang C , Lee P S , Redondo T C , Bishop D T , Goel A
Published: August 2004

Aims:The primary aim of this study was to look for possible correlations between molecular genetic changes in primary colorectal cancer and the presence or absence of micrometastases in the accompanying pericolonic lymph nodes. The secondary aim was to correlate the data on these molecular genetic changes and micrometastases with survival.

Methods:One hundred and twenty five Dukes’s stage B colorectal cancers from 1989 to 1992 were analysed. The primary tumours were evaluated for Ki-ras mutation, adenomatous polyposis coli (APC) loss of heterozygosity (LOH), deleted in colon cancer (DCC) LOH, and microsatellite instability using standard molecular techniques. All available lymph nodes were immunohistochemically stained for micrometastases.

Results:Micrometastases were present in 41% of patients. There were significantly more lymph nodes removed in the patients with micrometastases. Micrometastases were not associated with Ki-ras mutation, APC LOH, DCC LOH, or microsatellite instability, even when controlling for the number of lymph nodes removed. None of the molecular variables considered had a significant impact on either overall survival or on death with disease.

Conclusions:There are insufficient data to justify using molecular genetic changes in primary colorectal carcinomas as prognostic markers. Micrometastases do not provide prognostic information on survival. There is value in increasing the numbers of lymph nodes removed and analysed along with the primary tumour.
Morules in endometrial carcinoma and benign endometrial lesions differ from squamous differentiation tissue and are not infected with human papillomavirus
Authors: Chinen K , Kamiyama K , Kinjo T , Arasaki A , Ihama Y , Hamada T , Iwamasa T
Published: August 2004

Background:Squamous differentiation/squamous metaplasia is often associated with endometrial adenocarcinoma and benign lesions, such as endometrial hyperplasia and chronic endometritis. Morules have distinct histological characteristics, and are referred to as squamous metaplasia or squamoid metaplasia.

Aim:To focus on the histological characteristics of morules and clarify the difference between morules and squamous differentiation.

Materials/Methods:Twenty endometrioid carcinomas with morules or squamous differentiation, five adenosquamous carcinomas, and eight non-carcinomatous endometrial lesions with morules were investigated. Numerous antibodies for epithelial membrane antigen (EMA), involucrin, cytokeratins, neuropeptides, and oncofetal antigens were used for immunohistochemistry. In situ hybridisation and polymerase chain reaction were used to detect human papillomavirus (HPV).

Results:The morules observed were uniform cell clusters, with no squamous differentiation. They were immunonegative for epithelial antigens including involucrin, EMA, and cytokeratins, but were positive for neurone specific enolase. A few morules were immunopositive for acetylcholine esterase, and one case was positive for somatostatin; neither oncofetal nor proliferative cell markers, including blood group A, B, and AB, or other neuropeptides were demonstrated in the morules. HPV DNA was not found in either the morules in the carcinomas or in the benign lesions. However, true squamous differentiation tissue in four endometrioid carcinomas and two adenosquamous carcinomas was HPV positive using in situ hybridisation.

Conclusion:Morules are histologically distinct from squamous metaplasia/squamous differentiation tissue. Morules are thought to be neuroectodermal-like cell clusters, and are not infected with HPV. In contrast, some of the true squamous differentiation tissue was associated with HPV infection.
Les écoulements et le transport glaciaires dans la partie septentrionale du Nunavik (Québec)
Authors: Daigneault Robert-André , Bouchard Michel A
Published: August 2004

In northern Nunavik, orientation of ice-flow features and dispersal patterns of lithologic indicators suggest three major regional ice-flow phases. The oldest ice-flow phase is related to the buildup of an outflow centre, the Ungava centre, over the high plateaux located north of the Povungnituk Hills. During that event, probably of Early Wisconsinan age, ice flows towards the south and southeast carried Cape Smith Belt rock fragments over a maximum distance of 65 km. The second phase is characterized by ice flow mainly towards the north from an outflow ice centre located south of the studied area (Payne centre). The most recent ice-flow phase is related to the presence of the northern extension of the New-Quebec ice divide. From that northwest-trending ice divide extending between Ivujivik and Lake Nantais, ice was flowing outward on the peninsula. The orientation of most of the ice-flow features and dispersal patterns is associated with that last ice flow. North of the Cape Smith Belt, glacial transport was at least 70 km. In Hudson Strait, ice-flow and glacial transport data support the existence of an eastward flowing ice stream.
MONOTONIC INDEPENDENCE, MONOTONIC CENTRAL LIMIT THEOREM AND MONOTONIC LAW OF SMALL NUMBERS
Authors: MURAKI NAOFUMI
Published: August 2004

