bluuebunny/crossref_metadata_2025 huggingface dataset:
High number of tumour‐infiltrating lymphocytes is associated with apoptosis in non‐small cell lung carcinoma
Authors: Törmänen‐Näpänkangas U. , Soini Y. , Pääkkö P.
Published: August 2010

Aim: To test whether the number of tumour‐infiltrating mononuclear cells (MNC), namely T‐lymphocytes (TIL) and, to a lesser degree, B‐lymphocytes and macrophages, is associated with tumour cell apoptosis in non‐small cell lung carcinoma (NSCLC). Methods and results: Eighty‐four non‐small cell lung tumours were analysed with specific antibodies and the extent of apoptosis was determined using 3′‐end labelling of fragmented DNA (TUNEL). All parameters were determined from the same tumour areas. In general, adenocarcinomas showed a higher number of MNC than squamous cell carcinomas (p=0.04). The number of MNC increased concurrently with the grade of tumour, occurrence being highest in high grade (III) tumours (p=0.05). The number of apoptotic cells was significantly higher in tumours with a high number of CD3 + and CD8+ lymphocytes (p=0.01) and B‐cells (p=0.05). Tumours showing abnormal p53 protein expression had a significantly lower count of CD8 + T‐cells compared to p53‐negative tumours (p=0.03). Conclusions: Our results showed an association between lymphocytic infiltration and extent of apoptosis is NSCLC, suggesting that an attempt to suppress the growth of transformed tumour cells exists even when the tumour has reached an advanced stage.
Monilethrix: a keratin hHb6 mutation is co‐dominant with variable expression
Authors: Zlotogorski A. , Horev L. , Glaser B.
Published: August 2010

Monilethrix is a rare autosomal dominant disease characterized by hair fragility and hyperkeratotic papules. Mutations in type‐II hair specific keratins hHb6 and hHb1 have recently been reported. We describe a large family with a E410D mutation in the evolutionary conserved helix termination motif of keratin hHb6 that was variably expressed among 12 heterozygous members, and severely expressed among 3 homozygous members. These 3 patients had essentially complete lack of scalp hair since the age of 2 months with no improvement over time as well as follicular keratotic involvement extensively expressed over the scalp and large body areas. The variability seen in heterozygous patients, along with seasonal and pregnancy‐related improvement suggest that other genetic or environmental factors may modify keratin gene expression. This represents the first report of a co‐dominant keratin hHb6 mutation resulting in severe disease.
Hair growth‐modulation by adrenergic drugs
Authors: Peters E. M. J. , Maurer M. , Botchkarev V. A. , Gordon D. S. , Paus R.
Published: August 2010

Abstract:Since we have recently shown that the β2‐adrenoreceptor (β2‐AR) expression of selected regions of the hair follicle (HF) epithelium as well as the number of adrenergic nerve fibers in murine skin change in a hair cycle‐dependent manner, this has raised the possibility that adrenergic nerves may exert “trophic” functions during HF cycling. To further explore this concept, we have investigated the effect of neuro‐pharmacological manipulations on hair growth (anagen) induction in quiescent telogen mouse skinin vivo. Here, we demonstrate that subcutaneous injections of the noradrenaline (NA)‐depleting agent guanethidine, or of the neurotoxin 6‐hydroxydopaine, but not of the β2‐AR agonist isoproterenol induce a premature onset of anagen in the lower back skin of C57BL/6 mice. On day 20 after the start of treatment, more than 80% of the guanethidine‐treated mice and ca. 65% of the 6‐hydroxydopamine‐treated (6‐OHDA) mice exhibited premature skin darkening and hair growth at the site of drug application, whereas less than one‐third of all control animals showed macroscopic signs of anagen developent. This was confirmed by histology, demonstrating mature anagen VI HFs only at the immediate site of treatment with guanethidine of 6‐OHDA as opposed to resting telogen HFs in the neighboring untreated skin area. This observation further supports the concept that sympathetic nerves are intimately involved in hair growth control and invites one to explore the neuro‐pharmacological manipulation of piloneural interactions as a novel therapeutic strategy for the management of hair growth disorders.
Proteinase‐activated receptor‐2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase
Authors: Steinhoff M. , Corvera C. U. , Thoma M. S. , Kong W. , McAlpine B. E. , Caughey G. H. , Ansel J. C. , Bunnett N. W.
Published: August 2010

Abstract: Proteinase‐activated receptor‐2 (PAR‐2) is a G‐protein coupled receptor. Tryptic proteases cleave PAR‐2 exposing a tethered ligand (SLIGKV), which binds and activates the receptor. Although PAR‐2 is highy expressed by cultured keratinocytes and is an inflammatory mediator, its precise localization in the normal and inflamed human skin in unknown, and the proteases that activate PAR‐2 in the skin have not been identified. We localized PAR‐2 in human skin by immunohistochemistry, examined PAR‐2 expression by RT‐PCR and RNA blotting, and investigated PAR‐2 activation by mast cell tryptase. PAR‐2 was localized to keratinocytes, especially in the granular layer, to endothelial cells, hair follicles, myoepithelial cells of sweat glands, and dermal dendritic‐like cells. PAR‐2 was also highly expressed in keratinocytes and endothelial cells of inflamed skin. PAR‐2 mRNA was detected in normal human skin by RT‐PCR, and in cultured human keratinocytes and dermal microvascular endothelial cells by Northern hybridization. Trypsin, tryptase and a peptide corresponding to the tethered ligand (SLIGKVNG2) increased [Ca2+]i in keratinocytes, measured using Fura‐2/AM. Although tryptase‐containing mast cells were sparsely scattered in the normal dermis, they were numerous in the dermis in atopic dermatitis, and in the dermis, dermal‐epidermal border, and occasionally within the lower epidermis in psoriasis. Tryptase may activate PAR‐2 on keratinocytes and endothelial cells during inflammation.
The vitamin D endocrine system of human sebocytes
Authors: Reichrath J. , Schuler CH. , Seifert M. , Zouboulis CH. , Tilgen W.
Published: August 2010

