bluuebunny/crossref_metadata_2025 huggingface dataset:
Protective effects of vasonatrin peptide against hypobaric hypoxia‐induced pulmonary hypertension in rats
Authors: Yu Jun , Feng Hua‐Song , Chen Bao‐Ying , Qu Ping , Liu Li‐Bing , Chen Jian‐Kang , Tie Ru , Huang Xiao‐Jun , Zhao Yu‐Feng , Zhu Xiao‐Xing , Zhu Miao‐Zhang
Published: June 2009

1. The aim of the present study was to investigate thein vivoeffects of vasonatrin peptide (VNP) on hypoxia‐induced pulmonary hypertension (HPH).

2. The HPH model was developed by subjecting rats to hypobaric hypoxia. The HPH rats were then treated with either VNP (50 μg/kg per day, i.p.) or saline (0.5 mL, i.p.) every day for 7 days. Haemodynamic indices, right ventricular hypertrophy (RVH) and remodelling of the pulmonary arteries were evaluated. In addition, plasma levels of atrial natriuretic peptide (ANP), endothelin (ET)‐1 and angiotensin II (AngII) were determined, as was natriuretic peptide receptor‐C (NPR‐C) mRNA expression in the right ventricle.

3. Hypobaric hypoxia induced severe HPH compared with the normoxic control group. Treatment of HPH rats with VNP for 1 week significantly reduced mean pulmonary arterial pressure, pulmonary vascular resistance, RVH and muscularization of the pulmonary arteries, although pulmonary blood flow was increased in this group. In addition, significantly lower levels of plasma ET‐1 and AngII and cardiac NPR‐C mRNA expression were observed in VNP‐treated compared with saline‐treated HPH rats, whereas higher plasma concentrations of ANP were found in the former group. Acute intravenous administration of 50 μg/kg VNP significantly ameliorated pulmonary haemodynamics in HPH rats.

4. Taken together, the date indicate that VNP has certain preventative and therapeutic effects against HPH.
Clinical and experimental evidence of sympathetic neural dysfunction during inflammatory bowel disease
Authors: Boissé Lysa , Chisholm Susan P , Lukewich Mark K , Lomax Alan E
Published: June 2009

1. Inflammatory bowel diseases (IBD) alter the function of the enteric nervous system and the sensory innervation of the gastrointestinal (GI) tract. Less is known about whether IBD also affects the sympathetic nervous system (SNS). Given the importance of the SNS in regulating GI function and possibly immune system activation, the present review examines the evidence of sympathetic dysfunction during IBD and its possible consequences.

2. Sympathetic axons within the GI tract innervate several cell types, including vascular myocytes, enteric neurons and immune cells. The major neurotransmitters released from sympathetic varicosities are noradrenaline, neuropeptide Y and ATP or a related purine.

3. Clinical studies of IBD patients have provided evidence of an association between IBD and axonal or demyelinating neuropathy. Assays of autonomic function suggest that ulcerative colitis and Crohn’s disease, the two major forms of IBD, have contrasting effects on sympathetic neural activity.

4. Animal models of IBD have been used to examine the effects of these diseases on sympathetic neurophysiology. A decrease in the release of noradrenaline from sympathetic varicosities in inflamed and uninflamed regions of the GI tract has consistently been reported. Recent findings suggest that the decrease in neurotransmitter release may be due to inhibition of N‐type voltage‐gated Ca2+current in post‐ganglionic sympathetic neurons.

5. Interest in the role of the SNS in IBD is rapidly increasing. However, much work needs to be done to enhance understanding of how SNS function is altered during IBD and what contribution, if any, these changes make to pathogenesis.
Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload‐induced cardiac hypertrophy to heart failure
Authors: Li Xiao‐Mei , Ma Yi‐Tong , Yang Yi‐Ning , Liu Fen , Chen Bang‐Dang , Han Wei , Zhang Jian‐Fa , Gao Xiao‐Ming
Published: June 2009

1. Transition from compensated left ventricular (LV) hypertrophy to decompensated heart failure was characterized using a pressure‐overload induced model to elucidate the temporal relationship between cardiomyocyte apoptosis and survival signalling in this transition.

2. Mice were subjected to transverse aortic constriction (TAC) or sham operation for 1–16 weeks and were studied by echocardiography, catheterization and histology. Relevant gene expression and phosphorylation of extracellular signal‐regulated kinase (ERK) 1/2, Akt and glycogen synthase kinase (GSK)‐3β were determined.

3. Transverse aortic constriction resulted in myocyte hypertrophy and fibrosis from Week 4 and a progressive increase in left ventricular (LV) dimensions and wall thicknesses with maintained contractile function by Week 12. However, a sharp decline in contractile function and elevated LV end‐diastolic pressure from 12 to 16 weeks were observed after TAC, indicating functional decompensation.

4. Following TAC, mRNA levels of atrial natriuretic peptide, B‐type natriuretic peptide, β‐myosin heavy chain (MHC) and transforming growth factor‐β1 were increased time dependently, whereas mRNA expression of α‐MHC, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and Bcl‐2 were decreased. The ratio of Bcl‐2/Bax was decreased and this was consistent with progressively increased myocyte apoptosis demonstrated by terminal deoxyribonucleotidyl transferase‐mediated dUTP–digoxigenin nick end‐labelling staining. Phosphorylation of ERK1/2 was increased by Week 4, but decreased thereafter. Levels of phosphorylated Akt declined from Week 8, whereas GSK3β phosphorylation increased from 1 to 8 weeks, then decreased from Week 12 after TAC.

