bluuebunny/crossref_metadata_2025 huggingface dataset:
The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function
Authors: Horne William C. , Sanjay Archana , Bruzzaniti Angela , Baron Roland
Published: May 2006

Summary:  The osteoclast resorbs mineralized bone during bone development, homeostasis, and repair. The deletion of the gene encoding the nonreceptor tyrosine kinase c‐Src produces an osteopetrotic skeletal phenotype that is the consequence of the inability of the mature osteoclast to efficiently resorb bone. Src–/– osteoclasts exhibit reduced motility and abnormal organization of the apical secretory domain (the ruffled border) and attachment‐related cytoskeletal elements that are necessary for bone resorption. A key function of Src in osteoclasts is to promote the rapid assembly and disassembly of the podosomes, the specialized integrin‐based attachment structures of osteoclasts and other highly motile cells. Once recruited to the activated integrins, especially αvβ3, by the adhesion tyrosine kinase Pyk2, Src binds and phosphorylates Cbl and Cbl‐b, homologous multisite adapter proteins with ubiquitin ligase activity. The Cbl proteins in turn recruit and activate additional signaling effectors, including phosphatidylinositol 3‐kinase and dynamin, which play key roles in the development of cell polarity and the regulation of cell attachment and motility. In addition, Src and the Cbl proteins contribute to signaling cascades that are activated by several important receptors, including receptor activator of nuclear factor κB and the macrophage colony‐stimulating factor receptor, and also downregulate the signaling from many of these receptors.
Rheumatic diseases: the effects of inflammation on bone
Authors: Walsh Nicole C. , Crotti Tania N. , Goldring Steven R. , Gravallese Ellen M.
Published: May 2006

Summary:  Rheumatoid arthritis, juvenile idiopathic arthritis, the seronegative spondyloarthropathies including psoriatic arthritis, and systemic lupus erythematosus are all examples of rheumatic diseases in which inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or on the axial or appendicular skeleton. Studies in human disease and in animal models of arthritis have identified the osteoclast as the predominant cell type mediating bone loss in arthritis. Many of the cytokines and growth factors implicated in the inflammatory processes in rheumatic diseases have also been demonstrated to impact osteoclast differentiation and function either directly, by acting on cells of the osteoclast‐lineage, or indirectly, by acting on other cell types to modulate expression of the key osteoclastogenic factor receptor activator of nuclear factor (NF) κB ligand (RANKL) and/or its inhibitor osteoprotegerin (OPG). Further elucidation of the mechanisms responsible for inflammation‐induced bone loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases. In this review, we provide an overview of the cell types, inflammatory mediators, and mechanisms that are implicated in bone loss and new bone formation in inflammatory joint diseases.
Role of interleukin‐7 in bone and T‐cell homeostasis
Authors: Lee Sun‐Kyeong , Surh Charles D.
Published: May 2006

Summary:  Initially defined as a B‐cell growth factor, the pleiotropic nature of interleukin‐7 (IL‐7) has increasingly become appreciated. Besides its well‐known roles in B‐ and T‐cell lymphopoiesis, IL‐7 is now known to regulate the homeostasis of both mature T cells and bone cells. In bone, the precise nature of how IL‐7 affects osteoclasts and osteoblasts is controversial, since it has a variety of actions in different target cells. These activities are gender‐specific and are dependent on whether IL‐7 is delivered systemically or locally. In mature T cells, IL‐7 is essential for the survival of nearly all subsets. Naïve T cells are also dependent on IL‐7 for survival and homeostatic proliferation in response to lymphopenia. In addition, IL‐7 plays a role in the survival of memory CD8+ cells, and at high concentrations, it can compensate for the absence of IL‐15. The role of IL‐7 on memory CD4+ cells remains controversial and has yet to be firmly established.
Persistence of drug use during imprisonment: relationship of drug type, recency of use and severity of dependence to use of heroin, cocaine and amphetamine in prison
Authors: Strang John , Gossop Michael , Heuston Joan , Green John , Whiteley Christopher , Maden Anthony
Published: May 2006

Aim  To investigate the persistence of use of heroin, cocaine and amphetamine drugs during imprisonment, and to identify factors associated with increased levels of persistence.

Design  The use of heroin, cocaine and amphetamine by current prison inmates has been examined and, in particular, the relationship between drug use within prison and the type of drug used prior to imprisonment, recency of use and severity of dependence. 

Setting and participants A randomly selected sample of 1009 adult male prisoners in 13 prisons in England and Wales during 1994/95; structured confidential interviews conducted by independent research staff. Enquiry about prior use of heroin, cocaine or amphetamine focused on three time‐periods (ever, last year and last month pre‐prison) and the use of these drugs during the first month of imprisonment.

Findings  A total of 557 (55%) of the 1009 prisoners had used previously one of the three drugs selected for study: 58% had used heroin, 69% cocaine and 75% amphetamine. More than half (59%; 327/557) had used these drugs in the month before the current imprisonment. Drug use in prisons was most likely to occur among those who had used in the month prior to imprisonment. The persistence of heroin use in prison occurred more frequently (70%) than use of cocaine (20%) or amphetamine (15%). Of those using heroin pre‐imprisonment, 67% considered they were dependent, compared to 15% and 22%, respectively, for cocaine and amphetamine users.