Locally produced vitamin D metabolites are of high importance for growth regulation in various tissues. Using real‐time PCR, we have characterized expression of key components of the vitamin D system vitamin D receptor (VDR), vitamin D‐25‐hydroxylase (25OHase), 25‐hydroxyvitamin D−1 α‐hydroxylase (1αOHase), and 1,25‐dihydroxyvitamin D‐24‐hydroxylase (24OHase) in the SZ95 human sebaceous gland cell line. Incubation of SZ95 cells with 1,25‐dihydroxyvitamin D resulted in a dose‐dependent suppression of cell proliferation. RNA levels for VDR, 25OHase, 1αOHase, and 24OHase were characterized in SZ95 cells treated with various vitamin D analogs. In conclusion, our findings demonstrate that key components of the vitamin D system are strongly expressed in the SZ95 human sebaceous gland cell line and that local synthesis or metabolism of vitamin D metabolites may be of importance for growth regulation and various other cellular functions in sebaceous glands. Moreover, we conclude that sebaceous glands represent promising targets for therapy with vitamin D analogs or for pharmacological modulation of calcitriol synthesis/metabolism.
Decline of hormones with increasing age regulates the biological activity of human sebocytes
Authors: Makrantonaki E. , Zouboulis C. C.
Published: August 2010

Hormone deficiency occurring with age leads among other systemic disorders to deterioration of the skin quality. Systemic substitution with estradiol in females and GH in males reversed the observed alterations and retarded the skin aging process in single controlled studies. In order to evaluate the importance of sex steroids and growth factors on skin aging in vitro, human sebocytes were treated with GH, IGF‐I, 17β‐estradiol, DHEA, testosterone and progesterone in combination and as single agents in concentrations corresponding to those circulating in young (f20) and postmenopausal women (f60). Cell proliferation and lipid synthesis were measured by means of the 4‐methylumbelliferyl heptanoate fluorescence assay and nile‐red microassay/fluorescence microscopy, respectively. Cells incubated with all hormones mentioned above at f60 showed significantly lower content of sebaceous lipids (P < 0.001) vs. cells at f20 relating to in vivo observations, which have documented a decline of epidermal lipids in aged skin. While progesterone and DHEA, as single agents, showed no effect on lipid synthesis, after treatment with IGF‐I for 48 h at f20 and f60 concentrations, a significant dose‐dependent increase of neutral (P < 0.001) and polar lipids (P < 0.001) was observed at both concentrations tested. Cell size was also increased. On the other hand, GH at f20 and f60 enhanced significantly the production of neutral (P < 0.01 and P < 0.05, accordingly) and polar lipids (P < 0.05 and P < 0.01, accordingly) in sebocytes but not in such an extent as IGF‐I. 17β‐estradiol induced only polar lipid synthesis (P < 0.01) and cell size. No treatment affected the cell proliferation. In conclusion, sex steroids and growth factors and their decline with age play a key role in the regulation of the lipid synthesis in human sebocytes. Furthermore, among all hormones tested, the GH/IGF‐I axis seems to be the most potent regulator of skin lipids.
‘Neurotrophology’ of the hair follicle: neurotrophins act as auto‐ and paracrine growth factors and immunomodulators
Authors: Peters E. M. J. , Paus R.
Published: August 2010

Neurotrophins are increasingly appreciated as growth factors and immune modulators not only inside but also outside of the nervous system. They are now appreciated to affect a wide variety of epithelial tissues and have become intensely studied in the context of stress‐responses. In mouse skin, for example, the prototypic neurotrophin, nerve growth factor (NGF), is produced by hair follicles and regulates their growth during hair follicle morphogenesis and cycling and the cutaneous responses to psychoemotional stress. Fluctuations in NGF expression are mirrored by changes in nerve fiber density and neuro–immune interactions in hair follicles and interfollicular neural networks. Our recent findings document that, in organ‐cultured human hair follicles, NGF signaling inhibits hair growth (anagen) by the induction of apoptosis‐driven hair follicle regression (catagen). Interestingly, this process appears to depend on stimulation of the pan‐low‐affinity neurotrophin receptor p75, which has recently been identified as a high affinity receptor for the NGF prohormone, proNGF. Moreover, hair follicle regression by neurotrophin signaling may be induced by key stress mediators such as substance P and potentially involves neurogenic inflammation in analogy to the murine model and subsequent collapse of the hair follicle immune privilege. Thus mouse and human hair follicle epithelia are both a prominent peripheral source and a key target for neurotrophins and provide a highly instructive model for dissecting not only general growth‐modulatory activities of NTs in epithelial biology, but also neuro–immune interactions under physiological and pathological conditions.
Bidirectional modification of IL‐6 expression by angiotensin II in human dermal fibroblasts
Authors: Steckelings U. M. , Rompe F. , Reinemund J. , Artuc M. , Unger TH.
Published: August 2010

Recently, we demonstrated the presence of a complete rennin–angiotensin system in human skin and the up‐regulation of angiotensin AT1‐ and AT2‐receptors in cutaneous wounds. However, the characterisation of cutaneous actions of angiotensin II (Ang II) under physiological or pathophysiological conditions is only at the very beginning. It is well established for non‐cutaneous tissues that the AT1‐receptor (AT1‐R) mediates pro‐inflammatory actions. The role of the AT2‐receptor (AT2‐R) is far less understood. In order to look for a putative role of Ang II in cutaneous inflammation, we chose interleukin 6 (Il‐6) as a representative inflammation marker. Il‐6 expression was studied in response to Ang II with or without co‐stimulation by TNFalpha, and it was distinguished between AT1‐ or AT2‐receptor‐mediated responses, respectively.