5. In conclusion, TAC resulted in early concentric and late eccentric hypertrophy with eventual development of LV dysfunction. This transition was temporally associated with a progressive increase in cell size, fibrosis and myocyte apoptosis. Downregulation of ERK1/2, Akt and GSK3β and enhanced cardiomyocyte apoptosis are implicated as important mechanisms in the transition from compensated hypertrophy to heart failure.
Roles for novel pharmacological blockers of aquaporins in the treatment of brain oedema and cancer
Authors: Yool Andrea J , Brown Elizabeth A , Flynn Gary A
Published: June 2009

1. Aquaporins (AQPs) are targets for drug discovery for basic research and medicine. Human diseases involving fluid imbalances and oedema are of major concern and involve tissues in which AQPs are expressed. The range of functional properties of AQPs is continuing to expand steadily with ongoing research in the field.

2. Gating domains in AQPs are molecular sites for drug actions. Discovery of the arylsulphonamide AqB013 as an antagonist for AQP1 and AQP4 provided the first pharmacological agent with translational promise for the treatment of diseases in which AQPs have been implicated. The putative binding site for AqB013 in the internal vestibule of the AQP water pore involves amino acid residues that are located in the AQP loop D gating domain.

3. Aquaporins have been proposed as novel targets in cancer and oedema and are associated with a surprising array of important processes in the brain and body, such as angiogenesis, cell migration, development and neuropathological diseases. Functions beyond their simple role as water channels are suggested by the subtype‐specific regulation of AQP expression. In both cancer and brain oedema, current therapies are limited and new pharmacological approaches focused on AQPs offer exciting potential for clinical advances.
MicroRNAs and apoptosis: implications in the molecular therapy of human disease
Authors: Yang Bao‐Feng , Lu Yan‐Jie , Wang Zhi‐Guo
Published: June 2009

1. MicroRNAs (miRNAs), the small non‐coding RNAs of approximately 22 nucleotides, are now recognized as a very large family present throughout the genomes of plants and metazoans. These small transcripts modulate protein expression by binding to complementary or partially complementary target protein‐coding mRNAs and targeting them for degradation or translational inhibition.

2. The discovery of miRNAs has revolutionized our understanding of the mechanisms that regulate gene expression, with the addition of an entirely novel level of regulatory control. Considerable information on miRNAs has been accumulated in this rapidly evolving research field. We now know that miRNAs play pivotal roles in diverse processes, such as development and differentiation, control of cell proliferation and death, stress response and metabolism. Indeed, aberrant miRNA expression has been documented in human disease as well as in animal models, with evidence for a causative role in tumourigenesis.

3. One of the most active fields of miRNA research is miRNA regulation of apoptosis, a programmed cell death implicated in many human diseases, such as cancer, Alzheimer’s disease, hypertrophy and heart failure. Thus far, nearly 30 of 500 human miRNAs have been validated experimentally to regulate apoptosis; this number is likely to increase with future studies.

4. The present review provides a comprehensive summary and analysis of the currently available data, focusing on the transcriptional controls, target genes and signalling pathways linking the apoptosis‐regulating miRNAs and apoptotic cell death.
Interleukin‐6 enhances matrix metalloproteinase‐14 expression via the RAF–mitogen‐activated protein kinase kinase–extracellular signal‐regulated kinase 1/2–activator protein‐1 pathway
Authors: Feng Min , Cai Xiao‐Jun , Zhang Wei , Liu Xiao‐Ling , Chen Liang , Zhang Yun , Zhang Ming‐Xiang , Zhang Mei
Published: June 2009

1. Interleukin (IL)‐6 is a pivotal cytokine that regulates extracellular matrix (ECM) metabolism by increasing collagen degradation via activation of matrix metalloproteinases (MMPs), such as MMP‐14. In the present study, we investigated the role of IL‐6 in atherosclerotic plaque and signalling pathways in apolipoprotein E‐deficient (ApoE−/−) mice.

2. Twenty‐five male ApoE−/− mice were fed a high‐fat diet and atherosclerotic lesions in the right common carotid artery were induced by perivascular placement of a constrictive collar. Immunohistochemical analysis detected expression of IL‐6 and MMP‐14 in atherosclerotic lesions of the right common carotid artery.

3. On silencing activator protein (AP)‐1 expression with a specific small interfering RNA, 75% of the IL‐6‐induced increase in MMP‐14 expression was abolished through the RAF–mitogen‐activated protein kinase kinase–extracellular signal‐regulated kinase 1/2–AP‐1 pathway.

4. These findings suggest a novel molecular pathway for inflammation‐associated ECM dysregulation, which may account for atherosclerotic plaque rupture.
Platelet aggregation in arterial hypertension: Is there a nitric oxide–urea connection?
Authors: Moss Monique B , Siqueira Mariana A , Mann Giovanni E , Brunini Tatiana MC , Mendes‐Ribeiro Antônio C
Published: June 2009

1. Systemic arterial hypertension (SAH) is a major independent risk factor for cardiovascular disease. The physiopathology of SAH is multifactorial, complex and remains to be elucidated. Nitric oxide (NO) is an important regulator of vascular and haemostatic functions. The cationic amino acid l‐arginine serves as the substrate for NO synthases (NOS) and arginase, an enzyme of the urea cycle. We have previously reported inhibition of l‐arginine transport in erythrocytes and platelets in hypertension.