A notion of "monotonic independence" is formulated in the setting of C*-probability space. Based on this independence, a noncommutative central limit theorem and a noncommutative law of small numbers are given.
MALLIAVIN CALCULUS AND SKOROHOD INTEGRATION FOR QUANTUM STOCHASTIC PROCESSES
Authors: FRANZ UWE , LÉANDRE RÉMI , SCHOTT RENÉ
Published: August 2004

A derivation operator and a divergence operator are defined on the algebra of bounded operators on the symmetric Fock space over the complexification of a real Hilbert space [Formula: see text] and it is shown that they satisfy similar properties as the derivation and divergence operator on the Wiener space over [Formula: see text]. The derivation operator is then used to give sufficient conditions for the existence of smooth Wigner densities for pairs of operators satisfying the canonical commutation relations. For [Formula: see text], the divergence operator is shown to coincide with the Hudson–Parthasarathy quantum stochastic integral for adapted integrable processes and with the noncausal quantum stochastic integrals defined by Lindsay and Belavkin for integrable processes.
Membrane depolarization and NADPH oxidase activation in aortic endothelium during ischemia reflect altered mechanotransduction
Authors: Matsuzaki Ikuo , Chatterjee Shampa , DeBolt Kris , Manevich Yefim , Zhang Qunwei , Fisher Aron B.
Published: August 2004

We previously showed that “ischemia” (abrupt cessation of flow) leads to rapid membrane depolarization and increased generation of reactive oxygen species (ROS) in lung microvascular endothelial cells. This response is not associated with anoxia but, rather, reflects loss of normal shear stress. This study evaluated whether a similar response occurs in aortic endothelium. Plasma membrane potential and production of ROS were determined by fluorescence microscopy and cytochrome c reduction in flow-adapted rat or mouse aorta or monolayer cultures of rat aortic endothelial cells. Within 30 s after flow cessation, endothelial cells that had been flow adapted showed plasma membrane depolarization that was inhibited by pretreatment with cromakalim, an ATP-sensitive K+(KATP) channel agonist. Flow cessation also led to ROS generation, which was inhibited by cromakalim and the flavoprotein inhibitor diphenyleneiodonium. Aortic endothelium from mice with “knockout” of the KATPchannel (KIR6.2) showed a markedly attenuated change in membrane potential and ROS generation with flow cessation. In aortic endothelium from mice with knockout of NADPH oxidase (gp91phox), membrane depolarization was similar to that in wild-type mice but ROS generation was absent. Thus rat and mouse aortic endothelial cells respond to abrupt flow cessation by KATPchannel-mediated membrane depolarization followed by NADPH oxidase-mediated ROS generation, possibly representing a cell-signaling response to altered mechanotransduction.
Role of shear forces and adhesion molecule distribution on P-selectin-mediated leukocyte rolling in postcapillary venules
Authors: Kim Michael B. , Sarelius Ingrid H.
Published: August 2004

Rolling on the venular endothelium is a critical step in the recruitment of leukocytes during the inflammatory response. P-selectin is a key mediator of leukocyte rolling, which is an early event in the inflammatory cascade; this rolling is likely to be directly regulated by both local fluid shear forces and P-selectin site densities in the microvasculature. However, neither the spatial pattern of P-selectin expression in postcapillary venules nor the effect of local expression patterns on rolling behavior in intact functional venules is known. We investigated the influence of local shear forces and the spatial distribution of endothelial P-selectin in intact blood perfused post capillary venules in anesthetized mice using intravital confocal microscopy, high temporal resolution particle tracking, and immunofluorescent labeling. We demonstrated a shear-dependent increase in average leukocyte rolling velocity that was attributable to a shear-dependent increase in the occurrence of transient leukocyte detachments from the endothelial surface: translational velocity during leukocyte contact with the vessel wall remained constant. P-selectin expression was not different in venules with characteristically different shear rates or diameters but varied significantly within individual venules. In postcapillary venules, regions of high P-selectin expression correlated with regions of slow leukocyte rolling. Thus the characteristically variable leukocyte rolling in vivo is a function of the spatial heterogeneity in P-selectin expression. The study shows how the local hydrodynamic forces and the nonuniform pattern of P-selectin expression affect the behavior of interacting leukocytes, providing direct evidence for the local variation of adhesion molecule expression as a mechanism for the regulation of leukocyte recruitment.
Effects of nNOS antisense in the paraventricular nucleus on blood pressure and heart rate in rats with heart failure
Authors: Wang Yu , Liu Xue-Fei , Cornish Kurtis G. , Zucker Irving H. , Patel Kaushik P.
Published: August 2004

