bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal protein restriction leads to early life alterations in the expression of key molecules involved in the aging process in rat offspring
Authors: Martin-Gronert Malgorzata S. , Tarry-Adkins Jane L. , Cripps Roselle L. , Chen Jian-Hua , Ozanne Susan E.
Published: December 2007

Recent findings demonstrate that nutrition during the fetal and neonatal periods can affect the life span of an organism. Our previous studies in rodents using a maternal low protein diet have shown that limiting protein and growth during lactation [postnatal low protein (PLP group)] increases longevity, while in utero growth restriction (IUGR) followed by “catch up growth” (recuperated group) shortens life span. The aim of this study was to investigate mechanisms in early postnatal life that could underlie these substantial differences in longevity. At weaning, PLP animals had improved insulin sensitivity as suggested by lower concentrations of insulin required to maintain concentrations of glucose similar to those of the control group and significant upregulation of insulin receptor-β, IGF-1 receptor, Akt1, Akt2, and Akt phosphorylated at Ser 473 in the kidney. These animals also had significantly increased SIRT1 (mammalian sirtuin) expression. Expression of the antioxidant enzymes catalase, CuZnSOD, and glutathione peroxidase-1 was elevated in these animals. In contrast, recuperated animals had a significantly increased fasting glucose concentration, while insulin levels remained comparable to those of the control group suggesting relative insulin resistance. MnSOD expression was increased in these animals. These data suggest that early nutrition can lead to alterations in insulin sensitivity and antioxidant capacity very early in life, which may influence life span.
Presynaptic Release Probability Is Increased in Hippocampal Neurons From ASIC1 Knockout Mice
Authors: Cho Jun-Hyeong , Askwith Candice C.
Published: December 2007

Acid-sensing ion channels (ASICs) are H+-gated channels that produce transient cation currents in response to extracellular acid. ASICs are expressed in neurons throughout the brain, and ASIC1 knockout mice show behavioral impairments in learning and memory. The role of ASICs in synaptic transmission, however, is not thoroughly understood. We analyzed the involvement of ASICs in synaptic transmission using microisland cultures of hippocampal neurons from wild-type and ASIC knockout mice. There was no significant difference in single action potential (AP)–evoked excitatory postsynaptic currents (EPSCs) between wild-type and ASIC knockout neurons. However, paired-pulse ratios (PPRs) were reduced and spontaneous miniature EPSCs (mEPSCs) occurred at a higher frequency in ASIC1 knockout neurons compared with wild-type neurons. The progressive block of NMDA receptors by an open channel blocker, MK-801, was also faster in ASIC1 knockout neurons. The amplitude and decay time constant of mEPSCs, as well as the size and refilling of the readily releasable pool, were similar in ASIC1 knockout and wild-type neurons. Finally, the release probability, which was estimated directly as the ratio of AP-evoked to hypertonic sucrose-induced charge transfer, was increased in ASIC1 knockout neurons. Transfection of ASIC1a into ASIC1 knockout neurons increased the PPRs, suggesting that alterations in release probability were not the result of developmental compensation within the ASIC1 knockout mice. Together, these findings demonstrate that neurons from ASIC1 knockout mice have an increased probability of neurotransmitter release and indicate that ASIC1a can affect presynaptic mechanisms of synaptic transmission.
Predictors of Treatment Response for Depression and Inadequate Social Support – The ENRICHD Randomized Clinical Trial
Authors: Cowan Marie J. , Freedland Kenneth E. , Burg Matthew M. , Saab Patrice G. , Youngblood Marston E. , Cornell Carol E. , Powell Lynda H. , Czajkowski Susan M.
Published: December 2007

Objective: To determine whether the ‘dose’ of treatment exposure, delivery of specific components of cognitive behavior therapy (CBT), patient adherence and/or use of antidepressants predict favorable depression and social support outcomes after 6 months of cognitive behavioral treatment. Methods: Secondary analyses of the intervention arm of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial involving persons with acute myocardial infarction (MI): n = 641 for the depression outcomes and n = 523 for the social support outcomes. The outcome measures were, for depression: the Beck Depression Inventory (BDI) and Hamilton Rating Scale for Depression (HAM-D); for social support: the ENRICHD Social Support Instrument (ESSI) and Perceived Social Support Scale (PSSS). Results: Better depression outcomes (measured by the BDI) were receiving a high number of depression-specific intervention components, p < 0.01, and completing a high proportion of homework assignments, p < 0.02. Better depression outcomes (measured by the HAM-D) were receiving a high number of the social communication and assertiveness components of the intervention, p < 0.01, and completing a high proportion of homework assignments, p < 0.01. Better social support outcomes (measured by the ESSI and PSSS) were predicted by membership in a racial or ethnic minority group, p < 0.02 and p < 0.01, respectively; and by completing a higher number of homework assignments, p < 0.01 and p < 0.05, respectively. Delivery of the social communication and assertiveness components of the intervention was an independent predictor of a worse social support outcome, p < 0.01 (measured by the PSSS). Conclusions: The standard components of CBT for depression are useful in treating comorbid depression in post-MI patients. Working on communication skills may help to improve depression but not necessarily social support outcomes in this patient population, while adherence to cognitive-behavioral homework assignments is important for both outcomes. Other components of the ENRICHD intervention that were designed to improve social support had no discernible effects on outcomes. Intervention refinements may be needed in order to achieve better results in future post-MI clinical trials. A greater emphasis on CBT homework adherence could improve both depression and social support outcomes.
Vascular Endothelial Growth Factor Partially Inhibits the Trastuzumab-Mediated Antibody-Dependent Cellular Cytotoxicity of Human Monocytes
Authors: Mimura Kousaku , Kono Koji , Takahashi Akihiro , Kawaguchi Yoshihiko , Mizukami Yoshiki , Fujii Hideki
Published: December 2007