Conclusions  Changes in the drug‐taking behaviour of drug users after imprisonment vary according to the type of drug being taken. Prisoners were much more likely to continue to use heroin than either cocaine or amphetamines while in prison. Heroin was most likely to be used by those who had been using heroin during the immediate pre‐imprisonment period, and particularly by the two‐thirds of heroin users who considered themselves dependent. In view of the high prevalence of prior use of these drugs by individuals currently imprisoned, continuing attention is required to study of their behaviour and of the impact of interventions that may be introduced during or following their incarceration.
Addition of cue exposure to cognitive‐behaviour therapy for alcohol misuse: a randomized trial with dysphoric drinkers
Authors: Kavanagh David J. , Sitharthan Gomathi , Young Ross M. , Sitharthan Thiagarajan , Saunders John B. , Shockley Natalie , Giannopoulos Vicki
Published: May 2006

Aim  To test whether addition of moderation‐orientated cue exposure (CE) or CE after dysphoric mood induction (emotional CE, ECE) improved outcomes above those from cognitive‐behaviour therapy alone (CBT) in people who drank when dysphoric.

Design  Multi‐site randomized controlled trial comparing CBT with CBT + CE and CBT + ECE.

Setting  Out‐patient rooms in academic treatment units in Brisbane and Sydney, Australia.

Participants  People with alcohol misuse and problems controlling consumption when dysphoric (n = 163). Those with current major depressive episode were excluded.

Intervention  Eight weekly 75‐minute sessions of individual treatment for alcohol problems were given to all participants, with CBT elements held constant across conditions. From session 2, CBT + CE participants resisted drinking while exposed to alcohol cues, with two priming doses of their preferred beverage being given in some sessions. After an initial CE session, CBT + ECE participants recalled negative experiences before undertaking CE, to provide exposure to emotional cues of personal relevance.

Measurements  Alcohol consumption, related problems, alcohol expectancies, self‐efficacy and depression.

Results  Average improvements were highly significant across conditions, with acceptable maintenance of effects over 12 months. Both treatment retention and effects on alcohol consumption were progressively weaker in CBT + CE and CBT + ECE than in CBT alone. Changes in alcohol dependence and depression did not differ across conditions.

Conclusions  These data do not indicate that addition of clinic‐based CE to standard CBT improves outcomes. A different approach to the management of craving may be required.
The medicines for children agenda in the UK
Authors: Stephenson Terence
Published: May 2006

Children can expect the medicines prescribed for them to have at least as good an evidence base as in adult practice. Current licensing arrangements in the UK ensure a rigorous assessment of most drugs used for adults, whereas prescribing outside the licence is relatively common for children. Until the evidence base is increased, consensus guidelines or formularies, such as the new British National Formulary for Children, provide some protection for children and prescribers. For the future, there is optimism that the dearth of research on which to base children’s prescribing will be addressed by new initiatives, such as the UK Medicines for Children Research Network and draft EU legislation providing incentives to industry.
Comparison of reactivity and epitope recognition between sera from American and Italian patients with oral pemphigoid
Authors: Mignogna M , Lanza A , Rossiello L , Ruocco V , Ahmed A R
Published: May 2006

Mucous membrane pemphigoid (MMP) (also known as cicatricial pemphigoid) is a rare autoimmune mucocutaneous blistering disease that affects mucous membranes derived from stratified squamous epithelium and the skin. A subset of MMP affects only the oral cavity and is referred to as the oral pemphigoid (OP). MMP and OP are characterized by subepithelial vesicles on histology and in vivo deposition of immunoglobulins and complement at the basement membrane zone (BMZ) on immunopathology. Previous studies have shown that sera of patients with MMP bind to human integrin β4, while sera of patients with oral pemphigoid bind to the integrin α6 component of the heterodimer. The prognosis in MMP is grave but excellent in OP. In this study we compare the binding of sera from patients with OP from Boston, MA, USA to Naples, Italy, and attempt to identify an epitope to which the anti-integrin α6 human autoantibody binds. Our results indicate that the sera from Boston and Naples are identical in their reactivity. They recognize a fragment I (AA 23–462) and its subfragment IB (AA 217–462) only, in the human integrin α6 molecule. Blocking studies, immunoprecipitation and immunoabsorbtion studies confirm the presence of this single 245 AA region. Antibodies to subfragment IB cause BMZ separation in organ culture using normal human oral mucosa as substrate. This preliminary study indicates that patients on both continents may have similar reactivity and suggests that an intercontinental study group could be established to advance our understanding of the pathogenesis of OP and the biology of anti-α6 integrin autoantibodies.
The role of corticosterone in human hypothalamic– pituitary–adrenal axis feedback
Authors: Raubenheimer Peter J. , Young Elizabeth A. , Andrew Ruth , Seckl Jonathan R.
Published: May 2006

Objective  In humans, the glucocorticoid corticosterone circulates in blood at 10–20‐fold lower levels than cortisol, but is found in higher relative amounts in postmortem brain samples. Access of cortisol and corticosterone to the central nervous system may not be equal. Additionally, the relative affinities for the glucocorticoid and mineralocorticoid receptors differ, such that corticosterone may play a significant role in human brain function.

Design  We measured cortisol and corticosterone levels in paired plasma and cerebrospinal fluid (CSF) samples. To test the relative potency of cortisol vs. corticosterone on hypothalamic–pituitary–adrenal (HPA) feedback, subjects underwent a three‐phase, single‐blind, randomized study assessing the postmetyrapone ACTH response over 3 h to an intravenous bolus of vehicle, cortisol or corticosterone (0·15 mg/kg and 0·04 mg/kg).

Participants  Outpatients undergoing diagnostic lumbar puncture who were subsequently deemed to be free of disease. Feedback was tested in healthy male volunteers.

Measurements  Plasma and CSF corticosterone to cortisol ratio was calculated and the ACTH response over time after the bolus glucocorticoid measured.