Using neuronal NO synthase (nNOS)-specific antisense oligonucleotides, we examined the role of nitric oxide (NO) in the paraventricular nucleus (PVN) on control of blood pressure and heart rate (HR) in conscious sham rats and rats with chronic heart failure (CHF). After 6–8 wk, rats with chronic coronary ligation showed hemodynamic and echocardiographic signs of CHF. In sham rats, we found that microinjection of sodium nitroprusside (SNP, 20 nmol, 100 nl) into the PVN induced a significant decrease in mean arterial pressure (MAP). SNP also induced a significant decrease in HR over the next 10 min. In contrast, the NOS inhibitor NG-monomethyl-l-arginine (l-NMMA, 200 pmol, 100 nl) significantly increased MAP and HR over the next 18–20 min. After injection of nNOS antisense, MAP was significantly increased in sham rats over the next 7 h. The peak response was 27.6 ± 4.1% above baseline pressure. However, in the CHF rats, only MAP was significantly increased. The peak magnitude was 12.9 ± 5.4% of baseline, which was significantly attenuated compared with sham rats ( P < 0.01). In sham rats, the pressor response was completely abolished by α-receptor blockade. HR was significantly increased from hour 1 to hour 7 in sham and CHF rats. There was no difference in magnitude of HR responses. The tachycardia could not be abolished by the β1-blocker metoprolol. However, the muscarinic receptor antagonist atropine did not further augment the tachycardia. We conclude that NO induces a significant depressor and bradycardiac response in normal rats. The pressor response is mediated by an elevated sympathetic tone, whereas the tachycardia is mediated by withdrawal of parasympathetic tone in sham rats. These data are consistent with a downregulation of nNOS within the PVN in CHF.
Impact of age and hyperglycemia on the mechanical behavior of intact human coronary arteries: an ex vivo intravascular ultrasound study
Authors: Tajaddini Azita , Kilpatrick Deborah L. , Schoenhagen Paul , Tuzcu E. Murat , Lieber Michael , Vince D. Geoffrey
Published: August 2004

Despite their advantages, percutaneous coronary interventional procedures are less effective in diabetic patients. Changes in the mechanical properties of vascular walls secondary to long-term hyperglycemia as well as other factors such as age may influence coronary distensibility. This investigation is aimed at deciphering the extent of these effects on distensibility of postmortem human coronary arteries in a controlled manner. Excised human left anterior descending (LAD) coronary arteries were obtained within 24 h postmortem. With the use of intravascular ultrasound, vascular deformation was analyzed at midregions of 51 moderate lesions. Intraluminal pressure was systematically altered using a computerized pressure pump system and monitored by a pressure-sensing guidewire. Distensibility, a normalized compliance term, was defined as the change in lumen area normalized by the initial reference area over a given pressure interval. With the use of multivariate analysis and repeated-measures ANOVA, coronary distensibility was independently influenced by hyperglycemia and age ( P < 0.05) through the entire pressure range. Within physiological pressure range, distensibility was significantly reduced with age in nonhyperglycemic coronary specimens (10.55 ± 4.41 vs. 6.99 ± 2.45, ×103 kPa−1, P = 0.01), whereas the hyperglycemic vessels were stiff even in the younger group (7.90 ± 5.82 vs. 7.20 ± 3.36, ×103 kPa−1, P = 0.79). Similar results were observed with stiffness index and elastic modulus of the arteries. Hyperglycemia and age independently influenced the distensibility of moderately atherosclerotic LAD coronary arteries. The stiffening with age was overshadowed in the hyperglycemic group by as-yet-undetermined factors.
Electrophysiology and anatomy of embryonic rabbit hearts before and after septation
Authors: Rothenberg F. , Nikolski V. P. , Watanabe M. , Efimov I. R.
Published: August 2004