2. The aim of the present study was to investigate the l‐arginine–NO pathway and urea cycle in platelets and their role in platelet function and systemic inflammatory responses in SAH patients. The expression and activity of NOS and arginase in platelets, platelet aggregation and plasma levels of C‐reactive protein (CRP) were evaluated in 20 SAH patients and 18 age‐matched healthy volunteers.

3. There was a reduction of NOS activity in hypertensive patients that was associated with activation of platelet aggregability induced by collagen, but not by ADP. Platelets from SAH patients exhibited compensatory overexpression of inducible NOS, but not endothelial NOS. Intraplatelet arginase activity in SAH patients was not affected, but systemic concentrations of CRP were increased compared with controls.

4. It is likely that diminished NO bioavailability in SAH contributes to cardiovascular complications. Our findings may provide the basis for developing new therapeutic approaches for the treatment of hypertension.
Post‐inflammatory modification of colonic afferent mechanosensitivity
Authors: Hughes PA , Brierley SM , Blackshaw LA
Published: June 2009

1. The present review discusses interactions between the immune and nervous systems in post‐infectious irritable bowel syndrome (PI‐IBS).

2. Visceral pain is the single symptom that most affects the quality of life of patients with irritable bowel syndrome (IBS), yet it is the least successfully managed. An underlying hypersensitivity of colonic afferents to mechanical stimuli has long been implicated in visceral pain in IBS, but little more is known of the physiological aetiology.

3. The PI‐IBS patients are a cohort of IBS patients who attribute their symptoms to a preceding gastrointestinal infection by pathogens such as Campylobacter or Salmonella. Current evidence suggests that the immune system remains activated in these patients and contributes to their visceral hypersensitivity. This is characterized by a shift in the phenotype of circulating immune cells towards a Type 1 (Th1 predominating) state. Products from these immune cells sensitize colonic afferents to mechanical stimuli.

4. Rectal instillation of trinitrobenzene sulphonic acid induces a Th1‐mediated inflammatory response, consistent with clinical observations in PI‐IBS. The visceral hypersensitivity observed in this model is biphasic, with an initial onset characterized by visceral hypersensitivity correlating with histological damage followed by a delayed phase that occurs after histological recovery. Interestingly, this chronic visceral hypersensitivity is mediated by afferents in closest apposition to blood vessels, but furthest from the initial site of damage.

5. Both clinical and experimental evidence indicates that chronic dysregulation of the immune system induces visceral afferent hypersensitivity and, therefore, may be the central mechanism underlying PI‐IBS.
Significance of endogenous sulphur‐containing gases in the cardiovascular system
Authors: Wang Xin‐Bao , Jin Hong‐Fang , Tang Chao‐Shu , Du Jun‐Bao
Published: June 2009

1. The sulphur‐containing gases hydrogen sulphide and sulphur dioxide can be generated endogenously in mammalian tissues and exert significant biological effects in the cardiovascular system. Hydrogen sulphide is considered to be the third novel gasotransmitter in addition to nitric oxide and carbon monoxide. The present review describes the effects of hydrogen sulphide on the cardiovascular system and its possible mechanisms under physiological conditions. We also discuss the pathophysiological effects of hydrogen sulphide on cardiovascular diseases. The therapeutic potential of hydrogen sulphide is summarized.

2. We recently discovered that sulphur dioxide, another endogenous sulphur‐containing gas, has important physiological and pathophysiological roles in the cardiovascular system. To some extent, the effect of sulphur dioxide is similar to that of the other gasotransmitters nitric oxide, carbon monoxide and hydrogen sulphide. Sulphur dioxide may also be a novel gas mediator in the cardiovascular system.
Gastroprotective effects of the insulin sensitizers rosiglitazone and metformin against indomethacin‐induced gastric ulcers in Type 2 diabetic rats
Authors: Morsy Mohamed A , Ashour Osama M , Fouad Amr A , Abdel‐Gaber Seham A
Published: June 2009

1. Gastric ulcers are common in Type 2 diabetic patients. Of all drugs used in the treatment of Type 2 diabetes, the insulin sensitizers thiazolidinediones (e.g. rosiglitazone) and metformin exhibit additional effects in ameliorating oxidative stress and inflammation, rendering them attractive candidates for the prevention of gastric ulcer in Type 2 diabetes. Thus, the aim of the present study was to evaluate the gastroprotective effects of rosiglitazone and metformin against indomethacin‐induced gastric ulcer in Type 2 diabetic and non‐diabetic rats.

2. Diabetes was induced by a single injection of streptozotocin (60 mg/kg, i.p., dissolved in 0.1 mol/L cold citrate buffer, pH 4.5), 15 min after administration of 120 mg/kg, i.p., nicotinamide. Three weeks after the successful induction of diabetes, rats were subjected to pyloric ligation and then injected immediately with 30 mg/kg, i.p., indomethacin. Three hours after indomethacin administration, rats were killed and gastric injury was evaluated. Ranitidine (50 mg/kg) was used as a reference drug and was administered in a single oral dose 1 h before indomethacin injection, as were rosiglitazone (3 mg/kg) and metformin (500 mg/kg).

