bluuebunny/crossref_metadata_2025 huggingface dataset:
Noninvasive detection of expiratory flow limitation in COPD patients during nasal CPAP
Authors: Dellacà R. L. , Rotger M. , Aliverti A. , Navajas D. , Pedotti A. , Farré R.
Published: January 2006

The difference between mean inspiratory and expiratory respiratory reactance (ΔX̄rs) measured with forced oscillation technique (FOT) at 5 Hz allows the detection of expiratory flow limitation (EFL) in chronic obstructive pulmonary disease (COPD) patients breathing spontaneously. This aim of this study was to evaluate whether this approach can be applied to COPD patients during noninvasive pressure support.

ΔX̄rswas measured in seven COPD patients subjected to nasal continuous positive airway pressure (CPAP) at 0, 4, 8 and 12 cmH2O in sitting and supine positions. Simultaneous recording of oesophageal pressure and the Mead and Whittenberger (M–W) method provided a reference for scoring each breath as flow-limited (FL), non-flow-limited (NFL) or indeterminate (I). For each patient, six consecutive breaths were analysed for each posture and CPAP level.

According to M–W scoring, 47 breaths were FL, 166 NFL and 51 I. EFL scoring using FOT coincided with M–W in 94.8% of the breaths. In the four patients who were FL in at least one condition, ΔX̄rswas reduced with increasing CPAP.

These data suggest that the forced oscillation technique may be useful in chronic obstructive pulmonary disease patients on nasal pressure support by identifying continuous positive airway pressure levels that support breathing without increasing lung volume, which in turn increase the work of breathing and reduce muscle effectiveness and efficiency.
Alveolar nitric oxideversusmeasures of peripheral airway dysfunction in severe asthma
Authors: van Veen I. H. , Sterk P. J. , Schot R. , Gauw S. A. , Rabe K. F. , Bel E. H.
Published: January 2006

Alveolar nitric oxide (NO) is a measure of peripheral airway inflammation in asthma, potentially associated with disease severity. The relationship between alveolar NO and physiological tests of peripheral airway (dys)function has not been investigated. The present authors hypothesised that peripheral airway inflammation and dysfunction are inter-related and associated with asthma severity.

Alveolar NO was compared between 17 patients with mild-to-moderate asthma and 14 patients with severe asthma and related to total lung capacity (TLC), residual volume (RV)/TLC, thoracic gas volume (FRC), slope of the single breath nitrogen washout curve (dN2), closing capacity (CC)/TLC and fall in forced vital capacity at the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second. In patients with severe asthma, strong correlations were found between alveolar NO and RV/TLC % pred, FRC % pred, dN2, and CC/TLC. Patients with oral steroid-dependent asthma had higher alveolar NO levels (2.7 ppb) compared with the other patients with severe (0.6 ppb) and mild-to-moderate asthma (0.3 ppb).

The present authors conclude that alveolar nitric oxide is closely related to parameters of peripheral airway dysfunction in patients with severe asthma, and that oral steroid-dependent asthmatics have more peripheral airway disease than nonsteroid-dependent asthmatics. This suggests that patients on chronic oral steroid treatment have more extensive disease and require additional anti-inflammatory treatment to better target the peripheral airways.
Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial
Authors: Andreas S. , Herrmann-Lingen C. , Raupach T. , Lüthje L. , Fabricius J. A. , Hruska N. , Körber W. , Büchner B. , Criée C-P. , Hasenfuß G. , Calverley P.
Published: January 2006

In chronic obstructive pulmonary disease (COPD), the sympathetic nervous system, as well as the renin–angiotensin system, is activated with possible negative systemic effects on skeletal muscles. Angiotensin II type-1 receptor blockers inhibit the sympathetic and renin–angiotensin systems and might improve skeletal and respiratory muscle strength in patients in whom these systems are activated.

The effects of the angiotensin receptor blocker irbesartan given over 4 months was evaluated in 60 patients with COPD and a forced expiratory volume in one second of <50% of the predicted value and without obvious cardiovascular disease that would necessitate the administration of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.

Irbesartan was well tolerated, but did not exert a significant effect on the primary end-point maximum inspiratory pressure. Spirometric results were not affected, but total lung capacity was reduced. Irbesartan led to a significant decrease in haematocrit (46.4±3.6 to 43.9±4.3%versus47.5±2.4 to 48.7±3.0% with placebo).

In conclusion, respiratory muscle strength in chronic obstructive pulmonary disease patients was not influenced by angiotensin II receptor blockade. However, the changes in haematocrit and total lung capacity following irbesartan raise the possibility that well-known cardiovascular drugs can produce unanticipated beneficial effects in chronic obstructive pulmonary disease patients.
Schizophrenia, neuroleptic medication and mortality
Authors: Joukamaa Matti , Heliövaara Markku , Knekt Paul , Aromaa Arpo , Raitasalo Raimo , Lehtinen Ville
Published: January 2006

Background

There is an excess of death from natural causes among people with schizophrenia.

Aims

Schizophrenia and its treatment with neuroleptics were studied for their prediction of mortality in a representative population sample of 7217 Finns aged ⩾30 years.

Method

A comprehensive health examination was carried out at baseline. Schizophrenia was determined using the Present State Examination and previous medical records.