Background: Vascular endothelial growth factor (VEGF) is produced by almost all cancer cells and VEGF receptor 1 (R1) (Flt-1) is abundantly expressed on human monocytes. In the present study, we investigated whether VEGF affects the antibody-dependent cell-mediated cytotoxicity (ADCC) of human monocytes mediated by trastuzumab. Methods: HER-2-expressing tumor cell lines (MKN-7, TE-4 and SKOV-3) were evaluated for trastuzumab-mediated ADCC of human monocytes in the presence of VEGF165. The trastuzumab-mediated, monocyte-derived ADCC were treated with the anti-human blocking VEGF R1 or VEGF R2 mAb. VEGF-induced intracellular signaling on monocytes was quantified with ELISA kits. Results: VEGF partially inhibited the ADCC of human monocytes mediated by trastuzumab. The VEGF-induced deficiency of human monocytes for ADCC was completely recovered by the anti-human blocking VEGF R1 mAb, while the anti-VEGF R2 blocking mAb did not have any effect. Furthermore, VEGF treatment enhanced the phospho-Erk 1/2 in human monocytes. Conclusion: VEGF partially inhibited the ADCC of human monocytes mediated by trastuzumab, and this inhibition was mainly mediated by VEGF R1 (Flt-1).
Creatinine-Based Glomerular Filtration Rates and Microalbuminuria for Detecting Metabolic Abnormalities in US Adults: The National Health and Nutrition Examination Survey 2003–2004
Authors: Foley Robert N. , Wang Changchun , Ishani Areef , Ibrahim Hassan N. , Collins Allan J.
Published: December 2007

Background/Aims: Guidelines suggest searching for metabolic complications of chronic kidney disease when glomerular filtration rates (GFR) or urinary albumin tests are abnormal. This study aimed to quantify diagnostic test characteristics of these measures for detecting metabolic abnormalities. Methods: Subjects were participants aged ≧20 years (n = 7,778) in the US National Health and Nutrition Examination Survey 2003–2004. Low GFR was defined as creatinine-based estimate <60 ml/min per 1.73 m2; abnormal urinary albumin-creatinine ratio as ≧20 mg/dl in men, ≧30 mg/dl in women; and metabolic abnormalities as abnormal potassium, hemoglobin, bicarbonate, phosphorus, or parathyroid hormone levels. Results: Of adults, 5.66% had low GFR and 8.14% abnormal urinary albumin-creatinine ratio. Overall, 15.09% had ≧ one metabolic abnormality, as did 34.07% with low GFR (p < 0.0001) and 24.27% with abnormal urinary albumin-creatinine ratio (p = 0.0021). Considered as a diagnostic test, the sensitivity, specificity, and positive and negative predictive values of low GFR for detecting ≧1 metabolic abnormality were 0.13, 0.96, 0.34, and 0.86, respectively. Corresponding values for abnormal urinary albumin-creatinine ratio were 0.13, 0.92, 0.24, and 0.86. Conclusions: A policy of searching for metabolic complications in every adult with low GFR or microalbuminuria has limited diagnostic yield.
Pharmacokinetics and Metabolism of All‐trans‐and 13‐cis‐Retinoic Acid in Pulmonary Emphysema Patients
Authors: Muindi Josephi R. , Roth Michae D. , Wise Rober A. , Connett Joh E. , O'Connor Georg T. , Ramsdell Jo W. , Schluger Nei W. , Romkes Marjorie , Branch Rober A. , Sciurba Frank C. ,   FORTE Study Investigators
Published: December 2007

Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers—all‐trans‐retinoic acid (ATRA) and 13‐cis‐retinoic acid (13‐cRA)—in subjects with emphysema, evaluated strategies to overcome self‐induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low‐dose ATRA (1 mg/kg/day, n = 21), or high‐dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13‐cRA (1 mg/kg/day, n = 40). High‐dose ATRA produced the highest peak plasma ATRA Cmax. However, at follow‐up, plasma ATRA Cmaxwas significantly decreased from baseline in subjects whose day 1 levels exceeded 100 ng/mL (P< .0001). In contrast, administration of 13‐cRA produced lower plasma ATRA Cmax(<100 ng/mL), but the levels were significantly higher at follow‐up than those on day 1 (P< .001). Plasma ATRA levels as determined on day 1 correlated with changes in pulmonary diffusing capacity at 6 months, consistent with concentration‐dependent biologic effects (r2= −0.25). The authors conclude that intermittent therapy with high‐dose ATRA produced the greatest ATRA exposure, but alternative approaches for limiting self‐induced ATRA catabolism should be sought.
Darunavir/Ritonavir Pharmacokinetics Following Coadministration With Clarithromycin in Healthy Volunteers
Authors: Sekar Vanith J. , Spinosa‐Guzman Sabrina , Paepe El D. , Pauw Martin D. , Vangeneugden Tony , Lefebvre Eric , Hoetelmans Richar M. W.
Published: December 2007