Results  Plasma corticosterone : cortisol was 0·069 ± 0·007; CSF corticosterone : cortisol was 0·387 ± 0·050 (P < 0·001). Cortisol and corticosterone (0·15 mg/kg) suppressed ACTH vs. vehicle (P = 0·002); there was no difference between corticosterone and cortisol. The 0·04 mg/kg dose had no effect on ACTH despite supraphysiological plasma corticosterone levels.

Conclusions  Corticosterone contributes almost 40% of total active glucocorticoids (cortisol and corticosterone) in the CSF. Significant effects on HPA axis suppression were only seen with supraphysiological levels of corticosterone, suggesting that corticosterone is not important in this model of nonstress‐induced ACTH hypersecretion, in which the effect of cortisol predominates.
Growth hormone and insulin‐like growth factor binding protein‐1 responses to oral glucose in patients with primary hyperparathyroidism
Authors: Díez Juan J. , Grande Cristina , Méndez Javier , González‐Gancedo Pilar , Iglesias Pedro
Published: May 2006

Background  GH and IGFBP‐1 both play a role in glucose homeostasis.

Objective  To assess the GH and IGFBP‐1 responses to an oral glucose load and their relationship with glucose homeostasis in patients with primary hyperparathyroidism.

Design  A cross‐sectional study with a control group followed by a longitudinal study after parathyroidectomy.

Patients and Methods  We studied 15 patients with primary hyperparathyroidism (eight women, aged 59·6 ± 2·2 years) and nine healthy normocalcaemic controls. All subjects were ambulatory and were studied as outpatients. Glucose, insulin, GH and IGFBP‐1 were measured during an oral glucose (75 g) tolerance test (OGTT).

Results  Patients with hyperparathyroidism showed similar glucose responses to OGTT to those found in controls. Insulin responses were higher in patients (peak insulin 96·33 ± 9·71 mU/l) in relation to values found in controls (58·11 ± 9·03 mU/l; P < 0·01). Suppression of GH levels after OGTT was more marked in patients [nadir 0·03 (0·02–0·05) µg/l] than in normocalcaemic subjects [nadir GH 0·12 (0·08–0·42) µg/l; P = 0·002]. However, baseline IGFBP‐1 concentration and its decrease after glucose load were similar in patients and controls. Normalization of calcium levels after parathyroidectomy was not followed by any significant changes in glucose, insulin and GH responses to OGTT. The minimum concentration of IGFBP‐1 and the area under the curve (AUC) of IGFBP‐1 after OGTT were higher after parathyroidectomy (3·34 ± 0·69 µg/l and 8·94 ± 1·72 µg.h/l, respectively) than at diagnosis (2·19 ± 0·42 µg/l and 6·74 ± 1·28 µg.h/l, respectively; P < 0·05). No correlation was found between PTH, calcium and phosphorus concentrations and GH and IGFBP‐1 values in patients before or after normalization of calcium metabolism.

Conclusion  GH and IGFBP‐1 do not seem to be directly involved in the hyperparathyroidism‐associated changes in carbohydrate metabolism. The postoperative changes in the depression of IGFBP‐1 after OGTT remain to be elucidated.
The fate of effector CD8 T cells in vivo is controlled by the duration of antigen stimulation
Authors: Huang Xiaopei , Yang Yiping
Published: May 2006

What controls the fate of the T‐cell response remains incompletely defined. Gain of effector function facilitated by costimulation has been thought to be a crucial factor in determining the outcome of the T‐cell response, i.e. long‐term memory in the presence of costimulation versus tolerance induction in the absence of costimulation. In this study, we show that while costimulation or cognate CD4 helps to promote the acquisition of effector function during the initial phase of the CD8 T‐cell response, the fate of effector CD8 T cells is controlled by the duration of subsequent antigenic stimulation. Effector CD8 T cells differentiate into memory cells only after clearance of antigen, whereas in the presence of persistent antigen, effector CD8 T cells are tolerized. Furthermore, protective immunity against tumour cannot develop in the persisting antigen environment. These results suggest that removal of persisting antigen by other means might be a prerequisite for effective immunotherapy in cancer.
The Tribolium chitin synthase genes TcCHS1 and TcCHS2 are specialized for synthesis of epidermal cuticle and midgut peritrophic matrix
Authors: Arakane Y. , Muthukrishnan S. , Kramer K. J. , Specht C. A. , Tomoyasu Y. , Lorenzen M. D. , Kanost M. , Beeman R. W.
Published: May 2006

Functional analysis of the two chitin synthase genes, TcCHS1 and TcCHS2, in the red flour beetle, Tribolium castaneum, revealed unique and complementary roles for each gene. TcCHS1‐specific RNA interference (RNAi) disrupted all three types of moult (larval–larval, larval–pupal and pupal–adult) and greatly reduced whole‐body chitin content. Exon‐specific RNAi showed that splice variant 8a of TcCHS1 was required for both the larval‐pupal and pupal‐adult moults, whereas splice variant 8b was required only for the latter. TcCHS2‐specific RNAi had no effect on metamorphosis or on total body chitin content. However, RNAi‐mediated down‐regulation of TcCHS2, but not TcCHS1, led to cessation of feeding, a dramatic shrinkage in larval size and reduced chitin content in the midgut.
Antioxidant gene expression in the blood‐feeding fly Glossina morsitans morsitans
Authors: Munks R. J. L. , Sant’Anna M. R. V. , Grail W. , Gibson W. , Igglesden T. , Yoshiyama M. , Lehane S. M. , Lehane M. J.
Published: May 2006