Mechanisms of cardiac pacemaking and conduction system (CPCS) development are difficult to study, in part because of the absence of models that are physiologically similar to humans in which we can label the entire CPCS. Investigations of the adult rabbit heart have provided insight into normal and abnormal cardiac conduction. The adult and the embryonic rabbit have an endogenous marker of the entire cardiac conduction system, neurofilament 160 (NF-160). Previous work suggested that ventricular septation correlates with critical phases in avian CPCS development, in contrast to the mouse CPCS. Combining high-resolution optical mapping with immunohistochemical analysis of the embryonic rabbit heart, we investigated the significance of ventricular septation in patterning the rabbit embryonic conduction system. We hypothesized that 1) completion of ventricular septation does not correlate with changes in the ventricular activation sequence in rabbit embryos and 2) CPCS anatomy determines the activation sequence of the embryonic heart. We found that preseptated ( days 11–13, n = 13) and postseptated (day 15, n = 5) hearts had similar “apex-to-base” ventricular excitation. PR intervals were not significantly different in either group. CPCS anatomy revealed continuity of the NF-160-positive tract connecting the presumptive sinoatrial node, atrioventricular (AV) junction, and ventricular conduction system. The presence of collagen in the AV junction coincided with the appearance of an AV interval. We conclude that the apex-to-base ventricular activation sequence in the rabbit embryo is present before completion of ventricular septation. CPCS anatomy reflects global cardiac activation as demonstrated by high-resolution optical mapping.
Changes in Smad expression and subcellular localization in bleomycin-induced pulmonary fibrosis
Authors: Venkatesan N. , Pini L. , Ludwig M. S.
Published: August 2004

Administration of bleomycin (BM) produces inflammation and fibrosis of the lung in humans and experimental animals. The molecular defects by which BM induces these pathological effects have not been studied in detail. We studied the expression of Smad family proteins, key molecules involved in mediating transforming growth factor (TGF)-β signaling from the cell membrane to the nucleus, during the early and late phases of BM-induced fibrogenesis. Pulmonary fibrosis was induced in male Sprague-Dawley rats by a single intratracheal injection (1.5 units) of BM. Control rats received saline. Rats were killed at 3, 5, 7, 14, and 28 days after BM, cytosolic and nuclear proteins were extracted and isolated from lung tissues, and Smad proteins were probed with specific antibodies. In BM-exposed lung tissue, compared with control, Smad3 decreased persistently in the cytosol and increased transiently in the nucleus. There was a persistent increase in phosphorylation and nuclear accumulation of Smad2/3. Smad4 was increased transiently in both the cytosol and nucleus. A significant and progressive decrease in the expression of Smad7, the endogenous inhibitor of TGF-β/Smad signaling, was observed after BM instillation. Collectively, our results indicate that an imbalance between agonistic Smads2–4 and antagonistic Smad7 may result in the unchecked activation of an autocrine TGF-β loop, which contributes to the pathogenesis of BM-induced pulmonary fibrosis.
Inhibiting cortisol response accelerates recovery from a photic phase shift
Authors: Mohawk Jennifer A. , Cashen Katherine , Lee Theresa M.
Published: August 2004

Jetlag results when a temporary loss of circadian entrainment alters phase relationships among internal rhythms and between an organism and the outside world. After a large shift in the light-dark (LD) cycle, rapid recovery of entrainment minimizes the negative effects of internal circadian disorganization. There is evidence in the existing literature for an activation of the hypothalamic-pituitary-adrenal (HPA) axis after a photic phase shift, and it is possible that the degree of HPA-axis response is a determining factor of reentrainment time. This study utilized a diurnal rodent, Octodon degus, to test the prediction that the alteration of cortisol levels would affect the reentrainment rate of circadian locomotor rhythms. In experiment 1, we examined the effects of decreased cortisol (using metyrapone, an 11β-hydroxylase inhibitor) on the rate of running-wheel rhythm recovery after a 6-h photic phase advance. Metyrapone treatment significantly shortened the length of time it took animals to entrain to the new LD cycle (11.5% acceleration). In experiment 2, we examined the effects of increased cortisol on the rate of reentrainment after a 6-h photic phase advance. Increasing plasma cortisol levels increased the number of days (8%) animals took to reentrain running-wheel activity rhythms, but this effect did not reach significance. A third experiment replicated the results of experiment 1 and also demonstrated that suppression of HPA activity via dexamethasone injection is capable of accelerating reentrainment rates by ∼33%. These studies provide support for an interaction between the stress axis and circadian rhythms in determining the rate of recovery from a phase shift of the LD cycle.
Vasoconstrictor mechanisms in the cerebral circulation are unaffected by insulin resistance
Authors: Erdös Benedek , Snipes James A. , Kis Bela , Miller Allison W. , Busija David W.
Published: August 2004

