bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial lipopolysaccharide induces apoptosis in the trout ovary
Authors: MacKenzie Simon , Montserrat Nuria , Mas Mario , Acerete Laura , Tort Lluis , Krasnov Aleksei , Goetz Frederick W , Planas Josep V
Published: August 2006

Background

In mammals it is well known that infections can lead to alterations in reproductive function. As part of the innate immune response, a number of cytokines and other immune factors is produced during bacterial infection or after treatment with lipopolysaccharide (LPS) and acts on the reproductive system. In fish, LPS can also induce an innate immune response but little is known about the activation of the immune system by LPS on reproduction in fish. Therefore, we conducted studies to examine the in vivo and in vitro effects of lipopolysaccharide (LPS) on the reproductive function of sexually mature female trout.

Methods

In saline- and LPS -injected brook trout, we measured the concentration of plasma steroids as well as the in vitro steroidogenic response (testosterone and 17alpha-hydroxyprogesterone) of ovarian follicles to luteinizing hormone (LH), the ability of 17alpha,20beta-dihydroxy-4-pregnen-3-one to induce germinal vesicle breakdown (GVBD) in vitro, and that of epinephrine to stimulate follicular contraction in vitro. We also examined the direct effects of LPS in vitro on steroid production, GVBD and contraction in brook trout ovarian follicles. The incidence of apoptosis was evaluated by TUNEL analysis. Furthermore, we examined the gene expression pattern in the ovary of saline- and LPS-injected rainbow trout by microarray analysis.

Results

LPS treatment in vivo did not affect plasma testosterone concentration or the basal in vitro production of steroids, although a small but significant potentiation of the effects of LH on testosterone production in vitro was observed in ovarian follicles from LPS-treated fish. In addition, LPS increased the plasma concentration of cortisol. LPS treatment in vitro did not affect the basal or LH-stimulated steroid production in brook trout ovarian follicles. In addition, we did not observe any effects of LPS in vivo or in vitro on GVBD or follicular contraction. Therefore, LPS did not appear to impair ovarian steroid production, oocyte final maturation or follicular contraction under the present experimental conditions. Interestingly, LPS administration in vivo induced apoptosis in follicular cells, an observation that correlated with changes in the expression of genes involved in apoptosis, as evidenced by microarray analysis.

Conclusion

These results indicate that female trout are particularly resistant to an acute administration of LPS in terms of ovarian hormone responsiveness. However, LPS caused a marked increase in apoptosis in follicular cells, suggesting that the trout ovary could be sensitive to the pro-apoptotic effects of LPS-induced inflammatory cytokines.
Deformed wing virus is not related to honey bees' aggressiveness
Authors: Rortais Agnès , Tentcheva Diana , Papachristoforou Alexandros , Gauthier Laurent , Arnold Gérard , Colin Marc Edouard , Bergoin Max
Published: August 2006

Guards of Cyprian honey bee colonies, Apis mellifera cypria, display a great defensive behaviour against hornets' attacks. The deformed wing virus (DWV) and the kakugo virus (KV) genomes are very similar, but unlike KV, the presence of DWV is not related to honey bees' aggressiveness. This discrepancy is further discussed.
Involvement of intracellular free Ca2+ in enhanced release of herpes simplex virus by hydrogen peroxide
Authors: Arimoto Emiko , Iwai Soichi , Sumi Tetsuro , Ogawa Yuzo , Yura Yoshiaki
Published: August 2006

Background

It was reported that elevation of the intracellular concentration of free Ca2+ ([Ca2+]i) by a calcium ionophore increased the release of herpes simplex virus type 1 (HSV-1). Freely diffusible hydrogen peroxide (H2O2) is implied to alter Ca2+ homeostasis, which further enhances abnormal cellular activity, causing changes in signal transduction, and cellular dysfunction. Whether H2O2 could affect [Ca2+]i in HSV-1-infected cells had not been investigated.