Human primary dermal fibroblasts (passage 3–5) were isolated from female thoracic skin derived in the course of cosmetic breast surgery. Fibroblasts were stimulated with Ang II (10−7 M) for 24 h and co‐incubated with irbesartan (10–5 M; AT1‐receptor antagonist) or PD 123319 (10–5 M; AT2‐receptor antagonist), respectively. The same experiment was performed on a second set of cells, additionally treated with TNFalpha (10 ng/ml) in order to stimulate Il‐6 expression and to examine the effect of Ang II on elevated Il‐6 levels. Moreover, AT2‐R mediated effects were determined by incubation of cells with the novel AT2‐R agonist Compound 21. Il‐6 mRNA was detected by Real‐Time‐PCR.

Ang II stimulated Il‐6 expression fivefold. This stimulation could be inhibited by irbesartan, but not by PD 123319. TNFalpha caused a marked increase in Il‐6 expression, which could be inhibited by AT2‐receptor stimulation (by Ang II in the presence of irbesartan or by Compound 21). The effect of Compound 21 was abrogated by PD 123319. Intracellular signalling leading to the induction of IL‐6 expression via the AT1‐R seemed to involve the CYP‐dependent arachidonic acid metabolite 20‐hydroxyeicosatetraenoic acid (20‐HETE). A CYP‐dependent metabolite involved in the AT2‐R mediated effects on IL‐6 expression could not be defined.

Thus, in human dermal fibroblasts, Il‐6 expression is stimulated by TNFalpha and to a lesser extent by Ang II via the AT1‐receptor. In contrast, Ang II via the AT2‐receptor diminishes TNFalpha‐induced Il‐6 expression. Consequently, Ang II may be involved in cutaneous inflammation by a dual mechanism: it acts pro‐inflammatory via the AT1‐receptor and anti‐inflammatory via the AT2‐receptor.
Role of proteinase‐activated receptors (PARs) during cutaneous inflammation and the immune response
Authors: Steinhoff M.
Published: August 2010

Proteinase‐activated receptors constitute a new subfamily of G protein‐coupled receptors with seven transmembrane domains which are activated by various exogenous or endogenous serine proteinases such as thrombin, cathepsin G, trypsins, tryptase, clotting factors (VV, Xa), bacterial proteases or mite antigens. In addition, PAR1 can be activated by MMP‐1. Recent knowledge indicate that proteases are not merely enzymes which cleave proteins in the extracellular space, but are signaling molecules involved in many processes by activating specific receptors in an autocrine, paracrine and endocrine fashion. MMP‐1 activates PAR1 and is thereby involved in the migration and invasive potential of melanoma cells. PAR2 is a receptor for mast cell tryptase or house dust mite allergens which is released during inflammation and allergic reactions. In the skin, PAR2 is diversly expressed by keratinocytes, endothelial cells and occasionally on sensory nerves of human skin in various disease states. Moreover, immunocompetent cells such as mast cells and neutrophils express functional PAR2 thereby contributing to inflammation and host defense. Own data revealed that PAR2 contributes to neurogenic inflammation by releasing neuropeptides from sensory nerves resulting in edema, plasma extravasation and infiltration of neutrophils. Thus, mast cells may communicate with sensory nerves in inflammatory tissues by activating PAR2 via tryptase. Vice versa, PAR2 activation of cutaneous mast cells leads to a release of histamine suggesting a bidirectional pathway of mast cell–nerve communication. Moreover, PAR2 agonists up‐regulate expression of certain cell adhesion molecules and cytokines such as interleukin‐6 and interleukin‐8 on dermal microvascular endothelial cells or regulate neutrophil migration or integrin expression – a role of PAR2 in leukocyte/endothelial interactions. These effects may be partly mediated by NF‐κB, an important transcription factor during inflammation and immune response. PAR2 stimulation results in the activation of NF‐κB on microvascular endothelial cells and keratinocytes thereby regulating ICAM‐1 expression. We also demonstrate evidence for a diverse expression of PAR2 in various skin diseases and highlight the recent knowledge about the important role of PAR2 during inflammation and the immune response. Together, PAR2‐modulating agents may be new tools for the treatment of inflammatory and allergic diseases in the skin.
The skin as a mirror of the ageing process in the human organism – results of the ageing research in the German National Genome Research Network 2
Authors: Zouboulis CH. C.
Published: August 2010