We report the characterization of 11 antioxidant genes from the tsetse fly Glossina m. morsitans. Through similarity searches which detected homology we suggest that these genes consist of two superoxide dismutases (one with a putative signal peptide), three thioredoxin peroxidases (one with a putative signal peptide), three peroxiredoxins, one further signal peptide‐containing peroxidase with its closest similarity to a glutathione peroxidase, one catalase and one thioredoxin reductase. We describe the changes occurring in the expression levels of these genes during fly development, in different adult tissues, in the adult midgut through the digestive cycle and following trypanosome infection. Overall, nine of the 11 genes studied showed responses to changes in physiological circumstance, with the peroxiredoxin group showing the smallest variations throughout.
Transplanted children's experiences of daily living: Children's narratives about their lives following transplantation
Authors: Olausson B. , Utbult Y. , Hansson S. , Krantz M. , Brydolf M. , Lindström B. , Holmgren D.
Published: May 2006

Abstract: Transplantation is often an appropriate choice of treatment for children with end‐stage renal, liver, heart or lung disease. Over the last decade, mortality and morbidity figures have been relatively stable and quality of life fairly good in children who have undergone organ transplantation. Few studies however, have focused on the experiences of transplantation from the child's perspective. The child's view is an important factor when evaluating the ‘true’ outcome and quality of life after transplantation. The aim of the present study was to illuminate the meaning of transplanted children's experiences of daily living. Unstructured interviews were carried out with 18 children and adolescents, aged 4–18 yr, who had undergone organ transplantation. Their narratives were transcribed and interpreted using a phenomenologic–hermeneutic method inspired by the philosophy of Ricoeur. Two main themes emerged: Being satisfied with life, with the themes: being able to live a normal life; someone who cares; coping with one's new life; and being dissatisfied with life, with the themes: not being able to live a normal life; lacking someone who cares; not being respected; existential thoughts. Most of the children and adolescents were of the opinion that they lived a normal life while the rest strived to achieve a normal life. Social support and mental support were of great importance and, when lacking, had negative consequences. Multi‐disciplinary co‐operation between healthcare professionals and between the healthcare system, the school and the family is crucial in order to optimize the outcome and quality of life after organ transplantation in children.
Transfusion recipient identification
Authors: Pagliaro P. , Rebulla P.
Published: May 2006

Recent reports from different haemovigilance systems indicate that errors in the whole‐blood transfusion chain – from initial recipient identification to final blood administration – occur with a frequency of approximately 1 in 1000 events. Although mistakes occur also within the blood transfusion service, about two‐thirds of errors are associated with incorrect blood recipient identification at the patient's bedside. To prevent the potentially fatal consequences of such mistakes, specific tools have been developed, including patient identification bracelets with barcodes and/or radio frequency identification devices, mechanical or electronic locks preventing access to bags assigned to other patients, and palm computers suitable for transferring blood request and administration data from the patient's bedside to the blood transfusion service information system in real time. The effectiveness of these systems in preventing mistransfusion has been demonstrated in a number of studies.
Intussusception: Trends in clinical presentation and management
Authors: JUSTICE FRANCES A , AULDIST ALEX W , BINES JULIE E
Published: May 2006

Background:  The association of a rotavirus vaccine and intussusception has renewed interest in understanding the incidence, clinical presentation and outcome of intussusception.

Methods:  A retrospective chart review of all patients diagnosed with intussusception at Royal Children’s Hospital, Melbourne over a 6.5‐year period (1 January 1995–30 June 2001) was conducted using patients identified by a medical record database (ICD‐9‐CM code 560.0 1993–1997; ICD‐10‐CM code 56.1 1998–2001). Patient profile, clinical presentation, diagnosis methods, treatment and outcome were analyzed and compared to data previously reported on children with intussusception at the same hospital during 1962–1968.

Results:  The hospitalization rate for primary idiopathic intussusception increased marginally from 0.19 to 0.27 per 1000 live births during the period 1962–1968 to 1995–2001. Most patients (80%) were <12 months of age (median age 7 months, range 2–72 months). The combination of abdominal pain, lethargy and vomiting was reported in 78% of infants. Air enema confirmed the diagnosis of intussusception in 186 of 191 cases (97%) and air reduction was successful in most cases (82%). Factors associated with increased risk of intestinal resection included abdominal distension (32%), bowel obstruction on abdominal X‐ray (27%) and hypovolemic shock (40%). No mortality was observed in the present study.

Conclusions:  Over the past 40 years at Royal Children’s Hospital, Melbourne the hospitalization rate due to primary idiopathic intussusception has marginally increased from 0.19 to 0.27 per 1000 live births. Diagnosis and treatment using air enema has been highly successful, resulting in a reduction in patients requiring surgery and reduced hospital stays.
Marked pneumoperitoneum 3 weeks after percutaneous endoscopic gastrostomy
Authors: Chen Wunbill , Kawahara Hiromu , Takahasi Masakatsu , Matsushima Akihiro , Takase Shujiro
Published: May 2006