This study investigated the steady‐state pharmacokinetic interaction between the HIV protease inhibitor, darunavir (TMC114), administered with low‐dose ritonavir (darunavir/ritonavir), and clarithromycin in HIV‐negative healthy volunteers. In a 3‐way crossover study, 18 individuals received darunavir/ritonavir 400/100 mg bid, clarithromycin 500 mg bid, and darunavir/ritonavir 400/100 mg bid plus clarithromycin 500 mg bid in 3 separate sessions for 7 days, with a washout period of at least 7 days between treatments. Pharmacokinetic assessment was performed on day 7. Safety and tolerability of the study medication were monitored throughout. Coadministration of darunavir/ritonavir with clarithromycin resulted in a reduction in darunavir maximum plasma concentration (Cmax) and area under the curve from administration until 12 hours postdose (AUC12 h) of 17% and 13%, respectively. Ritonavir Cmax and AUC12 h were unchanged. During coadministration with darunavir/ritonavir, clarithromycin Cmax and AUC12 h increased by 26% and 57%, respectively; 14‐hydroxy‐clarithromycin plasma concentrations were reduced to below the lower limit of quantification (<50 ng/mL). The study medication was generally well tolerated. Based on these pharmacokinetic findings, neither clarithromycin nor darunavir/ritonavir dose adjustments are necessary when clarithromycin is coadministered with darunavir/ritonavir.
Comorbid Depression in Adult Oncology
Authors: Jackson Cherry W. , Jackson Kenneth H.
Published: December 2007

Depression is a common medical disorder that frequently occurs comorbidly with other medical disorders. Unfortunately, depression often goes unrecognized either due to somatic symptoms, which may be confused with the physical effects of cancer, chemotherapy, and radiation, or due to the belief that depression is a normal part of the cancer diagnosis. A combination of pharmacotherapy and psychotherapy is the most effective treatment for depression in cancer patients. Selective serotonin reuptake inhibitors are the most frequently used antidepressants. Selection of an antidepressant should be based on the patient's symptoms. Recognition and treatment of depressive symptoms in oncology patients is very important, and effective treatment may improve the oncology patients' quality of life and may also affect survival.
Observations on Managing Medical Patients With Borderline Personality
Authors: Nordgren J. Chris
Published: December 2007

Patients with borderline personality present pharmacists with significant clinical management challenges in hospital and medical clinic settings. These challenges include patient behaviors that interfere with treatment, burn out providers, and interfere with other patients' treatment. Recognizing the dynamics of borderline personality and the common pitfalls of caring for these patients in a medical setting is essential to effectively managing their treatment.
Screening for Colorectal Cancer in Elderly Persons
Authors: Maheshwari Shail , Patel Tushar , Patel Parita
Published: December 2007

Objective: The aim of this study was to quantify the impact of age on the potential benefits of screening for colorectal cancer. Method: Life-table analysis of the risks of dying from colorectal cancer or from all other causes was performed. The impact of prematurely stopping screening was compared to the maximal potential benefit expected from lifelong screening. Results: The relative proportion of deaths from colorectal cancer compared to all other causes was greatest at the age of 62 and diminished thereafter. A total of 80% of the maximal benefit from screening was achieved by screening till the age of 82. The impact of prematurely stopping screening varied with gender and race. Discussion: The maximal societal benefit will be achieved by screening at younger ages because of competing causes of mortality among older people. Gender and ethnicity should be considered in individual decisions to stop screening at a given age.
Employment information needs of Chinese young adults in Sheffield
Authors: Webber Sheila , Wen Zhu
Published: December 2007

The authors investigate the question of how Chinese young adults (18—26 years old) in Sheffield seek employment information, and what sources and channels they use. Data collection was via a semi-structured questionnaire (78 responses) and via nine follow-up interviews with respondents to the questionnaire. Fifty-five percent felt that they had encountered barriers when seeking information. The channel which the largest number of employed respondents had used to find their current job was newspapers/magazines, and this was also the channel that the largest number would recommend to a friend. However, the Internet was respondents' favourite and most widely used channel and they perceived both advantages and disadvantages in using it for job seeking. We found that, as in previous studies, affective issues and personal connections were influential in choice of job, and that luck was also perceived as a factor. Recommendations for ways in which services could be better tailored to Chinese young people's needs are made.
Review: How Do Hospital Organizational Structure and Processes Affect Quality of Care?
Authors: Hearld Larry R. , Alexander Jeffrey A. , Fraser Irene , Jiang H. Joanna
Published: December 2007

Interest in organizational contributions to the delivery of care has risen significantly in recent years. A challenge facing researchers, practitioners, and policy makers is identifying ways to improve care by improving the organizations that provide this care, given the complexity of health care organizations and the role organizations play in influencing systems of care. This article reviews the literature on the relationship between the structural characteristics and organizational processes of hospitals and quality of care. The review uses Donabedian's structure—process—outcome and level of analysis frameworks to organize the literature. The results of this review indicate that a preponderance of studies are conducted at the hospital level of analysis and are predominantly focused on the organizational structure—quality outcome relationship. The article concludes with recommendations of how health services researchers can expand their research to enhance one's understanding of the relationship between organizational characteristics and quality of care.
Integrative Medicine and Clinical Practice: Diagnosis and Treatment Strategies
Authors: Salkeld Ellen J.
Published: December 2007