Results

H2O2 treatment increased the amount of cell-free virus and decreased the proportion of viable cells. After the treatment, an elevation in [Ca2+]i was observed and the increase in [Ca2+]i was suppressed when intracellular and cytosolic Ca2+ were buffered by Ca2+ chelators. In the presence of Ca2+ chelators, H2O2-mediated increases of cell-free virus and cell death were also diminished. Electron microscopic analysis revealed enlarged cell junctions and a focal disintegration of the plasma membrane in H2O2-treated cells.

Conclusion

These results indicate that H2O2 can elevate [Ca2+]i and induces non-apoptotic cell death with membrane lesions, which is responsible for the increased release of HSV-1 from epithelial cells.
Fine mapping of genes within the IDDM8region in rheumatoid arthritis
Authors: Hinks Anne , Barton Anne , John Sally , Shephard Neil , Worthington Jane
Published: August 2006

The IDDM8 region on chromosome 6q27, first identified as a susceptibility locus for type 1 diabetes, has previously been linked and associated with rheumatoid arthritis (RA). The region contains a number of potential candidate genes, including programmed cell death 2 (PDCD2), the proteosome subunit beta type 1 (PSMB1), delta-like ligand 1 (DLL-1) and TATA box-binding protein (TBP) amongst others. The aim of this study was to fine map the IDDM8 region on chromosome 6q27, focusing on the genes in the region, to identify polymorphisms that may contribute to susceptibility to RA and potentially to other autoimmune diseases. Validated single nucleotide polymorphisms (SNPs; n = 65) were selected from public databases from the 330 kb region of IDDM8. These were genotyped using Sequenom MassArray genotyping technology in two datasets; the test dataset comprised 180 RA cases and 180 controls. We tested 50 SNPs for association with RA and any significant associations were genotyped in a second dataset of 174 RA cases and 192 controls, and the datasets were combined before analysis. Association analysis was performed by chi-square test implemented in Stata software and linkage disequilibrium and haplotype analysis was performed using Helix tree version 4.1. There was initial weak evidence of association, with RA, of a number of SNPs around the loc154449 putative gene and within the KIAA1838 gene; however, these associations were not significant in the combined dataset. Our study has failed to detect evidence of association with any of the known genes mapping to the IDDM8 locus with RA.
S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules
Authors: Foell Dirk , Wittkowski Helmut , Vogl Thomas , Roth Johannes
Published: August 2006

Damage-associated molecular pattern (DAMP) molecules have been introduced as important proinflammatory factors of innate immunity. One example known for many years to be expressed in cells of myeloid origin are phagocytic S100 proteins, which mediate inflammatory responses and recruit inflammatory cells to sites of tissue damage. An emerging concept of pattern recognition involves the multiligand receptor foradvanced glycation end products (RAGE) and Toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including S100 proteins. S100A8, S100A9, and S100A12 are found at high concentrations in inflamed tissue, where neutrophils and monocytes belong to the most abundant cell types. They exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo. Although S100A12 binds to RAGE, at least part of the proinflammatory effects of the S100A8/S100A9 complex depend upon interaction with other receptors. Because of the divergent expression patterns, the absence of S100A12 in rodents, the different interaction partners described, and the specific intracellular and extracellular effects reported for these proteins, it is important to differentiate between distinct S100 proteins rather than subsuming them with the term “S100/calgranulins.” Analyzing the molecular basis of the specific effects exhibited by these proteins in greater detail bears the potential to elucidate important mechanisms of innate immunity, to establish valid biomarkers of phagocytic inflammation, and eventually to reveal novel targets for innovative anti-inflammatory therapies.
Psychiatric out-patient services: origins and future
Authors: Killaspy Helen
Published: August 2006