In November 2001, a 29‐year‐old woman was admitted to the hospital because of dysphagia due to an apallic state caused by cerebral anoxia. Nutritional support was maintained by nasogastric tube feeding for approximately 3 months. For improvement of the body state maintenance and quality of life, a percutaneous endoscopic gastrostomy (PEG) was performed. Three weeks after the PEG, the patient had a wound infection and abdominal distension appeared. Marked pneumoperitoneum was confirmed by radiological examination. No signs or symptoms of peritoneal inflammation developed. A gastrografin study showing that the PEG tube was in the stomach appropriately was checked, and it was noted to be firmly in place without extravasation of contrast. After suspension of the tube feeding and tube opening to decrease intragastric pressure, intravenous hyperalimentation was performed. The pneumoperitoneum resolved within 7 days. Forty days after the PEG, tube feeding was resumed successfully. No recurrence of pneumoperitoneum developed and the patient has remained stable until the present time. The etiology of this finding probably occurs by insufficient fixation of the PEG, causing leakage of air through the gastric wall which enters the free peritoneal space. We recommend that the external binder should be kept 1 cm away from the abdominal skin after the gastrostomy fistula has formed and matured, and periodic rotation of the tube to verify that the internal bumper is free and sufficiently fixed to the gastric wall. In the case of abdominal distension after PEG placement, a X‐ray examination and computed tomography (CT) scan with contrast medium would be helpful to ascertain pneumoperitoneum.
Posterior circulation ischemic stroke in Korean population
Authors: Lee J.‐H. , Han S.‐J. , Yun Y.‐H. , Choi H.‐C. , Jung S. , Cho S.‐J. , Yu K.‐H. , Lee S. M. , Hwang S.‐H. , Song H.‐K. , Kwon K. H. , Lee B.‐C.
Published: May 2006

To understand the characteristics of posterior circulation ischemic stroke (PCS) in the Korean population better, we retrospectively reviewed the data from the Hallym Stroke Registry (HSR). We analyzed the demographic features, risk factors, stroke subtypes, lesion distributions and clinical outcomes of 591 consecutive patients with PCS, enrolled in HSR between January 1996 and July 2002. PCS was 39.8% of all ischemic strokes. Mean age of PCS patients was 63.4 years and 55.7% were men. Hypertension was the most common risk factor (69.9%). However, potential cardioembolic sources were found only in 11.0%. The most frequent stroke subtype was large artery disease (50.0%), followed by small vessel disease (33.8%). Only 5.2% of patients were classified as affected with cardioembolism. The most common location of infarcts was in the middle territory (36.5%), followed by distal (28.1%), proximal (19.0%), and multiple territories (16.4%). The hospital mortality rate (4.1%) and discharge outcome of PCS were comparable with those of the anterior circulation stroke (ACS). In conclusion, the etiology and lesion topography of PCS in the Korean population appeared to be different from those of the Caucasians.
A genetic association study of dopamine metabolism‐related genes and chronic headache with drug abuse
Authors: Cevoli S. , Mochi M. , Scapoli C. , Marzocchi N. , Pierangeli G. , Pini L. A. , Cortelli P. , Montagna P.
Published: May 2006

To assess the role of dopamine metabolism‐related genes in the genetic liability to chronic headache with drug abuse (DA). We performed a genetic association study using four functional polymorphisms of the dopamine receptor 4 (DRD4), dopamine transporter (DAT), mono‐amino‐oxidase A (MAOA) and cathecol‐O‐methyl‐transferase (COMT) genes in 103 patients with chronic daily headache associated with DA (CDHDA). Control samples were 117 individuals without headache or DA (controls) and 101 patients with episodic migraine without aura and without DA (MO). No differences were found at the COMT and MAOA genes among the three groups investigated. Allele 4 of DRD4 was significantly overrepresented in patients with MO compared with both controls and CDHDA. Allele 10 of the DAT gene was significantly underrepresented in patients with CDHDA when compared with the MO group. Genetic variability at the DRD4 gene is involved in the predisposition to episodic MO but not to DA, while liability to CDHDA may involve genetic variability at the DAT gene in comparison with episodic MO.
An investigation into signal transduction mechanisms involved in insulin‐induced long‐term depression in the CA1 region of the hippocampus
Authors: Huang Chiung‐Chun , Lee Cheng‐Che , Hsu Kuei‐Sen
Published: May 2006

Recent work has demonstrated that brief application of insulin to hippocampal slices can induce a novel form of long‐term depression (insulin‐LTD) in the CA1 region of the hippocampus; however, the molecular details of how insulin triggers LTD remain unclear. Using electrophysiological and biochemical approaches in the hippocampal slices, we show here that insulin‐LTD (i) is specific to 3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptor‐ but not NMDA receptor‐mediated synaptic transmission; (ii) is induced and expressed postsynaptically but does not require the activation of ionotropic and metabotropic glutamate receptors; (iii) requires a concomitant Ca2+ influx through l‐type voltage‐activated Ca2+ channels (VACCs) and the release of Ca2+ from intracellular stores; (iv) requires the series of protein kinases, including protein tyrosine kinase (PTK), phosphatidylinositol 3‐kinase (PI3K), and protein kinase C (PKC); (v) is mechanistically distinct from low‐frequency stimulation‐induced LTD (LFS‐LTD) and independent on protein phosphatase 1/2 A (PP1/2 A) and PP2B activation; (vi) is dependent on a rapamycin‐sensitive local translation of dendritic mRNA, and (vii) is associated with a persistent decrease in the surface expression of GluR2 subunit. These results suggest that a PI3K/PKC‐dependent insulin signaling, which controls postsynaptic surface AMPA receptor numbers through PP‐independent endocytosis, may be a major expression mechanism of insulin‐LTD in hippocampal CA1 neurons.
Exogenous, but not endogenous nociceptin modulates mesolimbic dopamine release in mice
Authors: Koizumi Miwako , Midorikawa Naoko , Takeshima Hiroshi , Murphy Niall P.
Published: May 2006