Insulin-resistance (IR) impairs agonist-induced relaxation in cerebral arteries, but little is known about its effect on constrictor mechanisms. We examined the vascular responses of the basilar artery (BA) and its side branches in anesthetized Zucker lean (ZL) and IR Zucker obese (ZO) rats using a cranial window technique. Endothelin-1 (ET-1) constricted the BAs in both the ZL and ZO rats, but there was no significant difference between the two groups (ZL: 36 ± 8%; ZO: 33 ± 3% at 10−8 M). Inhibition of the ETA receptors by BQ-123 slightly increased the diameters of the BAs, with no difference shown between the ZL (6 ± 1%) and ZO (5 ± 3%) rats. Expressions of the ETA receptors and ET-1 mRNA examined by immunoblot analysis and RT-PCR, respectively, were also similar in the ZL and ZO groups. Phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC), and the thromboxane A2 (TxA2) mimetic U-46619 constricted the BAs, but similarly to ET-1, there was no significant difference between the ZL and ZO groups (10−6 M PDBu: ZL: 33 ± 2%; ZO: 32 ± 4%; and 10−7 M U-46619: ZL: 23 ± 1%; ZO: 19 ± 2%). Inhibition of Rho-kinase with Y-27632 induced dilation of the BAs, and these responses were also comparable in the ZL and ZO rats (ZL: 39 ± 4%; ZO: 38 ± 2% at 10−5 M). In contrast, nitric oxide-dependent relaxation to bradykinin was significantly reduced in the ZO rats (10−6 M: 10 ± 3%) compared with ZLs (29 ± 7%, P < 0.01). These findings indicate that vasoconstrictor responses of the BA mediated by ET-1, TxA2, PKC, and Rho-kinase are not affected by IR.
The involvement of Cry1 and Cry2 genes in the regulation of the circadian body temperature rhythm in mice
Authors: Nagashima Kei , Matsue Kenta , Konishi Masahiro , Iidaka Chisato , Miyazaki Koyomi , Ishida Norio , Kanosue Kazuyuki
Published: August 2004

The criptochrome genes ( Cry1 and Cry2) are involved in the molecular mechanism that controls the circadian clock, and mice lacking these genes ( Cry1−/−/ Cry2−/−) are behaviorally arrhythmic. It has been speculated that the circadian clock modulates the characteristics of thermoregulation, resulting in body temperature (Tb) rhythm. However, there is no direct evidence proving this speculation. We show here that Tb and heat production in Cry1−/−/ Cry2−/− mice are arrhythmic under constant darkness. In contrast, both rhythms occur under a light-dark cycle and/or periodical food restriction linked with spontaneous activity and/or eating, although they are not robust as those in wild-type mice. The relationship between heat production and Tb in Cry1−/−/ Cry2−/− mice is linear and identical under any conditions, indicating that their Tb rhythm is determined by heat production rhythm associated with activity and eating. However, Tb in wild-type mice is maintained at a relatively higher level in the active phase than the inactive phase regardless of the heat production level. These results indicate that the thermoregulatory responses are modulated according to the circadian phase, and the Cry genes are involved in this mechanism.
Enhanced metabolic efficiency contributes to weight regain after weight loss in obesity-prone rats
Authors: MacLean Paul S. , Higgins Janine A. , Johnson Ginger C. , Fleming-Elder Brooke K. , Donahoo William T. , Melanson Edward L. , Hill James O.
Published: August 2004