Results

During a 17-year follow-up, 39 of the 99 people with schizophrenia died. Adjusted for age and gender, the relative mortality risk between those with schizophrenia and others was 2.84 (95% CI 2.06–3.90), and was2.25 (95%CI1.61–3.15) after further adjusting for somatic diseases, blood pressure, cholesterol, body mass index, smoking, exercise, alcohol intake and education. The number of neuroleptics used at the time of the baseline survey showed a graded relation to mortality. Adjusted for age, gender, somatic diseases and other potential risk factors for premature death, the relative risk was 2.50 (95% CI1.46–4.30) per increment of one neuroleptic.

Conclusions

There is an urgent need to ascertain whether the high mortality in schizophrenia is attributable to the disorder itself or the antipsychotic medication.
Cannabis use and mental health in secondary school children
Authors: Monshouwer Karin , Van Dorsselaer Saskia , Verdurmen Jacqueline , Ter Bogt Tom , De Graaf Ron , Vollebergh Wilma
Published: January 2006

Background

Cannabis use is associated with mental health problems, and young people in particular are at risk.

Aims

To investigate the association between cannabis use and mental health in adolescence.

Method

Data from 5551 adolescents aged 12–16 years were drawn from the Dutch Health Behaviour in School-Aged Children school survey, carried out as part of the international 2001 World Health Organization project.

Results

After adjusting for confounding factors, cannabis use was linked to externalising problems (delinquent and aggressive behaviour) but not to internalising problems (withdrawn behaviour, somatic complaints and depression). An increasing frequency of use resulted in stronger links. No significant gender or age by cannabis interaction effects were found.

Conclusions

In a country with a liberal drug policy like The Netherlands, cannabis use is associated with aggression and delinquency, just as in other countries. Cannabis use was not associated with internalising problems. Alcohol use and regular smoking were strong confounding factors.
Brain white-matter hyperintensities and treatment outcome in
major depressive disorder
Authors: Iosifescu Dan V. , Renshaw Perry F. , Lyoo In Kyoon , Lee Ho Kyu , Perlis Roy H. , Papakostas George I. , Nierenberg Andrew A. , Fava Maurizio
Published: January 2006

Background

An increased incidence of brain white-matter hyperintensities has been
described in major depressive disorder, but the impact of such
hyperintensities on treatment outcome is still controversial.

Aims

To investigate the relationship of brain white-matter hyperintensities
with cardiovascular risk factors and with treatment outcome in younger
people with major depressive disorder.

Method

We assessed brain white-matter hyperintensities and cardiovascular risk
factors in 84 people with major depressive disorder prior to initiating
antidepressanttreatment. We also assessed hyperintensities in 35 matched
controls.

Results

We found no significant difference in the prevalence of white-matter
hyperintensities between the depression and the control groups.
Left-hemisphere subcortical hyperintensities correlated with lower rates
of treatment response. We found no correlation between global
hyperintensity measures and clinical outcome. Brain white-matter
hyperintensities correlated with hypertension and age and with total
cardiovascular risk score.

Conclusions

Subcortical white-matter hyperintensities in the left hemisphere (but not
in other brain areas) may be associated with poor response to
antidepressant treatment in major depression.
Influence of carer expressed emotion and affect on relapse in
non-affective psychosis
Authors: Kuipers E. , Bebbington P. , Dunn G. , Fowler D. , Freeman D. , Watson P. , Hardy A. , Garety P.
Published: January 2006

Background

High expressed emotion in carers predicts relapse in psychosis, but it is
not known why this is so. In our cognitive model of psychosis, we
postulated that the effect is mediated through affective changes.

Aims

To investigate the relationships between carer expressed emotion,
patients' symptoms and carer characteristics during a recent relapse of
psychosis.

Method

A total of 86 patients and carers were investigated in a cross-sectional
design.

Results

Patients whose carers showed high expressed emotion had significantly
higher levels of anxiety and depression, but not more psychotic symptoms
or lower self-esteem. Linear regression showed that carers' critical
comments predicted anxiety in patients. Critical comments were related to
low carer self-esteem and avoidant coping strategies. Low carer
self-esteem was also related to carer depression, stress and carer
‘burden’, and to low patient self-esteem.

Conclusions

Our hypothesis was partially supported. Carer criticism was associated
with patient anxiety, low carer self-esteem and poor carer coping
strategies. Family interventions should focus on improving these after a
relapse of symptoms of psychosis.
Intellectual asymmetry and genetic liability in first-degree
relatives of probands with schizophrenia
Authors: Kravariti Eugenia , Toulopoulou Timothea , Mapua-Filbey Francesca , Schulze Katja , Walshe Muriel , Sham Pak , Murray Robin M. , McDonald Colm
Published: January 2006

Intellectual asymmetry with superiority of verbal skills to spatial skills
frequently characterises patients with schizophrenia, but it is unclear
whether this pattern also reflects genetic susceptibility to the disorder.
We examined the association of a continuous measure of genetic liability to
schizophrenia with Verbal-Spatial Contrast IQ (an index of intellectual
asymmetry) in 108 first-degree relatives without psychosis of probands with
schizophrenia. Higher genetic liability was significantly associated with
greater intellectual asymmetry in favour of verbal skills. Intellectual
asymmetry with a relative superiority of verbal skills to spatial skills
represents a putative endophenotype of schizophrenia.
Neuroleptics and mortality: a 50-year cycle
Authors: Healy David
Published: January 2006