The effect of nociceptin (an endogenous ligand of the ORL1 receptor) on mesolimbic dopamine release and simultaneous horizontal locomotion was studied in freely moving mice undergoing microdialysis of the nucleus accumbens. Intracerebroventricular (i.c.v.) administration of nociceptin (7 nmol) induced a long‐lasting suppression of mesolimbic dopamine release and horizontal locomotion in wild‐type but not ORL1 knockout mice. I.c.v. administration of the recently reported peptide nociceptin antagonist [Nphe1, Arg14, Lys15] nociceptin‐NH2(known also as UFP‐101, 5 nmol) completely abolished the suppressive effect of nociceptin on mesolimbic dopamine release. However, UFP‐101 administration alone induced a mild and lasting suppression of mesolimbic dopamine release in both wild‐type and ORL1 knockout mice that was magnified in ORL1 knockout mice by coadministration of nociceptin. UFP‐101 administration alone suppressed locomotion in both genotypes. These results confirm that the suppressive action of nociceptin on mesolimbic dopamine release is mediated entirely by the ORL1 receptor, and that UFP‐101 effectively antagonizes this action. However, the lack of a stimulatory effect of UFP‐101 in wild‐type mice indicates that despite being sensitive to exogenous nociceptin action, basal mesolimbic dopaminergic activity is not determined by endogenous nociceptin in mice.
Identification of GABAAreceptor subunit variants in midbrain dopaminergic neurons
Authors: Okada Hideki , Matsushita Natsuki , Kobayashi Kenta , Kobayashi Kazuto
Published: May 2006

Modulation of the activity of dopamine (DA)‐producing neurons by GABA plays an important role in the control of DA‐mediated brain functions. Ionotropic GABAAreceptors exist as heteropentametric structures assembling different subunits composed of various subtypes. However, the expression pattern of these subunits in DA neurons in the ventral midbrain has not been fully defined. In the present study, we investigated the subunit composition of GABAAreceptors in DA neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). We isolated DA neurons from the ventral midbrain of transgenic mice that express green fluorescent protein under the control of the tyrosine hydroxylase (TH) gene promoter and analyzed expression of various GABAAreceptor subunits in single cells by using the reverse transcription‐polymerase chain reaction. This analysis showed the presence of the transcripts encoding α2, α3, α4, β1, β3 and γ2 subunits in the isolated DA neurons. Double fluorescencein situhybridization with probes for TH and GABAAreceptor subunit mRNAs revealed the expression of these six subunits in the majority of DA neurons in the SNc and the VTA.
Involvement of ERK MAP kinase in endoplasmic reticulum stress in SH‐SY5Y human neuroblastoma cells
Authors: Arai Ken , Lee Sun‐Ryung , Van Leyen Klaus , Kurose Hitoshi , Lo Eng H.
Published: May 2006

Endoplasmic reticulum (ER) stress has increasingly come into focus as a factor contributing to neuronal injury. Although caspase‐dependent mechanisms have been implicated in ER stress, the signaling pathways involved remain unclear. In this study, we examined the role of the extracellular signal‐regulated kinase (ERK), a mitogen‐activated protein (MAP) kinase pathway that is highly conserved in many systems for balancing cell survival and death. Prolonged treatment of the human neuroblastoma cell line SH‐SY5Y with thapsigargin, an inducer of ER stress, increased cell death over 24–48 h, as measured by LDH release. Caspases were involved; increased levels of active caspase‐3 and cleaved caspase substrate PARP were detected, and treatment with Z‐VAD‐FMK reduced thapsigargin‐induced cytotoxicity. In contrast, inhibition of calpain was not protective, although calpain was activated following thapsigargin treatment. An early and transient phosphorylation of ERK1/2 occurred after thapsigargin‐induced ER stress, and targeting this pathway with the MEK inhibitors U0126 or PD98059 significantly reduced cell death. Similar cytoprotection was obtained against brefeldin A, another ER stress agent. However, protection against ER stress via ERK inhibition was not accompanied by amelioration of caspase‐3 activation, PARP cleavage, or DNA laddering. These data indicate that ERK may contribute to non‐caspase‐dependent pathways of injury after ER stress.
Differential Regulation of the Alcohol Dehydrogenase 1B (ADH1B) and ADH1C Genes by DNA Methylation and Histone Deacetylation
Authors: Dannenberg Luke O. , Chen Hui‐Ju , Tian Huijun , Edenberg Howard J.
Published: May 2006

Background: The human class I alcohol dehydrogenase (ADH) genes (ADH1A, ADH1B, and ADH1C) differ in expression during development and in various tissues. They are repressed in the HepG2 human hepatoma cell line. We hypothesized that epigenetic modifications play a role in this repression and that class I ADH gene expression would be enhanced upon global inhibition of DNA methylation and histone deacetylation.

Methods: Southern blotting was used to assess the methylation status of each class I ADH gene. HepG2 and HeLa cells were treated with either the DNA methylation inhibitor 5‐aza‐2′‐deoxycytidine (5‐aza‐dC), the histone deacetylase inhibitor Trichostatin A (TSA), or both in combination, and class I ADH gene expression was analyzed. Chromatin immunoprecipitation assays were performed to analyze histone H3 acetylation. Transient transfections and gel mobility shift assays were used to analyze the role that methylation plays in inhibiting transcription factor binding and promoter function.

Results: We show that the upstream regions of ADH1A, ADH1B, and ADH1C are methylated in HepG2 cells. 5‐Aza‐2′‐deoxycytidine treatment enhanced expression of both ADH1B and ADH1C. Trichostatin A treatment elevated expression of ADH1C. ADH1A expression was not stimulated by either 5‐aza‐dC or TSA. H3 histones associated with a methylated upstream region of ADH1B were hyperacetylated in TSA‐treated, but not in 5‐aza‐dC–treated, HepG2 cells. A methylated upstream region of ADH1C achieved histone H3 hyperacetylation upon either 5‐aza‐dC or TSA treatment. Methylation of the ADH1B proximal promoter in vitro decreased its activity to 54% and inhibited the binding of the upstream stimulatory factor.

