bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitogen‐activated protein (MAP) kinases mediate PMMA‐induction of osteoclasts
Authors: Abbas S. , Clohisy J. C. , Abu‐Amer Y. 
Published: May 2003

AbstractInflammatory osteolysis induced by implant‐derived wear debris is associated with infiltration of various cell‐types to the implant–bone interface leading to abundant secretion of pro‐inflammatory cytokines and activation of proteinases that together lead to propagation of the localized inflammatory response and periprosthetic bone erosion. Tumor necrosis factor family members are considered to be direct mediators of inflammation and osteolysis. These cytokines exert their osteoclastic effects via activation of the transcription factor NF‐κB and certain MAP kinases, including c‐Jun, Erks and p38, all known to be essential for the development of osteoclasts. We have recently documented that the osteoclastogenic cytokines TNF and RANKL play a pivotal role in the development of inflammatory osteolysis. We have also found that PMMA particles stimulate osteoclastogenesis, at least in part, by induction of RANKL, TNF, and by activation of the transcription factor NF‐κB. More importantly, our data indicate that inhibitors of the osteoclastogenic factors, TNF and RANKL abrogate particle‐induced osteoclastogenesis. In the current study, we investigated if PMMA particles activate MAP kinases, and the potential role of these kinases as mediators of osteolysis. Using kinase assays, we show that in osteoclast precursors, PMMA particles markedly and rapidly activate p38 and ERK MAP kinases. This activation was specific, evident by complete blockade with specific inhibitory compounds. Similarly, we show that PMMA particles activate the JNK pathway, which is known to be involved in inflammatory and osteoclastogenic events. We also show that p38 MAP kinase regulates PMMA‐activation of NF‐κB, thus providing a possible mechanism for particle action in osteoclast precursors. Finally, we provide evidence that specific inhibitors of MAP kinases are capable of inhibiting PMMA‐stimulated osteoclastogenesis. These data provide evidence that MAP kinases are potent mediators of particle‐induced osteoclastogenesis.
Antibiotics and the development of resistant microorganisms. Can homeopathy be an alternative?
Authors: Viksveen Petter 
Published: May 2003

AbstractAntibiotic resistance is a global public health problem. Once confined primarily to hospitals it is now increasingly common in primary care. The prevalence of resistant bacteria is rising, and organisms resistant to almost all antibiotics have been identified. The main causes are indiscriminate prescribing and the use of antibiotics in animal feeds and other agricultural applications. Policies to restrict use of antibiotics have had limited success. Homeopathy may have a role to play in combating the development of antibiotic resistance. Clinical research suggests that homeopathy is effective in the treatment of upper respiratory tract infections in children, a frequent cause of inappropriate antibiotic prescribing. The EU recommends the use of homeopathy in organic animal husbandry, and it is used by significant numbers of farmers. At present there is little data on the effectiveness of homeopathy in this setting. Further research should be done.
Lone mothers, social exclusion and depression
Authors: TARGOSZ S. , BEBBINGTON P. , LEWIS G. , BRUGHA T. , JENKINS R. , FARRELL M. , MELTZER H. 
Published: May 2003

Background. In this paper, data from the British National Survey of Psychiatric Morbidity are used to assess depressive disorders and markers of social disadvantage in women bringing up children on their own.Method. The household component of the British National Surveys of Psychiatric Morbidity was based on a stratified random sample of >10000 subjects. This paper reports on 5281 women interviewed in person. Psychiatric symptoms and ICD-10 diagnoses were established by lay interviewers using the CIS-R. Results are presented in terms of depressive episode and mixed anxiety/depressive disorder. Housing tenure and access to a car were used as proxy measures of material status. The life event rate in the 6 months before interview was used to indicate overall exposure to stress, and subjects were asked in detail about perceived social support. Information was collected about various other sociodemographic attributes. Lone mothers were compared with supported mothers and with women not involved in care of children under 16.Results. Lone mothers had prevalence rates of depressive episode of 7%, about three times higher than any other group. The milder condition, mixed anxiety/depression, was also increased in frequency. These increased rates of depressive conditions were no longer apparent after controlling for measures of social disadvantage, stress and isolation.Conclusions. Lone mothers are increasing in numbers as marital stability declines. Their high rates of material disadvantage and of depressive disorder may have considerable implications for psychiatric and social policy.
Loss of mismatch repair proteins in sebaceous gland tumors
Authors: Popnikolov Nikolay K. , Gatalica Zoran , Colome‐Grimmer Maria I. , Sánchez Ramón L. 
Published: May 2003