Intrinsic human skin ageing is influenced by the individual genetic predisposition and reflects degradation processes of the body. Hormones are decisively involved in intrinsic ageing with reduced secretion of pituitary, adrenal glands, and gonads, which leads to characteristic body and skin phenotypes. A number of advances were recently made in understanding skin ageing mechanisms and major molecular changes, especiallly of the extracellular matrix, were identified. Gene expression patterns compatible with mitotic misregulation and alterations in intracellular transport and metabolism were identified in fibroblasts of ageing humans and humans with progeria. Age‐associated changes of extracellular matrix of the skin correlate well with changes been detected in the extracellular matrix of other organs of the human body. Within the National Genome Research Network 2 (NGFN‐2) in Germany, the explorative project ‘Genetic etiology of human longevity’ targets the identification of age‐related molecular pathways. For this purpose, skin models of ageing are used. Expression profiling employing cDNA microarrays from known and novel genes and RT‐PCR are employed for gene detection and confirmation. Among the potential candidate genes several interesting target genes have been identified. The evaluation of ageing‐associated genes in skin models will facilitate the understanding of global molecular ageing mechanisms in the future.
Vitamin D, clusterin and melanoma growth
Authors: Shannan B. , Seifert M. , Tilgen W. , Reichrath J.
Published: August 2010

The secretory glycoprotein clusterin (CLU) was shown to be involved in the regulation of various cell functions including cell growth and apoptosis. The nuclear (nCLU) and the secretory (sCLU) are two isoforms of CLU that are obtained by alternate splicing. While the pro‐apoptotic nCLU was shown to be involved in the regulation of cell‐cycle progression and apoptosis, sCLU has been shown to have cytoprotective properties. We have analyzed the expression of CLU (mRNA and protein) in various melanoma cell lines that have previously been characterized as sensitive (SK‐MEL‐28 and MeWo) or resistant (SK‐MEL‐5, SK‐MEL‐25) to antiproliferative effects of vitamin D analogues. Vitamin D‐resistant melanoma cell lines were shown to reveal a functional defect in vitamin D receptor‐mediated gene transcription. CLU mRNA and protein were present in all melanoma cells analyzed, with sCLU being the most dominant isoform in both vitamin D‐sensitive and resistant cells. 1,25‐dihydroxyvitamin D3[1,25(OH)2D3] treatment of vitamin D‐sensitive, but not of resistant, cells resulted in a time‐dependent up‐regulation of CLU mRNA levels, as measured using conventional PCR. Treatment with 1,25(OH)2D3 did neither in vitamin D‐sensitive nor in resistant cells alter the CLU splice variant pattern. Our findings indicate that; CLU is expressed in melanoma cells. sCLU represents the most dominant isoform both in vitamin D‐sensitive and resistant melanoma cells. CLU mRNA expression is increased after 1,25(OH)2D3 treatment in vitamin D‐sensitive but not in resistant melanoma cells. In conclusion, CLU may be of importance for the growth characteristics of melanoma cells. Our findings indicate (at least in melanoma cells) that CLU may be involved in signalling pathways that mediate the antiproliferative effects of 1,25(OH)2D3.
Role of serotonergic system in inflammation
Authors: Fiebich B. L.
Published: August 2010

Serotonin (5‐hydroxytryptamin, 5‐HT) is a peptide originally thought to be mainly produced in the nervous system and functioning as a neurotransmitter. There is increasing evidence that serotonin has an important role in cellular immune response since serotonin is also produced in peripheral cells and due to the fact that more 5‐HT receptors are expressed in immune cells than in neuronal cells. However, the role of serotonin in inflammation is not well understood. There is evidence from both human and animal research that 5‐hydroxytryptamin (5‐HT) 3 receptor antagonists, particularly tropisetron, exert analgesic and anti‐inflammatory activity, and we were therefore interested to elucidate the underlying mechanisms of these effects. We studied the anti‐inflammatory effects of tropisetron and ondansetron in various peripheral cells involved in inflammation. We were able to identify the two major splice variants of the 5‐HT3 receptors, the short A‐isoform and the long B‐isoform in T‐cells and monocytes. We furthermore found tropisetron to be an inhibitor of LPS‐stimulated tumor necrosis factor (TNF) α and interleukin‐(IL‐)1β secretion in monocytes and of IL‐2 expression in T‐cells. Besides the 5‐HT3 receptor, 5‐HT7 seems to be involved in immune regulation, since we found this receptor to mediate serotonin‐induced IL‐6 release in astrocytes. Overall, our data suggest that the serotonergic system plays an import role in peripheral immune function.
Hormone‐related hair disorders – from clinical needs to new therapeutic perspectives
Authors: Blume‐Peytavi U. , Mandt N. , Lademann J. , Vogt A.
Published: August 2010

The hair follicle and its appendages are important target structures for hormones. Plasma levels, local hormone metabolism and differential receptor expression regulate hair growth and hair cycling as well as sebaceous gland function. Even minor imbalances in this system, e.g. abnormal expression of hair follicle‐associated isoenzymes, may cause clinical symptoms such as hair loss, seborrhoea or hirsutism.

Conventional therapeutic strategies, which aim to control peripheral hyperandrogenism, include systemic administration of androgen inhibitors (e.g. oral contraceptives, GnRH analogues), peripheral androgen blockers (CPA, CMA, glutamide, finasteride) as well as topical application of estrogens. As our knowledge about hormone systems and their complex interactions increases, new molecules are gaining importance: rosiglitazone and metformin are compounds which increase the sensitivity to insulin, topical application of minoxidil has been shown to regulate perifollicular blood flow and vascularization, and anti‐inflammatory compounds can as well be beneficial in the treatment of androgenetic alopecia.