The paper by Joukamaa et al (2006, this issue) would have
interested Heinz Lehmann, a German émigré psychiatrist working at Verdun
hospital in Montreal, who was one of the first clinicians to investigate the
effects of chlorpromazine in North America and was the first to publish an
article outlining its clinical impact (Lehmann & Hanrahan, 1954).
Lehmann was no simple enthusiast for physical treatments, having
demonstrated that mute and deteriorated people with schizophrenia in
Verdun's back wards responded to placebo injections of ‘new experimental
hormones' when the injection site was painted with a disinfectant that left
a prominent red stain (Lehmann, 1993). However, chlorpromazine was
different. Although previous treatments had provided some benefits, nothing
produced quite such dramatic effects in the experience of senior researchers
such as Lehmann. Chlorpromazine ignited a wave of enthusiasm in psychiatry
sufficient to sweep aside post-War differences between the Germans and the
French, for instance, so that they and others convened to share their
experiences on the benefits of the new drugs at international meetings
rapidly organised by university departments rather than pharmaceutical
companies.
Research in the real world
Authors: Paxton Roger , Kennedy Peter , Carpenter John
Published: January 2006

A new approach to research and development (R&D) for mental health services is developing in the North-East, Yorkshire and Humber. It derives from experience with service redesign using the ‘collaborative’ approach developed by the US Institute for Health Improvement. Kennedy & Griffiths (2003) described such an approach involving 37 mental health trusts, each with a multidisciplinary team, with the aim of improving acute in-patient wards. After studying the patient's journey through care they agreed a set of improvement targets that all teams would work to achieve. Progress towards targets was measured and reported by all teams, who met periodically to compare performance and learn from each other. Remarkable energy to achieve objectives was released among front-line staff involved. Focus was sustained on what most concerned and benefited patients. Good ideas and results quickly spread to all these services affecting thousands of patients.
Employment status and occupational care planning for people using mental health services
Authors: Bertram Mark , Howard Louise
Published: January 2006

Aims and Method

The aim of the study was to identify the employment rates of people using local mental health services and examine any evidence in care plans for vocational or occupational interventions. We investigated case notes retrospectively.

Results

A total of 297 case notes were examined: 88% of the patients were unemployed, but there was evidence of documentation relating to vocational needs in only 18% of out-patients; 8% in patients of community mental health teams; and 39% in acute wards; 8% of patients were engaged in work schemes; 10% of patients were in education; and 9% were engaged in vocational interventions with their care coordinator; the latter was less likely if the patient was from a Black or minority ethnic group (OR=2.44, 95% CI 0.18–1.05).

Clinical Implications

Despite high rates of unemployment, patients with psychiatric disorders are not referred for vocational interventions. Growing professional awareness of vocational possibilities for patients with severe mental illness should mean that many patients could return to competitive employment and return to mainstream society.
A career in child and adolescent psychiatry? Survey of trainees' views
Authors: Lamb Graeme , Evans Navina , Baillie David
Published: January 2006

Aims and Method

The aim of the study was to elicit the views of senior house officers in psychiatry across London regarding the factors that influence their decision whether to pursue a career in child and adolescent psychiatry. Postal questionnaires were sent to a random sample of all senior house officers on London psychiatry training schemes.

Results

Of the respondents who recalled being taught child psychiatry at medical school, 91% found it interesting and 73% found it useful. Of those who recalled having such teaching during psychiatric training, 90% found it interesting and 85% found it useful. However, this had no significant impact upon subsequent career choice. Experience of working as a senior house officer in child psychiatry did influence future career intentions. Trainees who identified such placements as providing good clinical experience or job satisfaction were significantly more likely to consider the specialty for a future career.

Clinical Implications

Consultants and managers should create and maintain senior house officer posts that will encourage trainees to perceive the specialty as a future career.
New ways of working in the North Yorkshire Dales
Authors: Simpson Chris , Farrimond Paul
Published: January 2006

Developing new ways of working for consultant psychiatrists can be done differently depending on the consultants concerned. A group of consultants in rural North Yorkshire made some changes in their working patterns resulting in benefits to them, their teams and their patients. Close working relationships between managers and clinicians were the key to facilitating these changes.
Misapplication of mental impairment under the Mental Health Act 1983
Authors: Bashir Anjum , Tinto Sheila
Published: January 2006

As Professor Eastman (2000) has noted: the law is fond of ‘using’ psychiatry for its own ends at times, but the Mental Health Act 1983 is an example of psychiatrists using the law as a tool of public policy. This makes their education in and interpretation of it all the more vital. The MRCPsych part II module ‘Ethics and the Law’ requires candidates to demonstrate knowledge of relevant mental health and human rights legislation, and to illustrate the appropriate application of such information (Royal College of Psychiatrists, 2001). We submit a masked case study that in practice seems to us a misinterpretation of the Act.
Mechanisms of Hypertension Associated With BAY 43-9006
Authors: Veronese Maria Luisa , Mosenkis Ari , Flaherty Keith T. , Gallagher Maryann , Stevenson James P. , Townsend Raymond R. , O'Dwyer Peter J.
Published: January 2006

Purpose

BAY 43-9006 (sorafenib) is an inhibitor of Raf kinase, the vascular endothelial growth factor (VEGF) receptor-2, and angiogenesis in tumor xenografts. The current study investigated the incidence, severity, and mechanism of blood pressure (BP) elevation in patients treated with BAY 43-9006.