Background: Sebaceous gland neoplasms are rare tumors that are associated with visceral malignancies in patients with Muir–Torre syndrome (MTS). The majority of the MTS‐associated tumors reveal mutations in DNA mismatch repair (MMR) genes (most often hMSH‐2 and hMLH‐1) and microsatellite instability. The sebaceous gland lesions in patients with MTS can often precede or occur concurrently with the visceral neoplasms. The early recognition of those lesions and their differentiation from sporadic sebaceous gland tumors are critical for proper patient management. Here we investigate the MMR gene expression in a variety of sebaceous gland tumors, with or without associated visceral malignancy.Methods: We studied the expressions of hMLH‐1 and hMSH‐2 in 10 consecutive sebaceous hyperplasias, 10 sebaceus nevi, 12 sebaceous adenomas, seven sebaceous carcinomas and the adjacent normal sebaceous glands using immunohistochemistry and paraffin‐embedded sections.Results: The normal sebaceous glands and the glands of all the sebaceus nevi were positive for hMLH‐1 and hMSH‐2. Loss of hMSH‐2 expression was found in 1/10 (10%) sebaceous hyperplasias, 3/12 (25.0%) sebaceous adenomas, and 2/7 (28.6%) sebaceous carcinomas. Loss of hMLH‐1 expression was seen in 1/10 (10%) hyperplasias, 3/12 (25.0%) adenomas, and 1/7 (14.3%) carcinomas. No concurrent loss of both hMLH‐1 and hMSH‐2 was observed. Loss of MMR (either hMLH‐1 or hMSH‐2) was detected in 80% of the benign sebaceous lesions associated with malignancy. In comparison, only 23% of sebaceous lesions not associated with malignancy showed loss of MMR proteins. No loss of hMSH‐2 protein was found in the visceral cancer in one patient with hMSH‐2‐negative sebaceous adenoma.Conclusions: Our results confirm the previous reports of alterations of mismatch repair genes in the sebaceous neoplasms of patients with MTS. However, we showed that those changes also occur early at the stage of sebaceous hyperplasia, even in the absence of a visceral malignancy. This indicates the importance of the abnormal DNA mismatch repair in the progression of this disease.
Loss of expression of tuberin and hamartin in tuberous sclerosis complex‐associated but not in sporadic angiofibromas
Authors: Fackler Ingrid , DeClue Jeffrey E. , Rust Heidi , Vu Phuong‐Anh , Kutzner Heinz , Rütten Arno , Kaddu Steven , Sander Christian A. , Volkenandt Matthias , Johnson Michael W. , Vinters Harry V. , Wienecke Ralf 
Published: May 2003

Background:  Angiofibromas occur sporadically, and they develop in most patients with tuberous sclerosis complex (TSC), which is associated with alterations of the tumor suppressor genes TSC1 or TSC2. Loss of tuberin, the protein product of TSC2, has been shown in the interstitial fibroblast compartment of TSC‐associated angiofibromas. It is unclear whether there is also a loss of hamartin, the product of TSC1 in TSC‐associated and sporadic angiofibromas.Methods:  The expression of hamartin and tuberin was analyzed by immunohistochemistry in 59 TSC‐associated and 12 sporadic angiofibromas using affinity‐purified antibodies.Results:  Loss of expression of both tuberin and hamartin was detected in 14 angiofibromas, loss of only tuberin in three, and loss of only hamartin in four TSC‐associated angiofibromas; but there was no loss in the sporadic angiofibromas. Only the interstitial cells, but not the vascular cells, showed a loss of expression of tuberin or hamartin.Conclusions:  Loss of tuberin or hamartin occurred in a minority of the TSC‐linked angiofibromas, but not in the sporadic angiofibromas. The absence of both tuberin and hamartin in some of the tumors suggests that the stability of tuberin and hamartin, which are believed to form an active complex in vivo, is negatively affected by the absence of either of the partners.
Role of the bradykinin B2 receptor for the local and systemic inflammatory response that follows severe reperfusion injury
Authors: Souza Danielle G , Pinho Vanessa , Pesquero Jorge L , Lomez Eliane S , Poole Steve , Juliano Luiz , Correa Ary , de A Castro M Salete , Teixeira Mauro M 
Published: May 2003