Because such therapies are, still, rather unspecific, current research focuses on the development of individualized strategies which allow to specifically treat the various manifestations caused by hormone‐related disorders. From our perspective, the aims of future drug development are as follows.

In the first place, the identification of new targets, possibly beyond sex steroids in the narrow sense is highly important. Components of the POMC‐system, for example, have been shown to regulate cell differentiation and also hair cycling.

And secondly, to develop drug delivery systems, which allow to specifically directing active compounds to target structures. Such improved drug delivery may allow to reduce side‐effects and to increase the efficacy of current therapies. Studies by our group and others suggest that microparticles, due to their ability to aggregate in the hair follicle openings, are promising drug delivery systems. In fact, we recently reported that the penetration depths of transcutaneously applied microparticles into the follicular duct depends on the size of the particles and on the dimension of the hair follicle, suggesting that particle‐based drug delivery systems allow to selectively target hair follicle compartments such as the entry level of the sebaceous duct or the bulge region.
Effects of fasting on hematologic and clinical chemical values in cynomolgus monkeys (Macaca fascicularis)
Authors: Zeng X.‐C. , Yang C.‐M. , Pan X.‐Y. , Yao Y.‐S. , Pan W. , Zhou C. , Jiang Z.‐R. , Chang Y. , Ma J.
Published: August 2010

Background Fasting is an important pre‐analytical factor that may affect clinical pathology parameters in toxicological and pharmacological studies. Little information is available on how fasting affects clinical pathology parameters in cynomolgus monkeys (Macaca fascicularis).The aim of this study was to evaluate the influence of fasting on clinical pathology parameters in healthy adult cynomolgus monkeys.

Methods Five female and six male cynomolgus monkeys were fasted for 0, 8, 16, and 24 hours. Changes in body weight (BW), core hematologic, and serum clinical chemical parameters were evaluated.

Results The BW significantly decreased after 24 hours of fasting. Significant decreases in red blood cell count, hemoglobin, hematocrit, and mean corpuscular volume and increases in mean cell hemoglobin and mean cell hemoglobin concentration were observed at 16 hours in males. In females, increasing the duration of fasting caused a significant time‐dependent increase in platelets. Blood urea nitrogen showed significant decreases in female and male monkeys after fasting. Alkaline phosphatase increased in females after fasting. Aspartate transaminase significantly increased both in females and males at 8 hours. In females, alanine transaminase and lactate dehydrogenase significantly increased at 8 hours. Albumin significantly decreased in males 24 hours, but increased in females 16 hours after fasting. Serum glucose and triglyceride were not affected by fasting. Serum calcium decreased and inorganic phosphorus increased in males after fasting.

Conclusion These results suggested that clinical pathology data would vary after fasting. The decision to feed or fast before blood collection for clinical pathology tests should be made based on careful consideration.
Glycogen synthase kinase‐3β, or a link between amyloid and tau pathology?
Authors: Muyllaert D. , Kremer A. , Jaworski T. , Borghgraef P. , Devijver H. , Croes S. , Dewachter I. , Van Leuven F.
Published: August 2010

Phosphorylation is the most common post‐translational modification of cellular proteins, essential for most physiological functions. Deregulation of phosphorylation has been invoked in disease mechanisms, and the case of Alzheimer’s disease (AD) is no exception: both in the amyloid pathology and in the tauopathy are kinases deeply implicated. The glycogen synthase kinase‐3 (GSK‐3) isozymes participate in diverse cellular processes and important signalling pathways and have been implicitly linked to diverse medical problems, i.e. from diabetes and cancer to mood disorders and schizophrenia, and in the neurodegeneration of AD. Here, we review specific aspects of GSK‐3 isozymes in the framework of recent data that we obtained in novel transgenic mouse models that robustly recapitulate the pathology and mechanistical problems of AD.
Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence?
Authors: Thompson A. , Boekhoorn K. , Van Dam A.‐M. , Lucassen P. J.
Published: August 2010

This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the most common neurodegenerative disorders and their related animal models. We discuss recent literature in relation to Alzheimer’s disease and dementia, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, alcoholism, ischemia, epilepsy and major depression.
Cerebral amyloid angiopathy: pathogenetic mechanisms and link to dense amyloid plaques
Authors: Kumar‐Singh S.
Published: August 2010

Cerebral amyloid angiopathy (CAA) of the amyloid‐β (Aβ) type is the most common form of sporadic CAA and is now also accepted as an early and integral part of Alzheimer’s disease (AD) pathogenesis. Cerebral amyloid angiopathy is a risk factor for haemorrhagic stroke and is believed to independently contribute to dementia. Rare forms of hereditary cerebral amyloidosis caused by mutations within the Aβ domain of amyloid precursor protein (APP) have been identified, where mutant Aβ preferably deposits in vessels because of a decreased fibrillogenic potential and/or increased vasotopicity. A review of factors involved in CAA caused by wild‐type Aβ suggests that increased Aβ levels in brain without an increased Aβ42/Aβ40 ratio is one of the most important prerequisites for vascular amyloidosis. This is exemplified by CAA observed in APP duplication and Down’s syndrome patients, neprilysin polymorphism patients and knockout mice and Swedish APP (KM670/671NL) mice. Select presenilin mutations also lead to a prominent CAA, and importantly, presenilin mutations are shown to have varied effects on the production of Aβ40, the predominant amyloid found in CAA. Conversely, APP mutations such as Austrian APP (T714I) drastically decrease Aβ40 production and are deficient in CAA. Apolipoprotein E‐ɛ4 is also shown to be a risk factor for CAA, and this might be because of its specific role in the aggregation of Aβ40. Recent data also suggest that dense‐core senile plaques in humans and dense plaques in transgenic mice, composed predominantly of Aβ40, associate with vessels. This review highlights some of these aspects of genetics and biochemistry of CAA and pathological descriptions linked to a prominent CAA and/or dense plaques in humans and relevant mouse models and discusses how this knowledge has led to a better understanding of the processes involved in vascular amyloidosis, and in causing dementia, and thus has important therapeutic implications.
Biochemical bone markers in the assessment and pamidronate treatment of children and adolescents with osteogenesis imperfecta
Authors: Åström E , Magnusson P , Eksborg S , Söderhäll S
Published: August 2010