Metabolic adjustments occur with weight loss that may contribute to a high rate of weight regain. We have previously observed in obesity-prone, obese rats that weight reduction is accompanied by a suppression in resting metabolic rate beyond what would be predicted for the change in metabolic mass. In the present study, we examine if this adjustment in metabolic efficiency is affected by the length of time in weight maintenance and if it contributes to the propensity to regain after weight loss. Twenty-four-hour, nonresting, and resting energy expenditure (REE) were obtained by indirect calorimetry and normalized to metabolic mass estimated by dual-energy X-ray absorptiometry. A 10% loss in body weight in weight-reduced rats was accompanied by a 15% suppression in adjusted REE. This enhancement in metabolic efficiency was not altered with either 8 or 16 wk of weight maintenance, but it did resolve when the forced control of intake was removed and the weight was regained. The rate of weight regain increased with the time in weight maintenance and was exceptionally high early during the relapse period. During this high rate of weight gain, the suppression in REE persists while consumption increases to a level that is higher than when they were obese. In summary, an enhanced metabolic efficiency and an elevated appetite both contribute (60% and 40%, respectively) to a large potential energy imbalance that, when the forcible control of energy intake is relieved, becomes actualized and results in an exceptionally high rate of weight regain.
Modulation of microvascular function following low-dose exposure to the organophosphorous compound malathion in human skin in vivo
Authors: Boutsiouki Paraskevi , Clough Geraldine F.
Published: August 2004

This study investigates whether malathion, a widely used organophosphate insecticide, has its effects on cutaneous vasculature in healthy human volunteers through its anticholinergic activity or through the modulation of other, noncholinergic pathways. Acute, low-dose exposure to malathion (10 mg/ml for 5 h under occlusive dressing) caused a significant increase in cutaneous blood flux, monitored by using laser-Doppler flowmetry and imaging. It had little effect on tissue levels of ACh, nitric oxide, and histamine assayed in dermal dialysate collected from malathion-exposed and control-treated skin. The duration of the cutaneous vascular response to exogenous ACh (2%) delivered by iontophoresis was significantly enhanced by preexposure to malathion, both <1 h after its removal and 24 h later ( P < 0.001). At <1 h, the time to 50% decay of the response was 24 ± 4 and 50 ± 8 min in control and malathion-treated skin, respectively. Malathion also enhanced the size and duration of the axon reflex-mediated vasoresponse to ACh. The increase in blood flux to malathion and the endothelium-mediated response to exogenous ACh, both in the presence and absence of malathion, were attenuated by pretreatment of the skin with atropine and local anesthesia ( P < 0.01). We conclude that short-term exposure to a single low dose of malathion causes prolonged modulation of the physiological function of the cutaneous vasculature and that this is, in part, through its action on acetylcholinesterase at both neuronal and nonneuronal sites.
Medial vestibular nucleus mediates the cardiorespiratory responses to fastigial nuclear activation and hypercapnia
Authors: Hernandez Joseph P. , Xu Fadi , Frazier Donald T.
Published: August 2004

Electrical stimulation of the cerebellar fastigial nucleus (FN) evokes hyperventilation and hypertension responses that are similar to those induced by stimulation of the medial region of the vestibular nucleus (VNM). Because there are mutual projections between these two nuclei morphologically, we hypothesized that the FN-mediated cardiorespiratory responses were related to the integrity of the VNM. Experiments were conducted on 21 anesthetized, tracheotomized, and spontaneously breathing rats. Electrical stimulation (∼10 s) of the FN was used to evoke cardiorespiratory responses, and the same stimulus was repeated 30–45 min after bilateral lesions of the VNM by local microinjection of ibotenic acid (100 mM, 100 nl). We found that FN stimulation-induced hyperventilation and hypertension were attenuated significantly by the lesions. The role of the VNM in the ventilatory responses to chemical challenges was subsequently defined. The animals were exposed to hypercapnia (10% CO2) and hypoxia (10% O2) for 1–2 min randomly before and after VNM lesions. The results showed that VNM lesions significantly attenuated the cardiorespiratory responses to hypercapnia but not to hypoxia, with little effect on baseline respiratory variables. These findings suggest that the VNM is required for full expression of the cardiorespiratory responses to electrical stimulation of the FN as well as to hypercapnia. However, neurons within the VNM do not appear to be critical for maintaining eupneic breathing and the cardiorespiratory responses to hypoxia.
Physiological basis of muscle functional MRI: predictions using a computer model
Authors: Damon Bruce M. , Gore John C.
Published: August 2004