Conclusions: These findings suggest that the class I ADH genes are regulated by epigenetic mechanisms in human hepatoma cells. The temporal and tissue‐specific expression of these genes may in part result from differences in epigenetic modifications and the availability of key transcription factors.
Effects of Chronic Alcohol Dependence and Chronic Cigarette Smoking on Cerebral Perfusion: A Preliminary Magnetic Resonance Study
Authors: Gazdzinski Stefan , Durazzo Timothy C. , Jahng Geon‐Ho , Ezekiel Frank , Banys Peter , Meyerhoff Dieter J.
Published: May 2006

Background: Although approximately 80% of individuals with alcohol use disorders are chronic smokers and despite reported associations between chronic cigarette smoking and lower cerebral perfusion in nonalcoholics, previous brain perfusion studies with alcoholics did not account for the potential effects of concurrent chronic cigarette smoking.

Methods: One‐week‐abstinent alcohol‐dependent individuals in treatment (ALC) [19 smokers (sALC) and 10 nonsmokers (nsALC)] and 19 healthy light drinking, nonsmoking control participants (nsLD) were scanned with a pulsed arterial spin labeling method to measure cerebral perfusion without an exogenous contrast agent. Studies were performed with 2 different postlabeling delay times (time from labeling pulse to the excitation pulse; PLD=1,500 ms and PLD=1,200 ms) to assess the potential effect of arterial blood transit time on the perfusion. Average gray matter (GM) and white matter (WM) perfusion for the frontal and parietal lobes were calculated for each hemisphere from voxels containing at least 90% GM and 100% WM.

Results: At PLD=1,500 ms, multivariate analyses compared ALC (combined sALC and nsALC) with nsLD (p=0.04) and contrasted sALC, nsALC, and nsLD (p=0.006). ALC, as a group, showed 13% lower frontal GM perfusion (p=0.005) and 8% lower parietal GM perfusion than nsLD (p=0.03). With ALC separated into smokers and nonsmokers, sALC showed 19% lower frontal GM perfusion (p=0.001) and 12% lower parietal GM perfusion than nsLD (p=0.004). In sALC, a higher number of cigarettes smoked per day was associated with lower perfusion. Overall, regional perfusion did not differ significantly between nsALC and nsLD. Results obtained with PLD=1,200 ms generally confirmed the 1,500 ms findings.

Conclusions: This study provides preliminary evidence that chronic cigarette smoking adversely affects cerebral perfusion in frontal and parietal GM of 1‐week‐abstinent alcohol‐dependent individuals. These results are in line with our spectroscopic and structural magnetic resonance studies that suggest chronic cigarette smoking compounds the detrimental effects of alcohol dependence on brain neurobiology.
Effects of Alcohol on Sleep and the Sleep Electroencephalogram in Healthy Young Women
Authors: Van Reen Eliza , Jenni Oskar G. , Carskadon Mary A.
Published: May 2006

Background: Although the association between sleep and alcohol has been of interest to scientists for decades, the effects of alcohol on sleep and sleep electroencephalogram (EEG) have not been extensively studied in women. Our specific aim was to determine whether sleep stage variables and/or spectral characteristics of the sleep EEG are altered by alcohol administration in women.

Methods: Changes of sleep and the sleep EEG were investigated after administration of a moderate dose of alcohol (0.49 g/kg) in the hour before bedtime compared with placebo in young healthy women. After approximately 2 weeks at home on a fixed 8.5‐ or 9‐hour stabilization sleep schedule, sleep was continuously recorded by polysomnography for 3 consecutive nights [adaptation, placebo, alcohol (mean breath alcohol concentration 0.043 g/% before bedtime)] in the laboratory in 7 women (ages 22–25, mean=23.5, SD=1 year). Sleep stages were scored according to conventional criteria. Electroencephalogram power spectra of the bipolar derivations Fz/Cz (anterior) and Pz/Oz (posterior) were calculated using a fast Fourier transform routine.

Results: Only few changes in sleep and the sleep EEG were observed. Across the entire night rapid eye movement (REM) sleep decreased, while minutes of stage 4 sleep were increased in the first 2‐hour interval on alcohol nights compared with placebo nights. Spectral analysis of the EEG showed increased power in the α range (9–11 Hz) during all‐night non‐REM (NREM) sleep in anterior derivations after alcohol compared with placebo. Differences in spectral EEG power were also present in 2‐hour intervals of NREM sleep; in particular, EEG power was increased on the alcohol night for frequency bins within the α range in anterior derivations and within the δ range (3–4 Hz) in posterior derivations during the initial part of the night.

Conclusions: A moderate dose of alcohol just before bedtime resulted in a short‐lived increase in sleep intensity. A limitation of the study, however, was that only a single dose of alcohol was used to examine the effects of alcohol on sleep.
The Epidemiology of Drinking Among Women of Child‐Bearing Age
Authors: Caetano Raul , Ramisetty‐Mikler Suhasini , Floyd Louise R. , McGrath Christine
Published: May 2006

Objectives:To estimate the prevalence of drinking, binge drinking (4 or more drinks), and alcohol abuse and dependence and to identify predictors of heavier drinking among women of child‐bearing age (18–44 years).