Patients and Methods

Twenty patients received BAY 43-9006 400 mg orally twice daily. BP and heart rate were measured at baseline and then every 3 weeks for 18 weeks. VEGF, catecholamines, endothelin I, urotensin II, renin, and aldosterone were measured at baseline and after 3 weeks of therapy. We assessed vascular stiffness at baseline, after 3 to 6 weeks of therapy, and again after 9 to 10 months of therapy.

Results

Fifteen (75%) of 20 patients experienced an increase of ≥ 10 mmHg in systolic BP (SBP), and 12 (60%) of 20 patients experienced an increase of ≥ 20 mmHg in SBP compared with their baseline value, with a mean change of 20.6 mmHg (P < .0001) after 3 weeks of therapy. There were no statistically significant changes in humoral factors, although there was a statistically significant inverse relationship between decreases in catecholamines and increases in SBP, suggesting a secondary response to BP elevation. Measures of vascular stiffness increased significantly during the period of observation.

Conclusion

Treatment with BAY 43-9006 is associated with a significant and sustained increase in BP. The lack of significant change in circulating factors suggests that these humoral factors had little role in the increase in BP.
Adding Gemcitabine to Paclitaxel/Carboplatin Combination Increases Survival in Advanced Non–Small-Cell Lung Cancer: Results of a Phase II-III Study
Authors: Paccagnella Adriano , Oniga Francesco , Bearz Alessandra , Favaretto Adolfo , Clerici Maurizia , Barbieri Fausto , Riccardi Alberto , Chella Antonio , Tirelli Umberto , Ceresoli Giovanni , Tumolo Salvatore , Ridolfi Ruggero , Biason Rita , Nicoletto Maria Ornella , Belloni Paolo , Veglia Fabrizio , Ghi Maria Grazia
Published: January 2006

Purpose

Paclitaxel/carboplatin (PC) is one of the reference combinations in the treatment of non–small-cell lung cancer (NSCLC). No triplet novel agent combination has until now shown superiority over a two-drug combination for advanced NSCLC. We therefore conducted a clinical trial to test if paclitaxel/carboplatin/gemcitabine (PCG) increases overall survival (OS) and response rate (RR) over PC.

Methods

Stage IIIB patients not suitable for radical radiation treatment and stage IV chemotherapy-naive patients with measurable disease and performance status of 0 to 2 were randomly assigned to PC arm (paclitaxel 200 mg/m2 and carboplatin area under the concentration-time curve 6 day 1/q21 days) or the PCG arm (paclitaxel 200 mg/m2 and carboplatin area under the concentration-time curve 6 day 1, and gemcitabine 1,000 mg/m2 days 1 and 8 every 21 days).

Results

A total of 324 patients were randomly assigned to the two arms. The RR for PC arm and PCG arm were 20.2% and 46% (P < .0001). The median time to the progression was 5.1 months in the PC group and 7.6 months in the PCG group (P = .012; hazard ratio [HR] 1.34; 95% CI: 1.06 to 1.72). Median OS was 8.3 months and 10.8 months (P = .032; HR 1.309; 95% CI: 1.03 to 1.67) in favor of the PCG arm. One-year survival was 34% (PC arm) and 45% (PCG arm; P = .032). Only hematologic toxicity (neutropenia, thrombocytopenia, and anemia) was significantly increased in the PCG arm and the experimental arm required more platelet and red blood cell transfusions, and more granulocyte colony-stimulating factor usage. No toxic/early deaths were observed.

Conclusion

The PCG regimen offers a significant survival advantage over PC in advanced NSCLC, making PCG a treatment option for advanced NSCLC patients.
[18F]Fluorodeoxyglucose Positron Emission Tomography Is More Sensitive Than Skeletal Scintigraphy for Detecting Bone Metastasis in Endemic Nasopharyngeal Carcinoma at Initial Staging
Authors: Liu Feng-Yuan , Chang Joseph T. , Wang Hung-Ming , Liao Chun-Ta , Kang Chung-Jan , Ng Shu-Kung , Chan Sheng-Chieh , Yen Tzu-Chen
Published: January 2006

Purpose

Bone metastasis occurs frequently in patients with endemic nasopharyngeal carcinoma (NPC). The main objective of this study is to evaluate positron emission tomography (PET) using fluorine-18–labeled fluorodeoxyglucose ([18F]FDG) and conventional skeletal scintigraphy (SS) for detecting bone metastasis at initial staging. Auxiliary objectives are to identify risk factors for bone metastasis and features associated with poor survival in patients with bone metastasis.

Patients and Methods

Patients with endemic NPC before initiation of treatment were enrolled. PET and SS were performed at initial staging and compared using McNemar's paired-sample test. Bone metastasis was considered to be present if there was any reliable evidence identified within 1 year after primary diagnosis. Multiple logistic regression and Cox's proportional hazards models were used for auxiliary objectives.

Results

Thirty (15%) of 202 eligible patients were found to have bone metastasis. [18F]FDG PET was found to be more sensitive than SS in the patient-based analysis (P = .006) and in the region-based analysis at the spine (P = .001). Advanced N stage was the only significant risk factor (P < .0001), and the coexistence of hepatic metastasis was a prognosticator of poor survival (P = .017). The survival was not significantly better for patients with bone metastasis undetected at primary staging than for those with initially detectable bone metastasis (P = .620).