3. Both rosiglitazone and metformin exhibited gastroprotective effects, as evidenced by significant decreases in the ulcer index, free and total acid output in gastric juice and gastric mucosal malondialdehyde concentrations, with concomitant increases in gastric juice pH (only with rosiglitazone), mucin concentrations, gastric mucosal concentrations of nitric oxide and catalase activity compared with untreated diabetic rats. Conversely, rosiglitazone and metformin had no effect on peptic activity and gastric mucosal prostaglandin E2 content, particularly in the diabetic group, compared with the untreated groups.

4. In conclusion, rosiglitazone and metformin protect Type 2 diabetic rats against indomethacin‐induced gastric ulceration, most possibly via antisecretory actions, enhanced mucosal protection and anti‐oxidant activity. Rosiglitazone seems to be provide superior gastroprotection to metformin.
Strategies of treating cancer by cytokine regulation of chromosome end remodelling
Authors: Liu Jun‐Ping , Nicholls Craig , Chen Shi‐Ming , Li He , Tao Ze‐Zhang
Published: June 2009

1. Telomeres (ends of chromosomes) undergo constant remodelling during cell development, proliferation and differentiation, as well as in neoplastic cell immortalization and transformation. How the cellular microenvironment influences telomere remodelling (lengthening or shortening) remains largely unknown.

2. Recently, studies from our laboratories and others have indicated that growth factors and cytokines have significant roles in regulating telomere remodelling and thus influence cell functions and properties. Cancer cells must maintain their already short telomeres either by the enzyme telomerase or, more rarely, through alternative lengthening of telomeres, which functions independently of cellular regulation.

3. However, application of transforming growth factor‐β family cytokines induces transcriptional inhibition of telomerase in cancer cells, leading to telomere shortening, cell senescence (ageing) and apoptosis (death) by mechanisms dependent on telomerase inhibition. Furthermore, selective gene silencing of vascular endothelial growth factor and/or the telomerase catalytic subunit (i.e. telomerase reverse transcriptase) potently inhibits the growth of cervical cancer and laryngeal squamous cancer in mice.

4. The present paper summarizes our current understanding of the negative regulation by cytokines of telomere maintenance and thus cancer cell proliferation in cultured cells and mouse models.
Sympathetic nerves and the progression of chronic kidney disease during 5/6 nephrectomy: Studies in sympathectomized rats
Authors: Augustyniak Robert A , Picken Maria M , Leonard David , Zhou Xin J , Zhang Weiguo , Victor Ronald G
Published: June 2009

1. Chronically increased sympathetic nerve activity is present during chronic kidney disease (CKD); however, its role in contributing to hypertension or the progression of CKD remains poorly understood. The aim of the present study was to determine whether neonatal sympathectomy attenuates hypertension in 5/6 nephrectomized rats and affects renal structure and function in a blood pressure‐independent manner.

2. We performed 5/6 nephrectomy (referred to as CKD) in both sympathetically intact and sympathectomized (injected neonatally with guanethidine; referred to as CKD + Sympath) male Sprague‐Dawley rats. Sham‐operated sympathetically intact and sympathectomized rats (Sham and Sham + Sympath, respectively) were used as controls. Radiotelemetry was used to monitor blood pressure throughout the 6 week duration of the study, after which renal function and histology were assessed.

3. Overall average systolic arterial pressure and final urinary protein excretion were significantly lower in CKD + Sympath compared with CKD rats (168 ± 7 mmHg and 33 ± 5 mg/24 h vs. 184 ± 6 mmHg and 66 ± 7 mg/24 h, respectively). However, the level of proteinuria in the CKD + Sympath group was reduced to a greater extent than what would be expected solely on the basis of lower blood pressure. All other indices of renal function and histology were comparable between both CKD groups. All measurements were comparable between Sham and Sham + Sympath groups.

4. In conclusion, sympathectomy attenuated hypertension by approximately one‐third in 5/6 nephrectomized rats. Furthermore, sympathetic nerves to the kidney during 5/6 nephrectomy may contribute to proteinuria in a blood pressure‐independent manner.
Rhythm of digestion: keeping time in the gastrointestinal tract
Authors: Bron Romke , Furness John B
Published: June 2009

1. The best characterized mammalian circadian rhythms follow a light‐entrained central master pacemaker in the suprachiasmatic nucleus and are associated with fluctuations in the activities of clock genes, including Clock, Bmal1, Per and Cry, the products of which bind to sequences in the promoters of effector genes. This is the central clock.

2. In the present review, we discuss evidence for an independent, but interacting, gut‐associated circadian clock, the peripheral clock, which is entrained by food.

3. Disruption of circadian rhythms is associated with a wide range of pathologies, most prominently metabolism linked, but the effects of disruption of circadian rhythms on the digestive system are less well studied, although also likely to lead to functional consequences. There are clues suggestive of links between gastrointestinal disorders related to inflammation, cancer and motility and disruption of peripheral rhythms. Research aimed at understanding these links is still in its infancy.

4. We also discuss practical aspects of the presence of circadian rhythms in gastrointestinal tissues for researchers related to experimental design, data interpretation and the choice of animal models.