Bradykinin (BK) appears to play an important role in the development and maintenance of inflammation. Here, we assessed the role of the BK B2 receptor for the injuries that occur after ischemia and reperfusion (I/R) of the territory irrigated by the superior mesenteric artery.
Tissue (lung and duodenum) kallikrein activity increased after ischemia with greater enhancement after reperfusion. A selective inhibitor of tissue kallikrein, Phenylacetyl‐Phe‐Ser‐Arg‐N‐(2,3‐dinitrophenyl)‐ethylenediamine (TKI, 0.001–10 mg ml−1), inhibited kallikrein activity in a concentration‐dependent manner in vitro. In vivo, pretreatment with TKI (30 mg kg−1) prevented the extravasation of plasma and the recruitment of neutrophils.
Similarly, the bradykinin B2 receptor antagonists, HOE 140 (0.01–1.0 mg kg−1) or FR173657 (10.0 mg kg−1), inhibited reperfusion‐induced increases in vascular permeability and the recruitment of neutrophils in the intestine and lungs.
In a model of more severe I/R injury, HOE 140 (1.0 mg kg−1) inhibited the increase in vascular permeability, neutrophil recruitment, haemorrhage and tissue pathology. Furthermore, HOE 140 significantly inhibited the elevations of TNF‐α in tissue and serum and partially prevented lethality. This was associated with an increase in the concentrations of IL‐10 in tissue and serum.
Thus, our results demonstrate that, following intestinal I/R injury, there is an increase in tissue kallikrein activity and activation of BK B2 receptors. B2 receptor activation is essential for the development of inflammatory tissue injury and lethality. These results contrast with those of others showing that BK mostly exerts a protective role during I/R injury.

British Journal of Pharmacology (2003) 139, 129–139. doi:10.1038/sj.bjp.0705200
Downregulation of mdr1a expression in the brain and liver during CNS inflammation alters the in vivo disposition of digoxin
Authors: Goralski Kerry B , Hartmann Georgy , Piquette‐Miller Micheline , Renton Kenneth W 
Published: May 2003

Inflammation is a pathophysiological event that has relevance for altered drug disposition in humans. Two functions of P‐glycoprotein (P‐gp) are hepatic drug elimination and prevention of drug entry into the central nervous system (CNS). Our objective was to investigate if localized CNS inflammation induced by Escherichia coli lipopolysaccharide (LPS) would modify mdr1a/P‐gp expression and function in the brain and liver.
Our major finding was that the CNS inflammation in male rats produced a loss in the expression of mdr1a mRNA in the brain and liver that was maximal 6 h after intracranial ventricle (i.c.v.) administration of LPS. When 3H‐digoxin was used at discrete time points, as a probe for P‐gp function in vivo, an increase in brain and liver 3H‐radioactivity and plasma level of parent digoxin was produced 6 and 24 h following LPS treatment compared to the saline controls. Digoxin disposition was similarly altered in mdr1a+/+ mice but not in mdr1a−/− mice 24 h after administering LPS i.c.v.
In male rats, the biliary elimination of parent digoxin was reduced at 24 h (60%) and 48 h (40%) after LPS treatment and was blocked by the P‐gp substrate cyclosporin A. An observed loss in CYP3A1/2 protein and organic anion transporting polypeptide 2 mRNA in the liver may make a minor contribution to digoxin elimination in male rats after LPS treatment.
Conditions which impose inflammation in the CNS produce dynamic changes in mdr1a/P‐gp expression/function that may alter hepatic drug elimination and the movement of drugs between the brain and the periphery. The use of experimental models of brain inflammation may provide novel insight into the regulation of P‐gp function in that organ.

British Journal of Pharmacology (2003) 139, 35–48. doi:10.1038/sj.bjp.0705227
YM‐53601, a novel squalene synthase inhibitor, suppresses lipogenic biosynthesis and lipid secretion in rodents
Authors: Ugawa Tohru , Kakuta Hirotoshi , Moritani Hiroshi , Inagaki Osamu , Shikama Hisataka 
Published: May 2003