Although the definition of integrative, complementary and alternative medicine (CAM) remains under discussion by members of the clinical community, the medical literature contains few reports on the process of integration of CAM methods into clinical practice. This report describes a study of the clinical approach of holistic clinicians in one clinic over 14 months, based on selection of diagnoses and therapies. Methods included observations of clinical encounters and physician interviews. Findings suggest that physicians initially selected diagnoses and treatments that reflected their biomedical orientation. Subsequent diagnoses incorporated energy healing, homeopathy, and spiritual hypnotherapy. This gradual introduction of CAM modalities into practice allowed physicians to address body—mind—emotional and spiritual causes of disease. Incorporation of CAM modalities into clinical practice by these biomedically trained physicians with additional CAM experience gave them flexibility to offer patients different treatment options and alleviated the need to reconcile conflicting theories of disease etiology.
Mindfulness Meditation May Lessen Anxiety, Promote Social Skills, and Improve Academic Performance Among Adolescents With Learning Disabilities
Authors: Beauchemin James , Hutchins Tiffany L. , Patterson Fiona
Published: December 2007

Students with learning disabilities (LD; defined by compromised academic performance) often have higher levels of anxiety, school-related stress, and less optimal social skills compared with their typically developing peers. Previous health research indicates that meditation and relaxation training may be effective in reducing anxiety and promoting social skills. This pilot study used a pre—post no-control design to examine feasibility of, attitudes toward, and outcomes of a 5-week mindfulness meditation intervention administered to 34 adolescents diagnosed with LD. Postintervention survey responses overwhelmingly expressed positive attitudes toward the program. All outcome measures showed significant improvement, with participants who completed the program demonstrating decreased state and trait anxiety, enhanced social skills, and improved academic performance. Although not directly assessed, the outcomes are consistent with a cognitive-interference model of learning disability and suggest that mindfulness meditation decreases anxiety and detrimental self-focus of attention, which, in turn, promotes social skills and academic outcomes.
Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification
Authors: Gadner Helmut , Grois Nicole , Pötschger Ulrike , Minkov Milen , Aricò Maurizio , Braier Jorge , Broadbent Valerie , Donadieu Jean , Henter Jan-Inge , McCarter Robert , Ladisch Stephan
Published: December 2007

Multisystem Langerhans cell histiocytosis (MS-LCH) is associated with high mortality when patients have risk organ involvement (RO+) or are younger than 2 years. In an international randomized trial, LCH-II, we intensified their treatment: arm A consisted of 6 weeks of daily prednisone and weekly vinblastine followed by 18 weeks of daily 6-mercaptopurine with vinblastine/prednisone pulses; etoposide was added in arm B. Considering all 193 randomized risk patients, there were similar outcomes: rapid (6 weeks) response (arm A vs arm B: 63%/71%), 5-year survival probability (74%/79%), disease reactivation frequency (46%/46%), and permanent consequences (43%/37%). However, (1) patients younger than 2 years without RO involvement (RO−) had 100% survival and uniformly high (> 80%) rapid response, (2) RO+ patients not responding within 6 weeks had highest mortality, and (3) importantly, the more intensive arm B reduced mortality in RO+ patients (relative hazard rate, accounting for differences in risk organ involvement, of 0.54; 95% CI = 0.29-1.00). Finally, comparison of RO+ patients in LCH-I and LCH-II confirmed that increasing treatment intensity increased rapid responses (from 43% in arm A LCH-I to 68% in arm B LCH-II; P = .027) and reduced mortality (from 44% in arm A LCH-I to 27% in arm B LCH-II; P = .042). We conclude that intensified treatment significantly increases rapid response and reduces mortality in risk MS-LCH. This trial was registered at http://www.controlled-trials.com as no. ISRCTN57679341.
Oxidative stress as a risk factor for osteoporosis in elderly Mexicans as characterized by antioxidant enzymes
Authors: Sánchez-Rodríguez Martha A , Ruiz-Ramos Mirna , Correa-Muñoz Elsa , Mendoza-Núñez Víctor Manuel
Published: December 2007

Background

Oxidative stress (OxS) has recently been linked with osteoporosis; however, we do not know the influence of OxS as an independent risk factor for this disease.

Methods

We conducted a case-control study in 94 subjects ≥60 years of age, 50 healthy and 44 with osteoporosis. We measured total antioxidant status, plasma lipid peroxides, antioxidant activity of superoxide dismutase and glutathione peroxidase (GPx), and calculated the SOD/GPx ratio. Bone mineral density was obtained at the peripheral DXA in calcaneus using a portable Norland Apollo Densitometer®. Osteoporosis was considered when subjects had a BMD of 2.5 standard deviations or more below the mean value for young adults.

Results

GPx antioxidant activity was significantly lower in the group of subjects with osteoporosis in comparison with the group of healthy subjects (p< 0.01); in addition, the SOD/GPx ratio was significantly higher in the group of individuals with osteoporosis (p< 0.05). In logistic regression analysis, we found OxS to be an independent risk factor for osteoporosis (odds ratio [OR] = 2.79; 95% confidence interval [95% CI] = 1.08–7.23;p= 0.034).

Conclusion

Our findings suggest that OxS is an independent risk factor for osteoporosis linked to increase of SOD/GPx ratio.
The Internet for weight control in an obese sample: results of a randomised controlled trial
Authors: McConnon Áine , Kirk Sara FL , Cockroft Jennie E , Harvey Emma L , Greenwood Darren C , Thomas James D , Ransley Joan K , Bojke Laura
Published: December 2007

Background

Rising levels of obesity coupled with the limited success of currently available weight control methods highlight the need for investigation of novel approaches to obesity treatment. This study aims to determine the effectiveness and cost-effectiveness of an Internet-based resource for obesity management.