Aim: To assess the role of biochemical bone markers in classification of children with osteogenesis imperfecta (OI), their possible association with vertebral compression fractures in milder forms of OI and their role in monitoring of intravenous pamidronate (APD) treatment.

Methods: Serum total alkaline phosphatase (ALP), bone ALP isoforms (in a subgroup), osteocalcin, type I procollagen carboxy‐terminal propeptide, carboxy‐terminal telopeptide of type I collagen, and urine deoxypyridinoline (DPD) were measured in a cross‐sectional study of 130 untreated individuals, 0.25–20.9 years (median 6.7), with OI types I, III and IV. Of those, sixty‐nine were also assessed longitudinally during monthly APD treatment. Bone mineral density (BMD) was measured by dual‐energy X‐ray absorptiometry.

Results: Significant differences in bone markers, however not sufficient for individual clinical use, were found in the larger untreated group but not between subgroups with or without vertebral compressions. All bone markers decreased during treatment for 1.0–12.5 years, but with different relative amounts. Changes were not correlated to the improvement in BMD, mobility or pain.

Conclusion: Bone markers are, despite significant differences, not useful for the classification of OI type in the individual child and are not associated with vertebral compressions. Serum ALP and urinary DPD are sensitive in monitoring bisphosphonate treatment.
The role of cytokeratins 20 and 7 and estrogen receptor analysis in separation of metastatic lobular carcinoma of the breast and metastatic signet ring cell carcinoma of the gastrointestinal tract
Authors: Tot TIBOR
Published: August 2010

Metastatic signet ring cell carcinomas of unknown primary site can represent a clinical problem. Gastrointestinal signet ring cell carcinomas and invasive lobular carcinomas of the breast are the most common sources of these metastases. Immunohistochemical algorithms have been successfully used in the search for the unknown primary adenocarcinomas. In the present study a series of primary invasive lobular breast carcinomas (79 cases) and their metastases and a series of gastrointestinal signet ring cell carcinomas (22 primary and 13 metastases) were stained with monoclonal antibodies for cytokeratin (CK) 20 and CK7 and for estrogen receptors (ER). The staining was evaluated as negative (no staining), focally (less than 10% of the tumor cells stained) or diffusely positive. All the primary and metastatic gastrointestinal signet ring cell carcinomas proved to be CK20 positive, while only 2/79 (3%) of the primary and 1/21 metastatic lobulr carcinomas (5%) stained positively for this CK. None of the gastrointestinal carcinomas and the majority of the lobular carcinomas expressed ER. The majority of the tumors were CK7+. Using CK20 alone, 33 of 34 metastases could be properly classified as gastrointestinal (CK20+) or mammary (CK20‐). ER identified 31/34 of breast cancer metastases. By combining the results of CK20 and ER staining all the metastases could be properly classified as the CK20+/ER‐ pattern identified all the gastrointestinal tumors.
Intrinsic Growth Rates and Net Reproduction Rates in the Presence of Migration
Authors: Preston Samuel H. , Wang Haidong
Published: August 2010

Conventional measures of long‐term population growth such as the intrinsic growth rate and the net reproduction rate assume migration rates to be zero. We develop expressions for analogous measures that register the impact of net migration rates, and we develop a simple method of estimating their values. Applying these new measures to data for developed countries shows that allowance for migration raises net reproduction rates by 0.2‐0.3 in areas of overseas European settlement and by approximately half as much in Northern and Western Europe. The newly defined intrinsic growth rates in Eastern Europe are exceptionally low at ‐1.7 percent to ‐2.4 percent per annum. In contrast, the migration‐adjusted intrinsic growth rate of the United States exceeds those of Asia and Latin America. The formulas and estimation procedures described should allow a more precise understanding of the implications of current migration patterns for long‐term growth prospects.
Rethinking Historical Reproductive Change: Insights from Longitudinal Data for a Spanish Town
Authors: Reher David Sven , Sanz‐Gimeno Alberto
Published: August 2010

A set of linked reproductive histories taken from the Spanish town of Aranjuez between 1871 and 1950 is used to address key issues regarding reproductive change during the demographic transition. These include the role of child survival as a stimulus for reproductive change, the use of stopping and/or spacing strategies to achieve reproductive goals, and the timing of change. Straightforward demographic measures are used and robust results are achieved. Initial strategies of fertility limitation are shown to exist but are inefficient, are mostly visible during the latter part of the reproductive period, are designed mostly to protect families from the effects of increases in child survival, and are based almost entirely on stopping behavior. As mortality decline accelerates, strategies become much more efficient, are visible at the outset of married life, include spacing behavior, and eventually lead to important declines in completed family size. The results of this study have implications for our understanding of the demographic transition both in historical Europe and in other regions of the world.
Sexual Behavior in China: Trends and Comparisons
Authors: Parish William L. , Laumann Edward O. , Mojola Sanyu A.
Published: August 2010