5. There is currently sufficient evidence to suggest that circadian rhythms are important to gut function, metabolism and mucosal defence and that further investigation will uncover connections between disordered rhythms and gastrointestinal malfunction.
Effect of 17β‐oestradiol replacement on vascular responsiveness in ovariectomized diabetic rats
Authors: Ceylan‐Isik Asli F , Erdogan‐Tulmac Ozlem B , Ari Nuray , Ozansoy Gulgun , Ren Jun
Published: June 2009

1. Women with functional ovaries exhibit a gender advantage in terms of the prevalence of cardiovascular diseases. However, whether this gender bias pertains in diabetes is unknown.

2. The aim of the present study was to examine the effects of 17β‐oestradiol (E2) on vascular responsiveness in normal and diabetic ovariectomized (OVX) rats. Aged‐matched female rats were divided into four groups as follows: (i) OVX; (ii) OVX + E2 treated; (iii) diabetic OVX; and (iv) diabetic OVX + E2 treated. Bilateral ovariectomy was performed and streptozotocin was used to induce experimental diabetes. Rats were treated with 1 mg/kg per day, p.o., E2 for 8 weeks.

3. Although E2 treatment had no effect on blood glucose levels in normal and diabetic OVX rats, it significantly reduced systolic blood pressure and prevented diabetes‐induced loss of bodyweight gain.

4. In segments of the thoracic aorta, concentration‐dependent vasoconstrictor responses to KCl and phenylephrine were significantly attenuated following E2 treatment in both the normal and diabetic groups. The sarcoplasmic/endoplasmic reticulum calcium ATPase inhibitor thapsigargin (10−6 mol/L) and the Ca2+ channel blocker nifedipine (10−6 mol/L) inhibited the transient vasoconstriction to PE in all groups. The constrictor effect of PE was increased by the nitric oxide synthase inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME; 10−6 mol/L), but was reduced by superoxide dismutase (SOD; 100 U/mL) and the cyclo‐oxygenase inhibitor indomethacin (10−6 mol/L) in all groups. Responses to acetylcholine (ACh; 10−6 mol/L) demonstrated reduced endothelium‐dependent relaxation in non‐E2‐treated groups. Relaxation responses to ACh were increased by 100 U/mL SOD and 10−6 mol/L indomethacin, but were reduced by 10−6 mol/L l‐NAME in all groups. There were no differences among the four groups in terms of relaxation responses to sodium nitroprusside (10−11 to 10−6 mol/L).

5. In conclusion, the results of the present study suggest that oestrogen treatment has beneficial effects on vascular function in both diabetic and non‐diabetic OVX rats due to Ca2+ regulation and anti‐oxidation.
Purinergic regulation of the epithelial Na+channel
Authors: O’Mullane Lauren M , Cook David I , Dinudom Anuwat
Published: June 2009

1. The epithelial Na+channel (ENaC) is a major conductive pathway that transports Na+across the apical membrane of the distal nephron, the respiratory tract, the distal colon and the ducts of exocrine glands. The ENaC is regulated by hormonal and humoral factors, including extracellular nucleotides that are available from the epithelial cells themselves.

2. Extracellular nucleotides, via the P2Y2 receptors (P2Y2Rs) at the basolateral and apical membrane of the epithelia, trigger signalling systems that inhibit the activity of the ENaC and activate Ca2+‐dependent Cl−secretion.

3. Recent data from our laboratory suggest that stimulation of the P2Y2Rs at the basolateral membrane inhibits ENaC activity by a signalling mechanism that involves Gβγ subunits freed from a pertussis toxin (PTX)‐sensitive G‐protein and phospholipase C (PLC) β4. A similar signalling mechanism is also partially responsible for inhibition of the ENaC during activation of apical P2Y2Rs.

4. Stimulation of apical P2Y2Rs also activates an additional signalling mechanism that inhibits the ENaC and involves the activated Gα subunit of a PTX‐insensitive G‐protein and activation of an unidentified PLC. The effect of this PTX‐insensitive system requires the activity of the basolateral Na+/K+/2Cl−cotransporter.
Evidence for the adaptive significance of circadian rhythms
Authors: Yerushalmi Shai , Green Rachel M.
Published: June 2009

Circadian (∼24 h) clock regulated biological rhythms have been identified in a wide range of organisms from prokaryotic unicellular cyanobacteria to higher mammals. These rhythms regulate an enormous variety of processes including gene expression, metabolic processes, activity and reproduction. Given the widespread occurrence of circadian systems it is not surprising that extensive efforts have been directed at understanding the adaptive significance of circadian rhythms. In this review we discuss the approaches and findings that have resulted. In studies on organisms in their natural environments, some species show adaptations in their circadian systems that correlate with living at different latitudes, such as clines in circadian clock properties. Additionally, some species show plasticity in their circadian systems suggested to match the demands of their physical and social environment. A number of experiments, both in the field and in the laboratory, have examined the effects of having a circadian system that does not resonate with the organism’s environment. We conclude that the results of these studies suggest that having a circadian system that matches the oscillating environment is adaptive.
The role of landmarks and boundaries in the development of spatial memory
Authors: Bullens Jessie , Nardini Marko , Doeller Christian F. , Braddick Oliver , Postma Albert , Burgess Neil
Published: June 2009