Muscle functional MRI (mfMRI) has been proposed as a tool for noninvasively measuring the metabolic and hemodynamic responses to muscle activation, but its theoretical basis remains unclear. One challenge is that it is difficult to isolate individually those variables affecting the magnitude and temporal pattern of the mfMRI response. Therefore, the purpose of this study was to develop a computer model of how physiological factors altered during exercise affect the mfMRI signal intensity time course and then predict the contributions made by individual factors. A model muscle containing 39,204 fibers was defined. The fiber-type composition and neural activation strategies were designed to represent isometric contractions of the human anterior tibialis muscle, for which published mfMRI data exist. Sustained isometric contractions at 25 and 40% maximum voluntary contraction were modeled, as were the vascular (capillary recruitment, blood oxygen extraction) and metabolic (lactate accumulation, phosphocreatine hydrolysis, pH) responses. The effects on the transverse relaxation of MRI signal were estimated, and the mfMRI signal intensity time course was measured from simulated images. The model data agreed well qualitatively with published experimental data, and at long exercise durations the quantitative agreement was also good. The model was then used to predict that NMR relaxation effects secondary to blood volume and oxygenation changes, plus the creatine kinase reaction, dominate the mfMRI time course at short exercise durations (up to ∼45 s) and that effects secondary to glycolysis are the main contributors at later times.
Continuous measurement of gas uptake and elimination in anesthetized patients using an extractable marker gas
Authors: Robinson Gavin J. B. , Peyton Philip J. , Terry David , Malekzadeh Shiva , Thompson Bruce
Published: August 2004

Measurement of pulmonary gas uptake and elimination is often performed, using nitrogen as marker gas to measure gas flow, by applying the Haldane transformation. Because of the inability to measure nitrogen with conventional equipment, measurement is difficult during inhalational anesthesia. A new method is described, which is compatible with any inspired gas mixture, in which fresh gas and exhaust gas flows are measured using carbon dioxide as an extractable marker gas. A system was tested in eight patients undergoing colonic surgery for automated measurement of uptake of oxygen, nitrous oxide, isoflurane, and elimination of carbon dioxide with this method. Its accuracy and precision were compared with simultaneous measurements made with the Haldane transformation and corrected for predicted nitrogen excretion by the lungs. Good agreement was obtained for measurement of uptake or elimination of all gases studied. Mean bias was −0.003 l/min for both oxygen and nitrous oxide uptake, −0.0002 l/min for isoflurane uptake, and 0.003 l/min for carbon dioxide elimination. Limits of agreement lay within 30% of the mean uptake rate for nitrous oxide, within 15% for oxygen, within 10% for isoflurane, and within 5% for carbon dioxide. The extractable marker gas method allows accurate and continuous measurement of gas uptake and elimination in an anesthetic breathing system with any inspired gas mixture.
Strain differences in murine ventilatory behavior persist after urethane anesthesia
Authors: Gonsenhauser Iahn , Wilson Christopher G. , Han Fang , Strohl Kingman P. , Dick Thomas E.
Published: August 2004

Differences in breathing pattern between awake C57BL/6J (B6) and A/J mice are such that A/J mice breathe slower, deeper, and with greater variability than B6. We theorized that urethane anesthesia, by affecting cortical and subcortical function, would test the hypothesis that strain differences require a fully functional neuroaxis. We anesthetized B6 and A/J mice with urethane, placed them in a whole-body plethysmograph, and measured the durations of inspiration and expiration, respiratory frequency (Fr), and peak amplitude during exposure to room air (21% O2), hyperoxia (5 min, 100% O2), hypoxia (5 min, 8% O2), and posthypoxic reoxygenation (5 min, 100% O2). Breathing variability was assessed by calculating the coefficient of variation (CV) and by applying spatial statistics to Poincaré plots constructed from the timing and amplitude data. Even though Fr in anesthetized B6 and A/J mice was greater than that for unanesthetized animals, anesthetized A/J mice still breathed slower, deeper, and with greater variability than B6 mice at rest and during hyperoxia. During the fourth minute of hypoxia, Fr and its CV were not significantly different between strains. Even though Fr was similar between strains immediately after hypoxia, its CV was significantly greater for B6 than A/J mice. Posthypoxic Fr was significantly less than baseline Fr in B6 but not A/J mice, and the CV for posthypoxic Fr was greater for B6 but less for AJ mice compared with baseline CV. This difference in patterning was confirmed by spatial statistical analysis. We conclude that strain-specific differences in respiratory pattern and its variability are robust genetic traits. The neural substrate for these differences, at least partially, exists within subcortical structures generating the breathing pattern.
Predictors of Discharge to a Skilled Nursing Facility following Hip Fracture Surgery in New York State
Authors: Aharonoff Gina B. , Barsky Alla , Hiebert Rudi , Zuckerman Joseph D. , Koval Kenneth J.
Published: August 2004