Conclusion

[18F]FDG PET is more sensitive than SS for detecting bone metastasis in endemic NPC at initial staging, whereas SS can be considered as supplementary in this setting.
Increased Toxicity With Gefitinib, Capecitabine, and Radiation Therapy in Pancreatic and Rectal Cancer: Phase I Trial Results
Authors: Czito Brian G. , Willett Christopher G. , Bendell Johanna C. , Morse Michael A. , Tyler Douglas S. , Fernando Nishan H. , Mantyh Christopher R. , Blobe Gerard C. , Honeycutt Wanda , Yu Daohai , Clary Bryan M. , Pappas Theodore N. , Ludwig Kirk A. , Hurwitz Herbert I.
Published: January 2006

Purpose

Overexpression of epidermal growth factor receptor (EGFR) has been associated with aggressive tumor phenotypes, chemotherapy, and radiation resistance, as well as poor survival in preclinical and clinical models. The EGFR inhibitor gefitinib potentiates chemotherapy and radiation tumor cytotoxicity in preclinical models, including pancreatic and colorectal cancer. We initiated two phase I trials assessing the combination of gefitinib, capecitabine, and radiation in patients with localized pancreatic and rectal cancer.

Patients and Methods

Patients with pathologically confirmed adenocarcinoma of the pancreas and rectum were eligible. Pretreatment staging included computed tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external-beam radiation therapy to the tumor in 28 fractions. Capecitabine and gefitinib were administered throughout the radiation course. Following completion, patients were restaged and considered for resection. Primary end points included determination of dose-limiting toxicity (DLT) and a phase II dose; secondary end points included determination of non-DLTs and preliminary radiographic and pathologic response rates.

Results

Ten patients were entered in the pancreatic study and six in the rectal study. DLT was seen in six of 10 patients in the pancreatic study and two of six patients in the rectal study. The primary DLT in both studies was diarrhea. Two patients developed arterial thrombi.

Conclusion

The combination of gefitinib, capecitabine, and radiation in pancreatic and rectal cancer patients resulted in significant toxicity. A recommended phase II dose was not determined in either of our studies. Further investigation with this combination should be approached with caution.
Multicenter Phase II Trial of S-1 Plus Cisplatin in Patients With Untreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
Authors: Ajani Jaffer A. , Lee Fa-Chyi , Singh Deepti A. , Haller Daniel G. , Lenz Heinz-Josef , Benson Al B. , Yanagihara Ronald , Phan Alexandria T. , Yao James C. , Strumberg Dirk
Published: January 2006

Purpose

S-1 plus cisplatin is considered highly active in Japanese gastric cancer patients. We conducted a phase II multi-institutional trial, in the West, in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma to evaluate activity and safety of this combination.

Methods

Patients received cisplatin intravenously at 75 mg/m2 on day 1 and S-1 orally at 25 mg/m2/dose bid (50 mg/m2/d) on days 1 to 21, repeated every 28 days. Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with a Karnofsky performance status (KPS) of ≥ 70% and near-normal organ function were eligible. All patients provided a written informed consent. To observe a 45% confirmed overall response rate (ORR), 41 assessable patients were needed.

Results

All 47 patients were assessed for safety and survival, and 41 patients were assessed for ORR. The median age was 56 years and median KPS was 80%. The median number of chemotherapy cycles was four. The confirmed ORR was 51% (95% CI, 35% to 67%) and it was 49% by an independent review. At the 6-month interval, 71% of patients were alive, with a median survival time of 10.9 months. Frequent grade 3 or 4 toxicities included fatigue (26%), neutropenia (26%), vomiting (17%), diarrhea (15%), and nausea (15%); however, stomatitis (2%) and febrile neutropenia (2%) were uncommon. There was one (2%) treatment-related death.

Conclusion

S-1 plus cisplatin is active against gastric cancer and has a favorable toxicity profile. A global phase III study of S-1 plus cisplatin versus fluorouracil plus cisplatin currently is accruing patients.
The V-type H+ ATPase: molecular structure and function,physiological roles and regulation
Authors: Beyenbach Klaus W. , Wieczorek Helmut
Published: January 2006

It was nearly 30 years before the V-type H+ ATPase was admitted to the small circle of bona fide transport ATPases alongside F-type and P-type ATPases. The V-type H+ ATPase is an ATP-driven enzyme that transforms the energy of ATP hydrolysis to electrochemical potential differences of protons across diverse biological membranes via the primary active transport of H+. In turn, the transmembrane electrochemical potential of H+ is used to drive a variety of (i)secondary active transport systems via H+-dependent symporters and antiporters and (ii) channel-mediated transport systems. For example, expression of Cl- channels or transporters next to the V-type H+ ATPase in vacuoles of plants and fungi and in lysosomes of animals brings about the acidification of the endosomal compartment, and the expression of the H+/neurotransmitter antiporter next to the V-type H+ ATPase concentrates neurotransmitters in synaptic vesicles.