It has been suggested that learning an object’s location relative to (1) intramaze landmarks and (2) local boundaries is supported by parallel striatal and hippocampal systems, both of which rely upon input from a third system for orientation. However, little is known about the developmental trajectories of these systems’ contributions to spatial learning. The present study tested 5‐ and 7‐year‐old children and adults on a water maze‐like task in which all three types of cue were available. Participants had to remember the location of an object hidden in a circular bounded environment containing a moveable intramaze landmark and surrounded by distal cues. Children performed less accurately than adults, and showed a different pattern of error. While adults relied most on the stable cue provided by the boundary, children relied on both landmark and boundary cues similarly, suggesting a developmental increase in the weighting given to boundary cues. Further, adults were most accurate in coding angular information (dependent on distal cues), whereas children were most accurate in coding distance, suggesting a developing ability to use distal cues to orient. These results indicate that children as young as 5 years use boundary, intramaze landmark, and distal visual cues in parallel, but that the basic accuracy and relative weighting of these cues changes during subsequent development.
Evidence for intact memory‐guided attention in school‐aged children
Authors: Dixon Matthew L. , Zelazo Philip David , De Rosa Eve
Published: June 2009

Visual scenes contain many statistical regularities such as the likely identity and location of objects that are present; with experience, such regularities can be encoded and can ultimately facilitate the deployment of spatial attention to important locations. Memory‐guided attention has been extensively examined in adults with the ‘contextual cueing’ paradigm and has been linked to specific neural substrates – a medial temporal lobe (MTL)‐frontoparietal network. However, it currently remains unknown when this ability comes ‘online’ during development. Thus, we examined the performance of school‐aged children on an age‐appropriate version of the contextual cueing paradigm. Children searched for a target fish among distractor fish in new displays and in ‘old’ displays on a touchscreen computer. Old displays repeated across blocks of trials and thus provided an opportunity for prior experience with the invariant configuration of the stimuli to guide attentional deployment. We found that over time children searched old displays significantly faster than new displays, thus revealing intact memory‐guided attention and presumed function of an MTL‐frontoparietal network in 5‐ to 9‐year‐olds. More generally, our findings suggest that children are remarkably sensitive to the inherent structure of their visual environment and this enables attentional deployment to become more efficient with experience.
Time, space and structure in an e‐learning and e‐mentoring project
Authors: Loureiro‐Koechlin Cecilia , Allan Barbara
Published: June 2009

This study focuses on a project, EMPATHY Net‐Works, which developed a learning community as a means of encouraging women to progress into employment and management positions in the logistics and supply chain industries (LaSCI). Learning activities were organised in the form of a taught module containing face‐to‐face and online elements and e‐mentoring with successful professional women in the LaSCI. In this particular research, we have used structuration theory, a social theory that concentrates on the relationships between human agency (micro‐level) and social structures (macro‐level). We used structuration as an analytical tool to help us understand what happened within the project e‐learning and e‐mentoring processes. Our analysis suggests that there were two factors that influenced the way project participants carried out their learning activities: the first one being the issue of absence and presence in online environments, and the second one the issue of time frame changes for online users.
Project management in instructional design: ADDIE is not enough
Authors: Van Rooij Shahron Williams
Published: June 2009

In the digital age, instructional designers must possess both a sound instructional design knowledge base and solid project management skills that will enable them to complete courseware projects on time, on budget and in conformance with client expectations. Project management skills include the ability to apply repeatable processes, along with interpersonal skills such as communication and leadership skills. However, courses in project management are often absent from the higher education instructional design curriculum, creating a gap between what is learned in instructional design programmes and real‐world practice. In this paper, the author draws on the education and project management fields to examine this gap. The author argues that the gap between instructional design project management models and how instructional design practitioners view project management is a consequence of the divergent perspectives of higher education subcultures and the extent to which those subcultures are likely to embrace cross‐disciplinary subjects such as project management. The author proposes some research and advocacy opportunities for closing the gap between instructional design education and practice.
Botulinum toxin B increases mouth opening in patients with spastic trismus
Authors: Fietzek U. M. , Kossmehl P. , Barthels A. , Ebersbach G. , Zynda B. , Wissel J.
Published: June 2009

Background:  Severe generalized spastic movement disorders of various aetiologies often involve the jaw muscles and lead to a spastic trismus with masseter muscle hypertonia. We report a placebo‐controlled randomized study on patients with spastic trismus.

Methods:  Eleven patients with masseter hypertonia because of stroke, hypoxic encephalopathy or traumatic brain injury were allocated to either botulinum toxin serotype B (BoNT/B) injections into the masseter muscles or placebo treatment. The dental gap, the amount of saliva, salivation scales, and a clinical goal attainment were evaluated.

Results:  Three weeks after injection the BoNT/B group showed a significantly increased mouth opening compared with placebo treatment (P < 0.05). In addition to the muscle paralysing effect, a goal attainment scale demonstrated a clinical benefit for the BoNT/B group (P < 0.01).

Conclusions:  Botulinum toxin serotype B injections into the masseter muscles effectively reduce hypertonia and provide for better mouth opening, thereby contributing to a positive and desired clinical goal.
Novel non‐sense GCH1 mutation in a South African family diagnosed with dopa‐responsive dystonia
Authors: Bardien S. , Keyser R. , Lombard D. , Du Plessis M. , Human H. , Carr J.
Published: June 2009

Background:  Dopa‐responsive dystonia (DRD), a movement disorder characterized by onset in early childhood and a dramatic response to low doses of levodopa, has been shown to be caused by a number of different mutations in the GCH1 gene.