Methods

A randomised controlled trial conducted in a community setting, where obese volunteers (n = 221) were randomly assigned to Internet group (n = 111) or usual care group (n = 110). Objective measures of weight and height were obtained. Questionnaires were used to collect dietary, lifestyle, physical activity and quality of life data. Data were collected at baseline, six months and 12 months.

Results

Data were collected on 54 (49%) participants in the Internet group and 77 (70%) participants in the usual care group at 12 months. Based on analysis conducted on all available data, the Internet group lost 1.3 kg, compared with 1.9 kg weight loss in the usual care group at 12 months, a non-significant difference (difference = 0.6 kg; 95% CI: -1.4 to 2.5, p = 0.56). No significant differences in change in secondary outcome measures between the two groups at six or 12 months were revealed. Total costs per person per year were higher in the Internet group than the usual care group (£992.40 compared to £276.12), primarily due to the fixed costs associated with setting up the website, and QALYs were similar (0.78 and 0.77) for both groups.

Conclusion

This trial failed to show any additional benefit of this website in terms of weight loss or secondary outcome measures compared with usual care. High attrition and low compliance limits the results of this research. The results suggest that the Internet-based weight control resource was not a cost-effective tool for weight loss in the obese sample studied.

Trail Registration

ISRCTN 58621669
The development of a theory-based intervention to promote appropriate disclosure of a diagnosis of dementia
Authors: Foy Robbie , Francis Jillian J , Johnston Marie , Eccles Martin , Lecouturier Jan , Bamford Claire , Grimshaw Jeremy
Published: December 2007

Background

The development and description of interventions to change professional practice are often limited by the lack of an explicit theoretical and empirical basis. We set out to develop an intervention to promote appropriate disclosure of a diagnosis of dementia based on theoretical and empirical work.

Methods

We identified three key disclosure behaviours: finding out what the patient already knows or suspects about their diagnosis; using the actual words 'dementia' or 'Alzheimer's disease' when talking to the patient; and exploring what the diagnosis means to the patient. We conducted a questionnaire survey of older peoples' mental health teams (MHTs) based upon theoretical constructs from the Theory of Planned Behaviour (TPB) and Social Cognitive Theory (SCT) and used the findings to identify factors that predicted mental health professionals' intentions to perform each behaviour. We selected behaviour change techniques likely to alter these factors.

Results

The change techniques selected were: persuasive communication to target subjective norm; behavioural modelling and graded tasks to target self-efficacy; persuasive communication to target attitude towards the use of explicit terminology when talking to the patient; and behavioural modelling by MHTs to target perceived behavioural control for finding out what the patient already knows or suspects and exploring what the diagnosis means to the patient. We operationalised these behaviour change techniques using an interactive 'pen and paper' intervention designed to increase intentions to perform the three target behaviours.

Conclusion

It is feasible to develop an intervention to change professional behaviour based upon theoretical models, empirical data and evidence based behaviour change techniques. The next step is to evaluate the effect of such an intervention on behavioural intention. We argue that this approach to development and reporting of interventions will contribute to the science of implementation by providing replicable interventions that illuminate the principles and processes underlying change.
Cdc42 and the Ste20-like kinase Don3 act independently in triggering cytokinesis in Ustilago maydis
Authors: Böhmer Christian , Böhmer Maik , Bölker Michael , Sandrock Björn
Published: December 2007

In the dimorphic fungus Ustilago maydis the Rho-family GTP-binding protein Cdc42 and the Ste20-like kinase Don3 are both essential for triggering cell separation during cytokinesis. Since Don3 does not contain a Cdc42/Rac interaction and binding domain (CRIB), it is unclear how Cdc42 and Don3 cooperate in the regulation of cytokinesis. To analyse the regulatory network we generated an analogue-sensitive Don3 variant (Don3-as) that allows specific inhibition in vivo. The engineered kinase Don3M157A is fully active in vivo and can be specifically inhibited by low concentrations of the ATP-analogue NA-PP1. Inhibition of the Don3-as kinase activity immediately blocked cell separation resulting in the formation of clusters of nonseparated cells. Covalent labelling of cell wall proteins showed that, upon release of inhibition, cytokinesis was resumed instantaneously in all cells. By sequentially activating Don3 and Cdc42 we were able to demonstrate that both proteins act independently of each other and that Don3 activity precedes that of Cdc42. We provide evidence that Don3 and Cdc42 are crucial for the assembly of a contractile actomyosin ring, which is a prerequisite for secondary septum formation. We propose, that Don3 is involved in establishing a landmark, at which the Cdc42-dependent actomyosin ring formation will occur.
Novel Synthesis of meso-Tetraarylporphyrins by Using I2 as Catalyst and Air as Oxidant under Thermal or UV Conditions
Authors: Duan Le , Wang Yu-Lu , Fan Xue-Sen , Wang Jin-Ye
Published: December 2007

An efficient and novel synthesis of meso-tetraarylporphyrins is accomplished through iodine-catalyzed condensation of pyrrole, and aryl aldehydes and subsequent oxidation by air under thermal or ultraviolet (UV) irradiation conditions. The advantages of this procedure include good yields and a green nature.
Preparation of Cellulose Nanofibers/Nanoparticles via Electrospray
Authors: Sui Xiaofeng , Yuan Jinying , Yuan Weizhong , Zhou Mi
Published: December 2007