Dramatic political, economic, and social changes in China over the past several decades have been accompanied by much discussion in popular media and among academics of a fundamental transformation in Chinese sexual behavior. Several studies have examined current Chinese sexual behavior but have been limited to particular provinces or cities and have been based on non‐random samples. The potential threat of a generalized HIV epidemic in China highlights the dearth of population‐based information on current patterns of sexual behavior that could help design better intervention strategies and prevent misguided ones. This article uses data from the first national probability survey of adult sexual behavior in China completed during 1999–2000, along with a historical and literature review, to address three key questions: 1) Has there been a revolution in sexual behavior in China? 2) Is China unique compared to other countries in these transformations? 3) What are the implications of these findings for China's risk of a generalized HIV epidemic?
Religiousness and Fertility among European Muslims
Authors: Westoff Charles F. , Frejka Tomas
Published: August 2010

Based on official data on religion, national origin, and other indicators of ethnic origin, Muslim fertility in 13 European countries is higher than that for other women, but in most countries with trend data the differences are diminishing over time. Fertility varies by country of origin of immigrants. Various European survey data show that higher proportions of Muslim women are married and their commitment to traditional family values is greater than among other women. Muslim women are more religious than non‐Muslim women and religiousness is directly associated with fertility. Among Muslim women, religiousness and commitment to family values are equally important for fertility, while for non‐Muslim women religiousness is much less important.
A COMPARISON OF RADIOGRAPHY, COMPUTED TOMOGRAPHY, AND MAGNETIC RESONANCE IMAGING FOR THE DIAGNOSIS OF PALMAR PROCESS FRACTURES IN FOALS
Authors: Kaneps Andris J. , Koblik Philip D. , Freeman Dominique M. , Pool Roy R. , O'Brien Timothy R.
Published: August 2010

The relative sensitivity of radiography, computed tomography, and magnetic resonance imaging for detecting palmar process fractures of the distal phalanx in foals was determined and the imaging findings were compared with histomorphologic evaluations of the palmar processes. Compared to radiography, computed tomography and magnetic resonance imaging did not improve the sensitivity for detection of palmar process fractures. Statistical agreement for palmar process fracture diagnosis was excellent among the three imaging modalities. Histomorphologic evaluations were more sensitive for diagnosis of palmar process fracture than any of the imaging modalities. Three‐dimensional image reconstructions and volume measurements of distal phalanges and palmar process fracture fragments from computed tomography studies provided more complete anatomical information than radiography. Magnetic resonance imaging confirmed that the deep digital flexor tendon insertion on the distal phalanx is immediately axial to the site where palmar process fractures occur, and differentiated cartilage, bone, and soft tissue structures of the hoof.
INTERMITTENT CRANIAL LUNG HERNIATION IN TWO DOGS
Authors: GUGLIELMINI CARLO , DE SIMONE ANTONIO , VALBONETTI LUCA , DIANA ALESSIA
Published: August 2010

Two aged dogs with chronic obstructive airway disease were evaluated because of intermittent swelling of the ventral cervical region. Radiographs made at expiration and caudal positioning of the forelimbs allowed identification of intermittent cervical lung herniation of the left and right cranial lung lobe in both dogs. Pulmonary hyperinflation, increased expiratory effort, and chronic coughing were considered responsible for the lung herniation. Cervical lung hernia should be included in the differential diagnoses of intermittent cervical swelling in dogs with chronic respiratory disorders associated with increased expiratory effort and chronic coughing.
ECHOCARDIOGRAPHIC REFERENCE VALUES IN WHIPPETS
Authors: BAVEGEMS VALÉRIE , DUCHATEAU LUC , SYS STANISLAS U. , DE RICK ANDRÉ
Published: August 2010

The aim of the study was to establish reference echocardiographic values for whippets, to compare these values with previously published reference values for the general dog population, and to determine whether there is an influence of gender and breeding lines on echocardiographic measurements. Echocardiographic parameters from 105 apparently healthy whippets without cardiac symptoms were used to establish reference values for the breed and to compare these values with two previously reported reference ranges. The coefficients of the allometric equationY=aMb, useful to reconstruct normal M‐mode and two‐dimensional average values for whippets of varying weights, were calculated, as well as the lower and upper limits of the 95% prediction interval. First, we found that whippets have a significantly larger left ventricular diameter, increased left ventricular wall, and interventricular septum thickness than expected, in diastole as well as in systole. Fractional shortening was significantly lower than the reference value. Second, comparing males and females, taking body weight differences into account, females had a significantly larger left ventricular diameter in diastole and systole. Minor differences were found between racing and show pedigree dogs. In conclusion, the results of this study confirm that breed‐specific reference values are needed in echocardiography. In whippets, the values found in this study can be used as references in order to avoid overinterpretation of cardiac dilation, hypertrophy, and/or decreased contractility in these dogs.
IMAGING DIAGNOSIS—BILATERAL ADRENAL ADENOMAS AND MYELOLIPOMAS IN A DOG
Authors: MORANDI FEDERICA , MAYS JAMIE L. , NEWMAN SHELLEY J. , ADAMS WILLIAM H.
Published: August 2010