First found in association with endosomal membranes, the V-type H+ ATPase is now also found in increasing examples of plasma membranes where the proton pump energizes transport across cell membranes and entire epithelia. The molecular details reveal up to 14 protein subunits arranged in (i) a cytoplasmic V1 complex, which mediates the hydrolysis of ATP, and (ii) a membrane-embedded V0 complex, which translocates H+ across the membrane. Clever experiments have revealed the V-type H+ ATPase as a molecular motor akin to F-type ATPases. The hydrolysis of ATP turns a rotor consisting largely of one copy of subunits D and F of the V1 complex and a ring of six or more copies of subunit c of the V0 complex. The rotation of the ring is thought to deliver H+ from the cytoplasmic to the endosomal or extracellular side of the membrane, probably via channels formed by subunit a. The reversible dissociation of V1 and V0complexes is one mechanism of physiological regulation that appears to be widely conserved from yeast to animal cells. Other mechanisms, such as subunit-subunit interactions or interactions of the V-type H+ATPase with other proteins that serve physiological regulation, remain to be explored. Some diseases can now be attributed to genetic alterations of specific subunits of the V-type H+ ATPase.
Effects of larval nutrition on the endocrinology of mosquito egg development
Authors: Telang Aparna , Li Yiping , Noriega Fernando G. , Brown Mark R.
Published: January 2006

Reproduction by female mosquitoes is dependent on energy resources but modulated by hormones. Our study focused on blood-meal-dependent, anautogenous Aedes aegypti and autogenous Ochlerotatus atropalpus that rely on larval-derived nutrient stores to develop eggs. To determine how larval nutrition affects the endocrinology of egg development in these females, we manipulated the quantity of larval food and measured in vitro production of juvenile hormone (JH) by corpora allata (CA) and ecdysteroids by ovaries. Newly emerged A. aegypti contain lower larval-derived protein reserves, and their CA produce high amounts of JH, in comparison with similarly staged Oc. atropalpus. Ecdysteroid production was initiated in newly emerged Oc. atropalpus females,which have higher protein reserves and which develop eggs without a blood meal, which is required by A. aegypti females to complete egg development.
Dynamics of the aerial maneuvers of spinner dolphins
Authors: Fish Frank E. , Nicastro Anthony J. , Weihs Daniel
Published: January 2006

The spinner dolphin (Stenella longirostris) performs spectacular leaps from the water while rotating around its longitudinal axis up to seven times. Although twisting of the body while airborne has been proposed as the mechanism to effect the spin, the morphology of the dolphin precludes this mechanism for the spinning maneuver. A mathematical model was developed that demonstrates that angular momentum to induce the spin was generated underwater, prior to the leap. Subsurface corkscrewing motion represents a balance between drive torques generated by the flukes and by hydrodynamic forces at the pectoral fins, and resistive torques, induced by the drag forces acting on the rotating control surfaces. As the dolphin leaps clear of the water, this balance is no longer maintained as the density of the air is essentially negligible, and a net drive torque remains, which permits the dolphin's rotation speed to increase by as much as a factor of three for a typical specimen. The model indicates that the high rotation rates and orientation of the dolphin's body during re-entry into the water could produce enough force to hydrodynamically dislodge unwanted remoras.
Temperature sensitivities of cytosolic malate dehydrogenases from native and invasive species of marine mussels (genusMytilus):sequence-function linkages and correlations with biogeographic distribution
Authors: Fields Peter A. , Rudomin Emily L. , Somero George N.
Published: January 2006

The blue mussel Mytilus galloprovincialis, a native of the Mediterranean Sea, has invaded the west coast of North America in the past century, displacing the native blue mussel, Mytilus trossulus, from most of its former habitats in central and southern California. The invasive success of M. galloprovincialis is conjectured to be due, in part, to physiological adaptations that enable it to outperform M. trossulusat high temperatures. We have examined the structure and function of the enzyme cytosolic malate dehydrogenase (cMDH) from these species, as well as from the more distantly related ribbed mussel, Mytilus californianus,to characterize the effects of temperature on kinetic properties thought to exhibit thermal adaptation. The M. trossulus cMDH ortholog differs from the other cMDHs in a direction consistent with cold adaptation, as evidenced by a higher and more temperature-sensitive Michaelis-Menten constant for the cofactor NADH (KmNADH). This difference results from minor changes in sequence: the M. trossulus ortholog differs from the M. galloprovincialis ortholog by only two substitutions in the 334 amino acid monomer, and the M. californianusand M. trossulus orthologs differ by five substitutions. In each case, only one of these substitutions is non-conservative. To test the effects of individual substitutions on kinetic properties, we used site-directed mutagenesis to create recombinant cMDHs. Recombinant wild-type M. trossulus cMDH (rWT) has high KmNADHcompared with mutants incorporating the non-conservative substitutions found in M. californianus and M. galloprovincialis - V114H and V114N, respectively - demonstrating that these mutations are responsible for the differences found in substrate affinity. Turnover number(kcat) is also higher in rWT compared with the two mutants, consistent with cold adaptation in the M. trossulusortholog. Conversely, rWT and V114H appear more thermostable than V114N. Based on a comparison of KmNADH and kcat values among the orthologs, we propose that immersion temperatures are of greater selective importance in adapting kinetic properties than the more extreme temperatures that occur during emersion. The relative warm adaptation of M. galloprovincialis cMDH may be one of a suite of physiological characters that enhance the competitive ability of this invasive species in warm habitats.
Perturbation of the activity of a single identified neuron affects long-term memory formation in a molluscan semi-intact preparation
Authors: Lowe M. R. , Spencer G. E.
Published: January 2006