Methods:  We identified a South African family which presented with DRD in three family members. Polymerase chain reaction (PCR) primers were designed to span all six exons of GCH1 and the PCR products were screened for pathogenic mutations using direct sequencing.

Results:  A novel non‐sense mutation (c.233delT; p.I78fsX79) was identified in the DRD patients, which would produce a markedly truncated protein of only 78 amino acids. This mutation was also present in a number of asymptomatic family members.

Conclusions:  A novel non‐sense mutation in the GCH1 gene can be associated with DRD and reduced penetrance in South African patients.
An exploration of anger phenomenology in multiple sclerosis
Authors: Nocentini U. , Tedeschi G. , Migliaccio R. , Dinacci D. , Lavorgna L. , Bonavita S. , Bresciamorra V. , Comanducci G. , Coniglio G. , Livrea P. , Mannu R. , Orefice G. , Paciello M. , Patti F. , Quattrone A. , Salemi G. , Savettieri G. , Simone I.L. , Valentino P. , Zappia M. , Bonavita V. , Musicco M. , Caltagirone C.
Published: June 2009

Background and purpose:  Multiple sclerosis (MS) patients are often emotionally disturbed. We investigated anger in these patients in relation to demographic, clinical, and mood characteristics.

Patients and methods:  About 195 cognitively unimpaired MS patients (150 relapsing–remitting and 45 progressive) were evaluated with the State Trait Anger Expression Inventory, the Chicago Multiscale Depression Inventory, and the State Trait Anxiety Inventory. The patients’ anger score distribution was compared with that of the normal Italian population. Correlation coefficients among scale scores were calculated and mean anger scores were compared across different groups of patients by analysis of variance.

Results:  Of the five different aspects of anger, levels of withheld and controlled Anger were respectively higher and lower than what is expected in the normal population. Although anger was correlated with anxiety and depression, it was largely independent from these mood conditions. Mean anger severity scores were not strongly influenced by individual demographic characteristics and were not higher in more severe patients.

Conclusions:  The presence of an altered pattern of anger, unrelated to the clinical severity of MS, suggests that anger is not an emotional reaction to disease stress. An alteration of anger mechanisms might be a direct consequence of the demyelination of the connections among the amygdale, the basal ganglia and the medial prefrontal cortex.
Serum VEGF levels in acute ischaemic strokes are correlated with long‐term prognosis
Authors: Lee S.‐C. , Lee K.‐Y. , Kim Y.‐J. , Kim S. H. , Koh S.‐H. , Lee Y. J.
Published: June 2009

Background and purpose:  We investigated whether serum vascular endothelial growth factor (VEGF) levels in acute‐stage ischaemic stroke patients with small vessel disease (SVD) or large vessel disease (LVD) are correlated with long‐term prognoses, based on the difference in NIH Stroke Scale (NIHSS) scores between acute and chronic stages.

Methods:  From March 2007 to May 2008, we evaluated patients who experienced an ischaemic stroke for the first time, defined as SVD (n = 89) or LVD (n = 91) using the TOAST classification. Serum samples were taken immediately after admission (within 24 h of stroke onset) to evaluate VEGF levels. After 3 months, follow‐up NIHSS scores were collected for all patients.

Results:  Serum VEGF levels in the acute stage (within 24 h of stroke onset) were higher in the LVD group than in the SVD group and were correlated with infarction volume. The increase in serum VEGF levels in the acute stage was proportional to an improved NIHSS score after 3 months. After adjustment for covariates, serum VEGF levels in the acute stage were still significantly correlated with the long‐term prognosis of ischaemic stroke.

Conclusion:  Serum VEGF levels are correlated with long‐term prognoses in acute ischaemic stroke patients.
Morphological characterization of pecteneal hyalocytes in the developing quail retina
Authors: Llombart Cristina , Nacher Víctor , Ramos David , Luppo Mariana , Carretero Ana , Navarro Marc , Melgarejo Verònica , Armengol Clara , Rodríguez‐Baeza Alfonso , Mendes‐Jorge Luisa , Ruberte Jesús
Published: June 2009

The periphery of the vitreous body contains a population of cells termed hyalocytes. Despite the existence for more than one century of publications devoted to the pecten oculi, a convoluted coil of blood vessels that seems to be the primary source of nutrients for the avian avascular retina, little information can be found concerning the pecteneal hyalocytes. These cells are situated on the inner limiting membrane in close relationship with the convolute blood vessels. To characterize the origin and macrophagic activity of pecteneal hyalocytes, we have analysed two different stages of quail eye development using histochemistry and immunohistochemistry. Pecteneal hyalocytes express the QH1 epitope and cKit, confirming that these cells belong to the haematopoietic system. They also express vimentin, an intermediate filament protein present in cells of mesenchymal origin and very important for differentiation of fully active macrophages. However, similarly as described in porcine hyalocytes, pecteneal hyalocytes express the glial fibrillary acidic protein, a recognized neuroglial marker. Pecteneal hyalocytes did not express other neuroglial markers, such as glutamine synthetase or S100. Acidic phosphatase was activated and Lep100 was found in secondary lysosomes, confirming phagocytic activity of pecteneal hyalocytes during ocular development. Pecteneal hyalocytes strongly react with RCA‐I, WFA, WGA, PNA, SNA, LEA and SBA lectins, whereas other avian macrophages from thymus and the bursa of Fabricius did not bind PNA, SNA and LEA lectins. Interestingly, WGA lectin reacts with all kinds of avian macrophages, including pecteneal hyalocytes, probably reflecting the specific binding of WGA to components of the phagocytic and endocytic pathways. In conclusion, pecteneal hyalocytes are a special subtype of blood‐borne macrophages that express markers not specifically associated with the haematopoietic system.
Deconstructing the PDD clinical phenotype: internal validity of the DSM‐IV
Authors: Lecavalier Luc , Gadow Kenneth D. , DeVincent Carla J. , Houts Carrie , Edwards Michael C.
Published: June 2009