A 10‐year‐old neutered female Pug was evaluated for a left adrenal mass detected previously by ultrasonography. Using computed tomography, a fat‐attenuating, rim‐enhancing left adrenal mass and a homogeneous, soft‐tissue attenuating, intensely enhancing right adrenal mass were found. A left adrenalectomy and right adrenal biopsy were performed and the final diagnosis was bilateral adrenal adenomas and myelolipomas. Myelolipomas are rare, benign, endocrinologically inactive tumors composed of well‐differentiated adipose tissue and a variable amount of hematopoietic cells of both lymphatic and myeloid lineages, which may account for the different appearance on tomographic images.
PRE‐ AND POST‐TREATMENT ULTRASONOGRAPHY IN HYPOTHYROID DOGS
Authors: TAEYMANS OLIVIER , DAMINET SYLVIE , DUCHATEAU LUC , SAUNDERS JIMMY H.
Published: August 2010

Primary hypothyroidism is a frequent endocrine disorder in the adult dog. However, false‐positive diagnoses are common because of the relatively low accuracy of most commonly used biochemical tests. The purpose of this study was to describe the ultrasonographic features of the thyroid gland in hypothyroid dogs, to calculate the diagnostic sensitivity of gray‐scale ultrasound using a combination of clinical symptoms and biochemical thyroid tests as gold standard, and to investigate the evolution of the ultrasonographic features after treatment of hypothyroidism. Eighteen dogs were studied prospectively. All dogs underwent an ultrasound examination at first presentation and 13 underwent one or two additional ultrasound examinations over time. At first presentation, a sensitivity of 76.5% (95% CI [50.0–93.0%]) for decreased echogenicity, 64.7% (95% CI [38.3–85.8%]) for inhomogeneity, 70.6% (95% CI [44.0–89.7%]) for irregular capsule delineation, 64.7% (95% CI [38.3–85.8%]) for abnormal lobe shape and 47.1% (95% CI [23.0–72.2%]) for decreased relative thyroid volume was obtained. Combining these five parameters together resulted in an overall sensitivity of 94.1% (95% CI [71.3–99.9%]) for gray‐scale ultrasound in the detection of acquired hypothyroidism at first presentation. A continuous decrease of thyroid volume was seen over time after treatment, while the other investigated parameters did not change significantly during the follow‐up period. None of the thyroid glands were considered normal at the last presentation. Grayscale ultrasound is a sensitive and quick test for the diagnosis of primary hypothyroidism in dogs.
SONOGRAPHIC ANATOMY OF THE PALMARODISTAL ASPECT OF THE EQUINE DIGIT
Authors: BOLEN GÉRALDINE , BUSONI VALERIA , JACQMOT OLIVIER , SNAPS FRÉDÉRIC
Published: August 2010

Although ultrasonography is widely used in equine orthopedics, its use in the distal portion of the digit is still limited. The purpose of this descriptive study was to document the normal ultrasonographic appearance of the palmarodistal aspect of the digital area imaged between the bulbs of the heels. Ultrasonographic images were obtained with a 7.5 MHz microconvex transducer in 10 fresh equine cadaver forelimbs and five sound horses. Sagittal, parasagittal, and transverse images were obtained from the proximal aspect of the middle phalanx to the distal sesamoid bone. Anatomic sections were obtained from five cadaver specimens to correlate the sonographic appearance with the anatomic findings. The remaining cadaver limbs were dissected to confirm normalcy. Ultrasonographic examinations were possible on all digits but distal images were more difficult to obtain in digits with long heels. Bony structures (palmar surface of the middle phalanx and proximal border of the distal sesamoid bone) and soft tissue structures (deep digital flexor tendon, digital tendon sheath, proximal palmar recess of the distal interphalangeal joint, proximal recess of the podotrochlear bursa, collateral sesamoidean ligaments) identified on the anatomic slices were seen on the matched sonographic images. Ultrasonography provides good anatomic details of the palmarodistal aspect of the digit. The images of this study will serve as a reference for clinical studies on ultrasonography of the palmarodistal aspect of the digit.
REPEATABILITY OF DOPPLER ULTRASONOGRAPHIC MEASUREMENT OF EQUINE DIGITAL BLOOD FLOW
Authors: MENZIES‐GOW NICOLA J. , MARR CELIA M.
Published: August 2010

The repeatability and sensitivity of Doppler ultrasonographic measurement of lateral digital arterial and venous blood flow has not been previously determined. Doppler ultrasonography was used to measure blood flow within the forelimb lateral digital vessels in one normal adult Thoroughbred horse on six occasions and in six normal adult Thoroughbred horses on three occasions, each occasion being at least 1 h apart, to determine the within‐ and between‐horse variation. The values obtained from the right and left lateral digital vessels did not differ significantly. The within‐horse coefficients of variation (CV) for arterial and venous measurements were all acceptable (<11%); the between‐horse CV were acceptable (<7%) for all parameters except TaVa (average velocity of first peak of arterial waveform) and TaVb (average velocity of remainder of arterial waveform). The within‐horse intraclass correlation coefficients (ICC) demonstrated excellent repeatability (≥0.71) for all parameters except venous diameter; the between‐horse ICC demonstrated good to excellent repeatability (≥0.67) for all parameters except TaVb. Doppler ultrasonography can detect differences of 0.005 and 0.01 ml/min in digital arterial and venous flow, respectively, using measurements from six horses on three occasions (80% power;P<0.05). Thus, the technique is sufficiently repeatable and sensitive to be able to detect changes in flow during different physiological or pathological states or following pharmacologic intervention.