The aim of this study was to investigate the neural basis of operant conditioning in a semi-intact preparation of the pond snail, Lymnaea stagnalis. Lymnaea learns, via operant conditioning, to reduce its aerial respiratory behaviour in response to an aversive tactile stimulus to its open pneumostome. Here we report the successful conditioning of naïve semi-intact preparations to show `learning in the dish' and long-term memory that persists for at least 18 h. The neurons that generate this behaviour are readily identifiable and, for the first time, we have recorded from a neuron during a training paradigm that leads to long-term memory formation in the same preparation. Specifically, we recorded from the respiratory neuron Right Pedal Dorsal 1 (RPeD1), which is part of the respiratory central pattern generator and initiates the aerial respiratory behaviour. Previous studies have shown that long-term memory of this behaviour results in reduced RPeD1 activity. In the present study, we demonstrate that preventing RPeD1 impulse activity between training sessions reduces the number of sessions needed to produce long-term memory in our semi-intact preparation.
Microtubule-dependent relocation of branchial V-H+-ATPase to the basolateral membrane in the Pacific spiny dogfish (Squalus acanthias): a role in base secretion
Authors: Tresguerres Martin , Parks Scott K. , Katoh Fumi , Goss Greg G.
Published: January 2006

We have previously shown that continuous intravenous infusion of NaHCO3 for 24 h (∼1000 μmol kg-1 h-1)results in the relocation of V-H+-ATPase from the cytoplasm to the basolateral membrane in the gills of the Pacific dogfish. To further investigate this putative base-secretive process we performed similar experiments with the addition of colchicine, an inhibitor of cytoskeleton-dependent cellular trafficking processes. Blood pH and plasma total CO2 were significantly higher in the colchicines-treated,HCO3--infused fish compared with fish infused with HCO3- alone. The effect of colchicine was highest after 24 h of infusion (8.33±0.06 vs 8.02±0.03 pH units,15.72±3.29 vs 6.74±1.34 mmol CO2l-1, N=5). Immunohistochemistry and western blotting confirmed that colchicine blocked the transit of V-H+-ATPase to the basolateral membrane. Furthermore, western blotting analyses from whole gill and cell membrane samples suggest that the short-term (6 h) response to alkaline stress consists of relocation of V-H+-ATPases already present in the cell to the basolateral membrane, while in the longer term (24 h) there is both relocation of preexistent enzyme and upregulation in the synthesis of new units. Our results strongly suggest that cellular relocation of V-H+-ATPase is necessary for enhanced HCO3- secretion across the gills of the Pacific dogfish.
Effects of limb mass distribution on mechanical power outputs during quadrupedalism
Authors: Raichlen David A.
Published: January 2006

Many researchers have suggested that cursorial mammals concentrate limb muscle mass proximally to reduce energy costs during locomotion. Although supported by experiments where mass is added to an individual's limbs, mammals with naturally occurring distally heavy limbs such as primates have similar energy costs compared with other mammals. This study presents a new hypothesis to explain how animals with distally heavy limbs maintain low energy costs. Since distal mass should increase energy costs due to higher amounts of muscular power outputs, this hypothesis is based on the divergent effects of stride frequency on internal and external power outputs (the power output to move the limbs and the body center of mass, respectively). The use of low stride frequencies reduces limb velocities and therefore decreases internal power, while associated long strides increase the vertical displacement of the body center of mass and therefore increase external power. Total power (the sum of internal and external power) may therefore not differ among mammals with different limb mass distributions. To test this hypothesis, I examined a sample of infant baboons (Papio cynocephalus) during ontogeny and compared them with more cursorial mammals. Limb mass distribution changes with age (from distal to more proximally concentrated) in baboons, and the infants used shorter strides and higher stride frequencies when limb mass was most proximally concentrated. Compared with non-primates who have more proximally concentrated limb mass, the infants used longer strides and lower stride frequencies. Relatively low internal power was associated with low stride frequencies in both the intra- and inter-specific samples. However, only in the inter-specific comparison were relatively long strides associated with high external power outputs. In both the intra-specific and the inter-specific samples, total power did not differ between groups who differed in limb mass distribution. The results of this study suggest that a trade-off mechanism is available to quadrupeds with distally heavy limbs allowing them to maintain similar total power outputs (and likely similar energy costs) compared with mammals with more proximally concentrated limb mass.
The relationship between 3-D kinematics and gliding performance in the southern flying squirrel,Glaucomys volans
Authors: Bishop Kristin L.
Published: January 2006