To better understand how it decreases plasma cholesterol and triglyceride levels, we evaluated the effect of (E)‐2‐[2‐fluoro‐2‐(quinuclidin‐3‐ylidene)ethoxy]‐9H‐carbazole monohydrochloride(YM‐53601) on lipogenic biosynthesis in the liver and lipid secretion from the liver in rats and hamsters.
Single administration of YM‐53601 in cholestyramine‐treated rats inhibited triglyceride and free fatty acid (FFA) biosynthesis at a similar dose range to that at which it inhibited cholesterol biosynthesis. YM‐53601 inhibited both triglyceride and FFA biosynthesis in hamsters treated with cholestyramine.
YM‐53601 by single oral administration decreased the enhanced plasma triglyceride levels in hamsters induced by an injection of protamine sulfate, which inhibits lipoprotein lipase (LPL) and consequently increases plasma very low‐density lipoprotein (VLDL) triglyceride levels. YM‐53601 also decreased the enhanced plasma triglyceride and cholesterol levels in hamsters treated with Triton WR1339, which also inhibits the degradation of VLDL. Plasma cholesterol was significantly decreased as soon as 1 h after single administration of YM‐53601 in hamsters fed a normal diet.
This is the first report that a squalene synthase inhibitor suppresses lipogenic biosynthesis in the liver and cholesterol and triglyceride secretion from the liver in vivo. We therefore suggest that the mechanism by which YM‐53601 decreases plasma triglyceride might include these effects. The finding that YM‐53601 rapidly decreased plasma cholesterol suggests that this compound may be effective in decreasing plasma cholesterol levels early in the course of treatment of hypercholesterolemia in humans.

British Journal of Pharmacology (2003) 139, 140–146. doi:10.1038/sj.bjp.0705229
Pharmacological characterisation of native somatostatin receptors in AtT‐20 mouse tumour corticotrophs
Authors: Cervia Davide , Nunn Caroline , Fehlmann Dominique , Langenegger Daniel , Schuepbach Edi , Hoyer Daniel 
Published: May 2003

The mouse corticotroph tumour cell line AtT‐20 is a useful model to investigate the physiological role of native somatostatin (SRIF, Somatotropin release inhibitory factor) receptor subtypes (sst1 – sst5). The objective of this study was to characterise the pharmacological features and the functional effects of SRIF receptors expressed by AtT‐20 cells using radioligand binding and cAMP accumulation.
[125I]LTT‐SRIF‐28, [125I]CGP 23996, [125I]Tyr10‐cortistatin‐14 and [125I]Tyr3‐octreotide labelled SRIF receptor binding sites with high affinity and in a saturable manner (Bmax=315, 274, 239 and 206 fmol mg−1, respectively). [125I]LTT‐SRIF‐28 labels significantly more sites than [125I]Tyr10 ‐cortistatin‐14 and [125I]Tyr3 ‐octreotide as seen previously in cells expressing pure populations of sst2 or sst5 receptors.
SRIF analogues displaced the binding of the four radioligands. sst2/5 receptor‐selective ligands showed much higher affinity than sst1/3/4 receptor‐selective ligands. The binding profile of [125I]Tyr3‐octreotide was different from that of [125I]LTT‐SRIF‐28, [125I]CGP 23996 and [125I]Tyr10‐cortistatin‐14. The sst5/1 receptor‐selective ligand L‐817,818 identified two binding sites, one with subnanomolar affinity (sst5 receptors) and one with micromolar affinity (sst2 receptors); however, the proportions were different: 70 – 80% high affinity with [125I]LTT‐SRIF‐28, [125I]CGP 23996, [125I]Tyr10‐cortistatin‐14, but only 20% with [125I]Tyr3‐octreotide.
SRIF analogues inhibited the forskolin‐stimulated cAMP levels depending on concentration. sst2/5 receptor‐selective ligands were highly potent, whereas sst1/3/4 receptor‐selective ligands had no significant effects. The sst2 receptor antagonist D‐Tyr8‐CYN 154806 competitively antagonised the effects of SRIF‐14 and sst2 receptor‐preferring agonists, but not those of L‐817,818.
The complex binding properties of SRIF receptor analogues indicate that sst2 and sst5 receptors are the predominant SRIF receptors expressed on AtT‐20 cell membranes with no or only negligible presence of sst1, sst3 and sst4 receptors. In the functional studies using cAMP accumulation, only sst2 and sst5 receptors appear to play a role. However, the ‘predominant’ receptor appears to be the sst2 receptor, although sst5 receptors can also mediate the effect, when the ligand is not able to activate sst2 receptors. This clearly adds flexibility to SRIF‐mediated functional effects and suggests that the physiological role of SRIF and its analogues may be mediated preferentially via one subtype over another.