Cellulose nanomaterials (100–500 nm in diameter) including fibers and particles have been produced from nonvolatile room-temperature ionic liquid (RTIL) solvent by electrospray. Solvents are extracted from the biopolymer materials after the formation using cosolvent–water. The fundamental role of concentration has been investigated. Structural, morphological, and crystalline phase features were studied by SEM, TGA, and XRD.
Cooperation Between Multiple Newsvendors with Warehouses
Authors: Özen Ulaş , Fransoo Jan , Norde Henk , Slikker Marco
Published: December 2007

This study considers a supply chain that consists of n retailers, each facing a newsvendor problem, and m warehouses. The retailers are supplied with a single product via some warehouses. In these warehouses, the ordered amounts of goods of these retailers become available after some lead time. At the time that the goods arrive at the warehouses, demand realizations are known by the retailers. The retailers can increase their expected joint profits if they can coordinate their orders and make allocations after demand realization. For this setting, we consider an associated cooperative game between the retailers. We show that this associated cooperative game has a nonempty core. Finally, we introduce a noncooperative game, where the retailers decide on their order quantities individually, and show that the set of payoff vectors resulting from strong Nash equilibria corresponds to the core of the associated cooperative game.
Dynamic Inventory Management with Learning About the Demand Distribution and Substitution Probability
Authors: Chen Li , Plambeck Erica L.
Published: December 2007

Awell-known result in the Bayesian inventory management literature is: If lost sales are not observed, the Bayesian optimal inventory level is larger than the myopic inventory level (one should “stock more” to learn about the demand distribution). This result has been proven in other studies under the assumption that inventory is perishable, so the myopic inventory level is equal to the Bayesian optimal inventory level with observed lost sales. We break that equivalence by considering nonperishable inventory. We prove that with nonperishable inventory, the famous “stock more” result is often reversed to “stock less,” in that the Bayesian optimal inventory level with unobserved lost sales is lower than the myopic inventory level. We also prove that making lost sales unobservable increases the Bayesian optimal inventory level; in this specific sense, the famous “stock more” result of other studies generalizes to the case of nonperishable inventory.

When the product is out of stock, a customer may accept a substitute or choose not to purchase. We incorporate learning about the probability of substitution. This reduces the Bayesian optimal inventory level in the case that lost sales are observed. Reducing the inventory level has two beneficial effects: to observe and learn more about customer substitution behavior and (for a nonperishable product) to reduce the probability of overstocking in subsequent periods.

Finally, for a capacitated production-inventory system under continuous review, we derive maximum likelihood estimators (MLEs) of the demand rate and probability that customers will wait for the product. (Accepting a raincheck for delivery at some later time is a common type of substitution.) We investigate how the choice of base-stock level and production rate affect the convergence rate of these MLEs. The results reinforce those for the Bayesian, uncapacitated, periodic review system.
Prevalence and Cluster of Cardiometabolic Biomarkers in Overweight and Obese Schoolchildren: Results from a Large Survey in Southwest Germany
Authors: Nagel Gabriele , Rapp Kilian , Wabitsch Martin , Büchele Gisela , Kroke Anja , Zöllner Iris , Weiland Stephan K , Koenig Wolfgang
Published: December 2007

Background: Obesity is associated with substantial metabolic changes and subclinical inflammation. We explored associations between body mass index (BMI) and cardiometabolic biomarkers and their clustering in overweight and obese schoolchildren.

Methods: In this population-based, cross-sectional study among 450 children 10 years old, we measured adiponectin, leptin, inflammatory markers, apolipoprotein (apo) AI and B, and lipoprotein-associated phospholipase A2 (Lp-PLA2). Except for adiponectin and apoAI (10th percentile) the 90th percentile was used as cutoff point. Body weight was categorized in age- and sex-specific BMI percentiles and overweight and obesity according to International Obesity Task Force definitions.

Results: In linear regression models, all cardiometabolic markers except apoB were statistically significantly associated with overweight. In logistic regression models, compared with the reference category (25th–75th percentile of BMI), overweight was associated with increased concentrations of leptin [odds ratio (OR) 59.80; 95% CI 16.68–214.39], C-reactive protein (6.30; 2.95–13.45), fibrinogen (2.82; 1.33–6.01), and low apoAI (2.62; 1.19–5.75). Overweight was positively associated with interleukin-6, Lp-PLA2, and apoB concentrations and inversely with adiponectin concentrations. Most importantly, in obese children 35% showed one, 20% two, 10% three, and 15% four or more abnormal cardiometabolic biomarkers. The number of abnormal cardiometabolic markers increased in overweight (ptrend <0.001) and obese (ptrend <0.001) children.