Methods:Subjects are part of a national multistage random sample from the 2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

Results:Binge drinking, abuse, and dependence are higher in younger (<30 years) pregnant and nonpregnant women. Among pregnant women, binge drinking is highest among Whites; alcohol abuse and dependence rates are relatively low and similar in all racial/ethnic groups. Among nonpregnant women, Whites and mixed race women have the highest rates of binge drinking. Alcohol abuse and dependence are highest among Native Hawaiian/Pacific Islanders, followed by Native American/Alaska Native women. Women who are White, younger (21–29 years), single, or cohabiting and with a higher income (>$40,000) are at a higher risk for heavier drinking.

Conclusions:Drinking and heavier drinking remain at high levels among women of child‐bearing age. Prevention efforts must be comprehensive and should target pregnant women who are drinking and those who could become pregnant and are drinking at high‐risk levels.
Both Global Gray Matter Volume and Regional Gray Matter Volume Negatively Correlate with Lifetime Alcohol Intake in Non–Alcohol‐Dependent Japanese Men: A Volumetric Analysis and a Voxel‐Based Morphometry
Authors: Taki Yasuyuki , Kinomura Shigeo , Sato Kazunori , Goto Ryoi , Inoue Kentaro , Okada Ken , Ono Shuichi , Kawashima Ryuta , Fukuda Hiroshi
Published: May 2006

Background: Non–alcohol‐dependent heavy drinkers, as well as alcohol‐dependent individuals, show brain atrophy. The purpose of this study was to evaluate whether there are correlations between global and regional gray matter volumes and the lifetime alcohol intake using volumetric analysis and voxel‐based morphometry (VBM) among Japanese non‐alcohol–dependent male individuals.

Methods: High‐resolution three‐dimensional magnetic resonance images were acquired from 405 Japanese non‐alcohol–dependent male individuals. The collected images were normalized, segmented for volumetric analysis, and additionally smoothed for VBM. For volumetric analysis, the partial correlation coefficient was estimated between the gray matter ratio, which represents the percentage of gray matter volume in the intracranial volume, and the lifetime alcohol intake adjusted for the age of each subject. Multiple regression analysis was performed among regional gray matter volume, lifetime alcohol intake, and age using VBM.

Results: Volumetric analysis revealed that gray matter ratio showed a negative correlation with the lifetime alcohol intake adjusted for age (p=0.059, partial correlation coefficient=−0.091). The VBM revealed that the gray matter volumes of the bilateral middle frontal gyri showed a significant negative correlation with the lifetime alcohol intake adjusted for age and systolic blood pressure (left side, p=0.006, Z=4.77; right side, p=0.023, Z=4.45, and p=0.046, Z=4.27).

Conclusions: Our study suggests that non‐alcohol–dependent Japanese male individuals show that both global gray matter volume and regional gray matter volume have negative correlations with the lifetime alcohol intake. Our study may contribute to clarifying the mechanism underlying the brain structural changes because of alcohol influence in healthy non‐alcohol–dependent individuals.
Genetically Engineered Plants, Endangered Species, and Risk: A Temporal and Spatial Exposure Assessment for Karner Blue Butterfly Larvae and Bt Maize Pollen
Authors: Peterson Robert K. D. , Meyer Steven J. , Wolf Amy T. , Wolt Jeffrey D. , Davis Paula M.
Published: May 2006

Genetically engineered maize (Zea mays) containing insecticidal endotoxin proteins from Bacillus thuringiensis (Bt) δ‐endotoxin proteins has been adopted widely in the Midwestern United States. The proteins are toxic to several lepidopteran species and because a variety of maize tissues, including pollen, may express the endotoxins, the probability of exposure to nontarget species, including endangered species, needs to be understood. The objective of this study was to assess the potential temporal and spatial exposure of endangered Karner blue butterfly larvae (Lycaeides melissa samuelis) to Bt maize pollen in Wisconsin using probabilistic exposure techniques and geographic information systems analysis. Based on degree‐day modeling of butterfly phenology and maize pollen shed, there is some potential for temporal exposure of larvae to maize pollen. However, in the majority of years and locations, maize pollen shed most likely will occur after the majority of larval feeding on wild lupine (Lupinus perennis). The spatial analysis indicates that some Karner blue butterfly populations occur in close proximity to maize fields, but in the vast majority of cases the butterfly's host plant and maize fields are separated by more than 500 m. A small number of potential or existing Karner blue butterfly sites are located near maize fields, including sites in two of the four counties where temporal overlap is most likely. The exposure assessment indicates that these two counties should receive the highest priority to determine if Karner blue butterfly larvae are actually at risk and then, if needed, to reduce or prevent exposure.
Effects of CnTAB Chain Length and Concentration on the Rheological Properties of Aqueous Suspensions of Alkylated Alumina Powders
Authors: Bock R. M. , Lange F. F.
Published: May 2006

Alumina particles have successfully been alkylated via a condensation reaction between surface hydroxide sites and different, long chain alcohol molecules, specifically decanol, dodecanol, and octadecanol. These hydrophobic particles have been successfully dispersed in water using different CnTAB surfactant molecules, where n=10, 12, 14, 16. The effect of the length of the surfactant molecule and its concentration was quantified with rheological experiments. Rheology and conductivity measurements were used to determine the minimum amount of the surfactant needed to disperse the alkylated powder. Slurries formulated with the alkylated powder and the proper amount of CnTAB exhibited Newtonian rheology for n≥10. ξ potential measurements showed that the surface charge on the particles was always positive confirming that the CnTAB molecules, with a positive head group, surrounded the alkylated particles. Such powder did not have an isoelectric point. In addition, the Newtonian behavior of the alkylated‐alumina/CnTAB slurry systems were independent of pH.