Gliding is the simplest form of flight, yet relatively little is known about its mechanics in animals. The goal of this study was to describe the body position and performance of a gliding mammal and to identify correlates between kinematics and aerodynamic performance. To do this, I used a pair of high-speed digital cameras to record a portion of the middle of glides by southern flying squirrels, Glaucomys volans. The squirrels launched from a height of 4 m and landed on a vertical pole. Reflective markers were applied to anatomical landmarks and the 3-D coordinates of these points were computed to describe the kinematics of the glides. From these data I estimated the lift and drag generated during the glide, and correlated these variables with gliding performance as measured by glide angle, glide speed and stability. In the majority of the glide sequences the squirrels accelerated in the downward direction and accelerated horizontally forward as they moved through the calibrated volume in the middle of the glide trajectory, rather than exhibiting a steady glide in which the body weight is balanced by the resultant aerodynamic force. Compared to human engineered airfoils, the angles of attack used by the squirrels were unexpectedly high, ranging from 35.4°to 53.5°, far above the angle of attack at which an aircraft wing would typically stall. As expected based on aerodynamic theory, there was a negative correlation between angle of attack and lift coefficient, indicating that the wings are stalled, and a positive correlation between angle of attack and drag coefficient. Also as expected, there was a negative correlation between lift-to-drag ratio and angle of attack, as increasing angle of attack produced both less lift and more drag. Within glides, there was a strong correlation between nose-down pitching rotations and limb movements that tended to increase the angle of attack of the wing membrane, suggesting that the animals actively control their pitch by moving their limbs. The squirrels used much steeper glide angles than those reported for other gliding animals, ranging from 40.4° to 57.4°. It is likely that this is because they did not launch from a great enough height to reach their minimum glide angle. In some trials the glide angle increased over the captured portion of the glide,whereas in others it decreased, and the magnitude of the changes varied substantially, rendering it difficult to ascertain which portion of the glide trajectory was represented. Decreases in glide angle were strongly correlated with increases in lift coefficient, but were uncorrelated with drag coefficient.
Hagfish slime ecomechanics: testing the gill-clogging hypothesis
Authors: Lim Jeanette , Fudge Douglas S. , Levy Nimrod , Gosline John M.
Published: January 2006

Hagfish are able to produce substantial amounts of slime when harassed, but the precise ecological function of the slime is unclear. One possibility is that the slime acts as a defence against gill-breathing predators, whose gills may become entangled with the slime's mixture of mucins and fibrous threads during an attack. We previously demonstrated that hagfish slime does not bind water tightly, but instead behaves like a fine sieve that slows water down via viscous entrainment. These properties are consistent with the gill-clogging hypothesis, which we tested here by quantifying the effects of hagfish slime on water flow through an artificial gill model and real fish gills. Our results indicate that the slime is capable of clogging gills and increasing the resistance that they present to the flow of water. We also characterized the behaviour of slime release from live hagfish and the effect of convective mixing on the formation of slime in vitro. Our observations show that exudate is locally released from the slime glands as a coherent jet and that hagfish do not appear to use their slime as a protective envelope. We found that convective mixing between the exudate and seawater is necessary for proper slime formation, but excessive mixing leads to the slime's collapse. We suggest that the loose binding of water by the slime may be an optimal solution to the problem of delivering an expanding jet of flow-inhibiting material to the gills of would-be predators.
Use of RNA Fluorescence In Situ Hybridization in the Prenatal Molecular Diagnosis of Myotonic Dystrophy Type I
Authors: Bonifazi Emanuela , Gullotta Francesca , Vallo Laura , Iraci Raniero , Nardone Anna Maria , Brunetti Ercole , Botta Annalisa , Novelli Giuseppe
Published: January 2006

Background: Myotonic dystrophy type 1 (DM1; OMIM #160900) is an autosomal-dominant genetic disorder with multisystemic clinical features associated with a CTG expansion in the 3′ untranslated region of the DMPK gene on chromosome 19q13.3. A long-PCR protocol to detect the DM1 expansion is rapid, sensitive, and accurate, but interpretative limitations can occur when the expansion size exceeds the PCR amplification range and in cases of somatic mosaicism.

Methods: To overcome these problems, we used RNA fluorescence in situ hybridization (RNA-FISH) to study cultured cells derived from chorionic villus samples (CVS) with the DM1 mutation. The RNA-FISH method is designed to detect the distinctive DM1 cellular phenotype, characterized by the presence of nuclei with focal ribonuclear inclusions (foci) containing the DMPK expanded transcripts. We analyzed 6 CVS from DM1-predicted pregnancies and 6 CVS from DM1-negative pregnancies.

Results: In 4 DM1-predicted fetuses with a CTG expansion >200 CTG, varying numbers of ribonuclear inclusions were clearly visible in all cells. One case with a somatic mosaicism for the DMPK mutation showed 15% of cells with no nuclear foci. No nuclear signals were detected in all controls examined (n = 6) and in 1 DM1-positive sample with a CTG expansion <100 copies.

Conclusion: Nuclear foci, and therefore the DM1 mutation they are caused by, can be detected efficiently on interphase nuclei of trophoblast cells with RNA-FISH when the CTG expansion is >200 copies.
Prediction of Hospital Mortality Rates by Admission Laboratory Tests
Authors: Froom Paul , Shimoni Zvi
Published: January 2006

Background: The aim of this study was to explore whether electronically retrieved laboratory data can predict mortality in internal medicine departments in a regional hospital.

Methods: All 10 308 patients hospitalized in internal medicine departments over a 1-year period were included in the cohort. Nearly all patients had a complete blood count and basic clinical chemistries on admission. We used logistic regression analysis to predict the 573 deaths (5.6%), including all variables that added significantly to the model.

Results: Eight laboratory variables and age significantly and independently contributed to a logistic regression model (area under the ROC curve, 88.7%). The odds ratio for the final model per quartile of risk was 6.44 (95% confidence interval, 5.42–7.64), whereas for age alone, the odds ratio per quartile was 2.01 (95% confidence interval, 1.84–2.19).

Conclusions: A logistic regression model including only age and electronically retrieved laboratory data highly predicted mortality in internal medicine departments in a regional hospital, suggesting that age and routine admission laboratory tests might be used to ensure a fair comparison when using mortality monitoring for hospital quality control.