Conclusions: Overweight and obesity in children are associated with complex metabolic changes and a low-grade inflammatory response, and thus might not only accelerate cardiovascular disease later on, but may also be associated with the initiation of atherosclerosis in early life.
Effects of Saporin-Induced Lesions of Three Arousal Populations on Daily Levels of Sleep and Wake
Authors: Blanco-Centurion Carlos , Gerashchenko Dmitry , Shiromani Priyattam J.
Published: December 2007

The hypocretin (HCRT) neurons are located only in the perifornical area of the lateral hypothalamus and heavily innervate the cholinergic neurons in the basal forebrain (BF), histamine neurons in the tuberomammillary nucleus (TMN), and the noradrenergic locus ceruleus (LC) neurons, three neuronal populations that have traditionally been implicated in regulating arousal. Based on the innervation, HCRT neurons may regulate arousal by driving these downstream arousal neurons. Here, we directly test this hypothesis by a simultaneous triple lesion of these neurons using three saporin-conjugated neurotoxins. Three weeks after lesion, the daily levels of wake were not changed in rats with double or triple lesions, although rats with triple lesions were asleep more during the light-to-dark transition period. The double- and triple-lesioned rats also had more stable sleep architecture compared with nonlesioned saline rats. These results suggest that the cholinergic BF, TMN, and LC neurons jointly modulate arousal at a specific circadian time, but they are not essential links in the circuitry responsible for daily levels of wake, as traditionally hypothesized.
Reciprocal Regulation of Presynaptic and Postsynaptic Proteins in Bipolar Spiral Ganglion Neurons by Neurotrophins
Authors: Flores-Otero Jacqueline , Xue Hui Zhong , Davis Robin L.
Published: December 2007

A unifying principle of sensory system organization is feature extraction by modality-specific neuronal maps in which arrays of neurons show systematically varied response properties and receptive fields. Only beginning to be understood, however, are the mechanisms by which these graded systems are established. In the peripheral auditory system, we have shown previously that the intrinsic firing features of spiral ganglion neurons are influenced by brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). We now show that is but a part of a coordinated package of neurotrophin actions that also includes effects on presynaptic and postsynaptic proteins, thus encompassing the input, transmission, and output functions of the spiral ganglion neurons. Using immunocytochemical methods, we determined that proteins targeted to opposite ends of the neuron were organized and regulated in a reciprocal manner. AMPA receptor subunits GluR2 and GluR3 were enriched in base neurons compared with their apex counterparts. This distribution pattern was enhanced by exposure to BDNF but reduced by NT-3. SNAP-25 and synaptophysin were distributed and regulated in the mirror image: enriched in the apex, enhanced by NT-3 and reduced by BDNF. Moreover, we used a novel coculture to identify potential endogenous sources of neurotrophins by showing that sensory receptors from different cochlear regions were capable of altering presynaptic and postsynaptic protein levels in these neurons. From these studies, we suggest that BDNF and NT-3, which are systematically distributed in complementary gradients, are responsible for orchestrating a comprehensive set of electrophysiological specializations along the frequency contour of the cochlea.
The Axon–Dendrite Targeting of Kv3 (Shaw) Channels Is Determined by a Targeting Motif That Associates with the T1 Domain and Ankyrin G
Authors: Xu Mingxuan , Cao Ruifeng , Xiao Rui , Zhu Michael X. , Gu Chen
Published: December 2007

Kv3 (Shaw) channels regulate rapid spiking, transmitter release and dendritic integration of many central neurons. Crucial to functional diversity are the complex targeting patterns of channel proteins. However, the targeting mechanisms are not known. Here we report that the axon–dendrite targeting of Kv3.1 is controlled by a conditional interaction of a C-terminal axonal targeting motif (ATM) with the N-terminal T1 domain and adaptor protein ankyrin G. In cultured hippocampal neurons, although the two splice variants of Kv3.1, Kv3.1a and Kv3.1b, are differentially targeted to the somatodendritic and axonal membrane, respectively, the lysine-rich ATM is surprisingly common for both splice variants. The ATM not only directly binds to the T1 domain in a Zn2+-dependent manner, but also associates with the ankyrin-repeat domain of ankyrin G. However, the full-length channel proteins of Kv3.1b display stronger association to ankyrin G than those of Kv3.1a, suggesting that the unique splice domain at Kv3.1b C terminus influences ATM binding to T1 and ankyrin G. Because ankyrin G mainly resides at the axon initial segment, we propose that it may function as a barrier for axon–dendrite targeting of Kv3.1 channels. In support of this idea, disrupting ankyrin G function either by over-expressing a dominant-negative mutant or by siRNA knockdown decreases polarized axon–dendrite targeting of both Kv3.1a and Kv3.1b. We conclude that the conditional ATM masked by the T1 domain in Kv3.1a is exposed by the splice domain in Kv3.1b, and is subsequently recognized by ankyrin G to target Kv3.1b into the axon.
Auditory Neurons Make Stereotyped Wiring Decisions before Maturation of Their Targets
Authors: Koundakjian Edmund J. , Appler Jessica L. , Goodrich Lisa V.
Published: December 2007