British Journal of Pharmacology (2003) 139, 109–121. doi:10.1038/sj.bjp.0705235
Muscle mass and function in thyrotoxic patients before and during medical treatment
Authors: Nørrelund Helene , Hove Karen Yde , Brems‐Dalgaard Eva , Jurik Anne Grethe , Nielsen Lars Peter , Nielsen Søren , Nielsen Steen , Jørgensen Jens Otto Lunde , Weeke Jørgen , Møller Niels 
Published: May 2003

OBJECTIVEDevelopment of muscle weakness and atrophy are well known complications of thyrotoxicosis, although little is known about its clinical course. The present longitudinal study was therefore undertaken to monitor muscle mass and strength before and during treatment of hyperthyroidism.DESIGN AND PATIENTSFive patients (2 male, 3 female; Age 41 ± 6 years; BMI 22.2 ± 1.1 kg/m2) with newly diagnosed hyperthyroidism were studied with respect to muscle area, muscle strength, body composition and substrate metabolism at baseline and after 1, 3, 6, 9 and 12 months of treatment.MEASUREMENTSMidthigh muscle areas were assessed by computed tomography (CT), while bioelectrical impedance analysis (BIA) was used for assessment of body composition. The isometric strength of the biceps brachialis and quadriceps muscles was assessed by means of a dynamometer and the maximal static ins‐ and ex‐piratory mouth pressures were measured with a respiratory pressure module.RESULTSPrior to treatment thyrotoxic patients all displayed elevated levels of total and free T3 and T4 together with suppressed TSH. BMI, fat mass and lean body mass increased significantly during the treatment period, while energy expenditure (EE) decreased. Thigh muscle areas increased by 24% (101.5 ± 11.5 vs. 125.3 ± 13.1 cm2, P < 0.05) from entry to peak. Peak time was 9 ± 0.9 months. During treatment a significant (P < 0.01) increase in muscle strength was observed; arm capacity increased by 48%, while leg capacity increased by 51%. Peak time (months) was: Right arm: 8 ± 3, left arm: 7 ± 2, right leg: 5 ± 3, left leg: 9 ± 2. Respiratory muscle strength, expressed as maximal ins‐ or ex‐piratory mouth pressure, was significantly impaired among patients at entry. A significant increase in inspiratory and expiratory strength was found from entry to peak (P < 0.05), as inspiratory strength increased by 35% and expiratory by 19%. Inspiratory strength peaked after 7 ± 1 months, expiratory muscle strength after 6 ± 1 months.CONCLUSIONSIn conclusion we find that in patients with thyrotoxicosis muscle mass is reduced by approximately 20% and muscle strength by approximately 40% and that between 5 and 9 months elapse before normal muscle mass and function are reestablished.
Initial characterization of the GH–IGF axis and nutritional status of the Ati Negritos of the Philippines
Authors: Clavano‐Harding Amabel B. , Ambler Geoffrey R. , Cowell Christopher T. , Garnett Sarah P. , Al‐Toumah Ban , Coakley John C. , Ho Ken K.Y. , Baxter Robert C. 
Published: May 2003

BACKGROUND AND OBJECTIVEThe Ati Negritos are a Pygmy‐like aboriginal population from the Philippines with physical characteristics of short stature, dark skin and woolly, kinked hair. Their final height, components of their GH–IGF axis and various nutritional markers are described.SUBJECTS, DESIGN AND MEASUREMENTSAuxological data and sera for the components of the GH–IGF axis and nutritional parameters were collected from 9 adult Ati Negritos in their native environment and 10 Filipinos in Sydney.RESULTSThe height SDS (− 3.66 ± 1.1 vs. ‐ 1.01 ± 1.2), weight SDS (− 2.30 ± 1.6 vs. 0.10 ± 0.7), and BMI SDS (− 1.4 ± 1.8 vs. − 0.2 ± 0.5) between the two groups were significantly different (P < 0.01). The mean height of the 6 male Ati Negritos was 149 ± 7 and 144 ± 3 cm for the females and are comparable with the African Pygmies and the Mountain Ok people of Papua New Guinea. The Ati Negritos showed lower growth hormone binding protein (GHBP), insulin‐like growth factor I (IGF‐I), insulin‐like growth factor binding protein 3 (IGFBP‐3), acid labile subunit (ALS), zinc, albumin, ferritin, iron, iron saturation and much higher insulin‐like growth factor binding protein 2 (IGFBP‐2) and plasma transferrin concentrations. No differences were noted in random growth hormone (GH), plasma insulin‐like growth factor II (IGF‐II), nor in their plasma concentrations of prealbumin, thyroid stimulating hormone (TSH) and free thyroxine (T4).CONCLUSIONPerturbations of both the GH–IGF‐I axis and nutritional markers exist in the Ati Negritos. These findings may be determinants of their stature; however, the aetiology of these changes remains to be fully elucidated.