Background:  Empirical studies of the structure of autism symptoms have challenged the three‐domain model of impairment currently characterizing pervasive developmental disorders (PDD). The objective of this study was to assess the internal validity of the DSM as a conceptual model for describing PDD, while paying particular attention to certain subject characteristics.

Methods:  Parents and teachers completed a DSM‐IV‐referenced rating scale for 3‐ to 12‐year‐old clinic referrals with a PDD (n = 730). Ratings were submitted to confirmatory factor analysis and different models were assessed for fit.

Results:  Measures of fit indicated that the three‐factor solution based on the DSM was superior to other models. Most indices of fit were acceptable, but showed room for improvement. Fit indices varied according to the rater (parent or teacher), child’s age (preschool versus school aged), PDD subtype (autism, Asperger’s, pervasive developmental disorder not otherwise specified (PDDNOS)), and IQ.

Conclusions:  More research needs to be done before discarding current classification systems. Subject characteristics, modality of assessment, and procedural variations in statistical analyses impact conclusions about the structure of PDD symptoms.
One factor or two parallel processes? Comorbidity and development of adolescent anxiety and depressive disorder symptoms
Authors: Hale III William W. , Raaijmakers Quinten A.W. , Muris Peter , Van Hoof Anne , Meeus Wim H.J.
Published: June 2009

Background:  This study investigates whether anxiety and depressive disorder symptoms of adolescents from the general community are best described by a model that assumes they are indicative of one general factor or by a model that assumes they are two distinct disorders with parallel growth processes. Additional analyses were conducted to explore the comorbidity of adolescent anxiety and depressive disorder symptoms and the effects that adolescent anxiety and depressive disorder symptoms have on each other’s symptom severity growth.

Methods:  Two cohorts of early (N = 923; Age range 10–15 years; Mean age = 12.4, SD = .59; Girls = 49%) and middle adolescent (N = 390; Age range 16–20 years; Mean age = 16.7, SD = .80; Girls = 57%) boys and girls from the general community were prospectively studied annually for five years. These two adolescent cohorts were divided into five groups: one group at‐risk for developing a specific anxiety disorder and four additional groups of healthy adolescents that differed in age and sex. Self‐reported anxiety and depressive disorder symptoms were analyzed with latent growth modeling.

Results:  Comparison of the fit statistics of the two models clearly demonstrates the superiority of the distinct disorders with parallel growth processes model above the one factor model. It was also demonstrated that the initial symptom severity of either anxiety or depression is predictive of the development of the other, though in different ways for the at‐risk and healthy adolescent groups.

Conclusions:  The results of this study established that the development of anxiety and depressive disorder symptoms of adolescents from the general community occurs as two distinct disorders with parallel growth processes, each with their own unique growth characteristics.
Polyglutamine expansion in huntingtin alters its interaction with phospholipids
Authors: Kegel Kimberly B. , Sapp Ellen , Alexander Jonathan , Valencia Antonio , Reeves Patrick , Li Xueyi , Masso Nicholas , Sobin Lindsay , Aronin Neil , DiFiglia Marian
Published: June 2009

Huntingtin has an expanded polyglutamine tract in patients with Huntington’s disease. Huntingtin localizes to intracellular and plasma membranes but the function of huntingtin at membranes is unknown. Previously we reported that exogenously expressed huntingtin bound pure phospholipids using protein‐lipid overlays. Here we show that endogenous huntingtin from normal (Hdh7Q/7Q) mouse brain and mutant huntingtin from Huntington’s disease (Hdh140Q/140Q) mouse brain bound to large unilamellar vesicles containing phosphoinositol (PI) PI 3,4‐bisphosphate, PI 3,5‐bisphosphate, and PI 3,4,5‐triphosphate [PI(3,4,5)P3]. Huntingtin interactions with multivalent phospholipids were similar to those of dynamin. Mutant huntingtin associated more with phosphatidylethanolamine and PI(3,4,5)P3 than did wild‐type huntingtin, and associated with other phospholipids not recognized by wild‐type huntingtin. Wild‐type and mutant huntingtin also bound to large unilamellar vesicles containing cardiolipin, a phospholipid specific to mitochondrial membranes. Maximal huntingtin‐phospholipid association required inclusion of huntingtin amino acids 171–287. Endogenous huntingtin recruited to the plasma membrane in cells that incorporated exogenous PI 3,4‐bisphosphate and PI(3,4,5)P3 or were stimulated by platelet‐derived growth factor or insulin growth factor 1, which both activate PI 3‐kinase. These data suggest that huntingtin interacts with membranes through specific phospholipid associations and that mutant huntingtin may disrupt membrane trafficking and signaling at membranes.