Cochlear ganglion neurons communicate sound information from cochlear hair cells to auditory brainstem neurons through precisely wired circuits. Understanding auditory circuit assembly is a significant challenge because of the small size of the otic vesicle and difficulties labeling and imaging embryonic neurons. We used genetic fate mapping in the mouse to visualize the morphologies of individual cochlear ganglion neurons throughout development, from their origin in theNeurogenin1-positive neurogenic domain in the otic vesicle to the formation of connections with targets in the cochlea and in the cochlear nucleus. We found that auditory neurons with different patterns of connectivity arise from discrete populations ofNeurogenin1-positive precursors that make stereotyped wiring decisions depending on when and where they are born. Auditory precursors are segregated from vestibular precursors early in neurogenesis. Within this population, cochlear ganglion neurons with type I and type II morphologies are apparent before birth and develop within common pools of precursors. The peripheral projections are initially complex and branched and then become simple and straight after reaching the edge of the sensory epithelium. Subsequently, a small number of projections attain obvious type II morphologies, beginning at embryonic day 16.5 (E16.5), when hair cells begin to differentiate. Centrally, cochlear ganglion axons are topographically organized in the auditory brainstem as early as E15.5, when the cochlear nucleus is still immature. These findings suggest thatNeurogenin1precursors possess intrinsic programs of differentiation that direct early auditory circuit assembly events before the maturation of presynaptic and postsynaptic target cells.
Expression and Localization of RGS9-2/Gβ5/R7BP ComplexIn VivoIs Set by Dynamic Control of Its Constitutive Degradation by Cellular Cysteine Proteases
Authors: Anderson Garret R. , Lujan Rafael , Semenov Arthur , Pravetoni Marco , Posokhova Ekaterina N. , Song Joseph H. , Uversky Vladimir , Chen Ching-Kang , Wickman Kevin , Martemyanov Kirill A.
Published: December 2007

A member of regulator of G-protein signaling family, RGS9-2, is an essential modulator of signaling through neuronal dopamine and opioid G-protein-coupled receptors. Recent findings indicate that the abundance of RGS9-2 determines sensitivity of signaling in the locomotor and reward systems in the striatum. In this study we report the mechanism that sets the concentration of RGS9-2in vivo, thus controlling G-protein signaling sensitivity in the region. We found that RGS9-2 possesses specific degradation determinants which target it for constitutive destruction by lysosomal cysteine proteases. Shielding of these determinants by the binding partner R7 binding-protein (R7BP) controls RGS9-2 expression at the posttranslational level. In addition, binding to R7BP in neurons targets RGS9-2 to the specific intracellular compartment, the postsynaptic density. Implementation of this mechanism throughout ontogenetic development ensures expression of RGS9-2/type 5 G-protein β subunit/R7BP complexes at postsynaptic sites in unison with increased signaling demands at mature synapses.
Inactivation of the Lateral But Not Medial Dorsal Striatum Eliminates the Excitatory Impact of Pavlovian Stimuli on Instrumental Responding
Authors: Corbit Laura H. , Janak Patricia H.
Published: December 2007

Conditioned stimuli are important guides for behavioral actions. This experiment determined the role of the dorsal striatum in conditioned-stimulus modulation of instrumental responding using the pavlovian-instrumental transfer (PIT) paradigm. Rats received pavlovian training wherein two different auditory stimuli predicted the delivery of two food rewards. Next, rats were trained to perform two instrumental actions earning the same two rewards. Finally, the impact of pavlovian stimuli on instrumental performance was assessed in extinction: the stimuli were periodically presented while rats were free to perform the lever-press response. Before testing, medial or lateral dorsal striatum was infused with saline or bacolfen/muscimol, to temporarily inactivate the region. Under saline, outcome-selective PIT was observed: presentation of a stimulus paired with the same outcome as the instrumental action elevated responding, whereas presentation of a stimulus paired with a different outcome did not. Inactivation of the dorsolateral striatum dramatically reduced this effect. Inactivation of the dorsomedial striatum left intact the ability of reward-related stimuli to invigorate responding; however, the selectivity of the stimulus effect was lost (i.e., both stimuli excited responding). These results indicate that subregions of the dorsal striatum play distinct roles in stimulus modulation of instrumental performance with the lateral region being vital for reward-related stimuli to excite responding and the medial region being involved in the integration of stimulus-reward associations with specific response-outcome associations to produce selective responding. These findings identify new roles for the dorsal striatum in mediating the incentive effects of reward-predictive stimuli on behavioral actions made to obtain reward.
Nanoscale Organization of the MEC-4 DEG/ENaC Sensory Mechanotransduction Channel inCaenorhabditis elegansTouch Receptor Neurons
Authors: Cueva Juan G. , Mulholland Atticus , Goodman Miriam B.
Published: December 2007

Hearing, touch and proprioception are thought to involve direct activation of mechano-electrical transduction (MeT) channels. InCaenorhabditis eleganstouch receptor neurons (TRNs), such channels contain two pore-forming subunits (MEC-4 and MEC-10) and two auxiliary subunits (MEC-2 and MEC-6). MEC-4 and MEC-10 belong to a large superfamily of ion channel proteins (DEG/ENaCs) that form nonvoltage-gated, amiloride-sensitive Na+channels. In TRNs, unique 15-protofilament microtubules and an electron-dense extracellular matrix have been proposed to serve as gating tethers critical for MeT channel activation. We combined high-pressure freezing and serial-section immunoelectron microscopy to determine the position of MeT channels relative to putative gating tethers. MeT channels were visualized using antibodies against MEC-4 and MEC-2. This nanometer-resolution view of a sensory MeT channel establishes structural constraints on the mechanics of channel gating. We show here that MEC-2 and MEC-5 collagen, a putative extracellular tether, occupy overlapping but distinct domains in TRN neurites. Although channels decorate all sides of TRN neurites; they are not associated with the distal endpoints of 15-protofilament microtubules hypothesized to be gating tethers. These specialized microtubules, which are unique to TRNs, assemble into a cross-linked bundle connected by a network of kinked filaments to the neurite membrane. We speculate that the microtubule bundle converts external point loads into membrane stretch which, in turn, facilitates MeT channel activation.