Background: Hip fracture is always a very traumatic event, especially for an older person. Often, it is followed by a marked decrease in the level of functioning a patient is able to achieve after recovery. It is even more debilitating when a previously independent person must be discharged to an institution. Objective: This study examined factors and trends associated with discharge to a skilled nursing facility following hip fracture surgery. Methods: Data were analyzed for 89,723 hip fracture patients admitted in New York State from 1986 to 1996. Factors examined included age, gender, race, type of fracture, surgical technique, comorbidities, length of hospitalization and year of admission. Results: Thirty-five percent (32,130) of the patients were discharged to skilled nursing facilities. They tended to be 85+ years old, female, white, have 3+ comorbidities, a history of dementia, have sustained an intertrochanteric fracture, and have been admitted after 1990. In addition, there was a gradual increase in institutionalizations after 1990. Conclusion: In this study, factors were found that predicted discharge to skilled nursing facilities following hip fracture.
Assessing Competence: The European Survey on Aging Protocol (ESAP)
Authors: Fernández-Ballesteros Rocío , Zamarrón María Dolores , Rudinger Georg , Schroots Johannes J.F. , Hekkinnen Eino , Drusini Andrea , Paul Constanza , Charzewska Jadwiga , Rosenmayr Leopold
Published: August 2004

Objectives: The main goal of this research project was to translate and adapt the European Survey on Ageing Protocol (ESAP) to 7 European countries/cultures. This article presents preliminary results from the ESAP, the basic assessment instrument of EXCELSA (European Longitudinal Study of Aging). Methods: 672 individuals aged 30–85, selected through quota sampling (by age, gender, education and living conditions), participated in this study, with 96 subjects from each of the 7 European countries. The basic research protocol for assessing competence and its determinants was designed to be administered in a 90-min in-home face-to-face interview. It contains a series of questions, instruments, scales and physical tests assessing social relationships and caregiving, mental abilities, well-being, personality, mastery and perceived control, self-reported health, lifestyles, anthropometry, biobehavioral measures and sociodemographic variables. Results: 84% of ESAP measures are age-dependent and 75% of them discriminate between education levels. Minor differences were found due to gender, and between people living in rural and urban areas. Exploratory factor analysis yielded 10 factors accounting for 67.85% of total variance, one of which was identified as cognitive and physical ‘competence’. This factorial structure was tested across countries through concordance coefficients. Finally, using structural equation modeling, our data were fitted into a model of competence. When the sample was split into younger groups (aged 30–49 years) and older ones (50 and more years), the same model was appropriate for our data. Discussion: The results are discussed in accordance with other findings on psychosocial, biophysical and sociodemographic components of competence, and also in accordance with theories on competence and successful aging.
Enantioselective Kinetic Disposition of Fenoprofen in Rats with Experimental Diabetes or Adjuvant-Induced Arthritis
Authors: Cristófani Poggi Josiane , Barissa Giuliano Rodrigo , Donadi Eduardo Antônio , Lanchote Vera Lucia , Lemos dos Reis Marina
Published: August 2004

This study was aimed to investigate the influence of diabetes or arthritis on the enantioselective metabolism and kinetic disposition of fenoprofen in rats with streptozotocin-induced diabetes or Mycobacteriumtuberculosis adjuvant-induced arthritis. Animals received i.v. 10 mg/kg racemic fenoprofen and blood samples were collected up to 24 h thereafter, with 5 animals studied at each time point. Plasma concentrations of the fenoprofen enantiomers were determined by HPLC. Diabetic and arthritic animals showed significant differences when compared with respective controls for the following pharmacokinetic variables of the (+)-(S)-fenoprofen eutomer: area under the plasma concentration time curve, total clearance and volume of distribution. The results indicate that experimental diabetes and adjuvant-induced arthritis influence the fenoprofen enantioselective metabolism.