Psychiatric out-patient services originated in the early-20th century to enable triage of new referrals to the asylum in order to differentiate between treatable and untreatable cases. They evolved to provide community follow-up of patients discharged from hospital and assessment of those newly referred to psychiatric services. Non-attendance at out-patient appointments represents an enormous waste of clinical and administrative resources and has potentially serious clinical implications for those who are most psychiatrically unwell. The place of out-patient clinics in modern community mental health services is explored with reference to the reasons for, and clinical and cost implications of, missed appointments. An alternative model is described that incorporates recent UK government guidance on the roles and implementation of community mental health teams, liaison with primary care and new roles for consultant psychiatrists.
The antidepressant tale: figures signifying nothing?
Authors: Healy David
Published: August 2006

This article reviews how data on the benefits and hazards of antidepressants have been analysed, and how conclusions drawn from these analyses conflict with the data. Randomised trials of antidepressants have for two decades consistently shown evidence of an increased risk of suicidal acts on active treatment compared with placebo, but an inappropriate application of significance testing has led to this evidence being dismissed. During the same period a minority of antidepressant trials have produced data indicative of benefits that have reached statistical significance at a 95% level. In this case significance testing appears to have led to an unrealistic impression of the likely benefits of treatment in practice. Current approaches to evidence-based medicine risk perpetuating misunderstandings of this type. Against a background of current developments in healthcare delivery, clinicians might need to reconsider how they handle and present clinical trial data.
Self-harm: a strategy for survival and nodal point of change
Authors: Nathan Jack
Published: August 2006

The author explores key issues related to psychotherapeutic work with people who self-harm. Particular attention is given to the powerful countertransference feelings that practitioners often experience in this work and the importance of managing these. Rather than maintaining a detached distance, therapists should emotionally engage with the patient's experience, creating a unique therapeutic relationship. The common patterns, functions and meanings of self-harm are discussed, with clinical vignettes that highlight the underlying dynamics of the behaviour. Self-harm is a survival stratagem, and methods for helping patients to find other ways to cope are suggested. One such is mentalisation, which can enhance the patient's capacity to think, not impulsively act. If patients learn how to assess more accurately their own and other people's states of mind, less destructive behaviours can emerge.
Behavioural phenotypes: causes and clinical implications
Authors: O'Brien Gregory
Published: August 2006

Behavioural phenotypes are patterns of behaviour that present in syndromes caused by chromosomal or genetic abnormalities. They have both physiological and behavioural manifestations with distinctive social, linguistic, cognitive and motor profiles. Their course is not static. Presentation typically varies according to level of learning disability and a host of environmental, developmental and therapeutic influences, and it changes with increasing age.
Allocating resources in mental health: a clinician's guide to involvement
Authors: Davies Mark
Published: August 2006

With fundamental changes to the way services are commissioned and resourced within the UK's National Health Service (NHS), optimising the efficient and effective use of resources has become a key task for mental health clinicians and managers. A core step in this process is ensuring that resources are optimally allocated across the service. This article outlines steps in resource allocation, including understanding how resources are managed through budgets, the link between resource matching and care delivery, and methods of reallocating resources to improve service performance. Influencing appropriate allocation is a critical role for psychiatrists, working with both managers and commissioners in the decision-making process. Understanding resource allocation from a management perspective should improve the ability of psychiatrists to influence this process more effectively.
Insight in psychosis and neuropsychological function
Authors: Aleman André , Agrawal Niruj , Morgan Kevin D. , David Anthony S.
Published: August 2006

Background

One factor contributing to impaired awareness of illness (poor insight) in psychotic disorders may be neurocognitive deficits.

Method

A systematic review and meta-analysis were conducted after data extraction. Following an overall analysis, in which measures of different cognitive domains were taken together, more finegrained analyses investigated whether there was a specific relation with frontal executive functioning, and whether this was influenced by diagnosis or the insight scales used.

Results

There was a significant mean correlation between insight ratings and neurocognitive performance (mean weightedr=0.17, 95% CI 0.13–0.21,z=8.3,P< 0.0001), based on 35 studies with a total of 2354 individuals. Further analyses revealed that the effect of general intellectual impairment was smaller than the specific association with executive function. This was only the case for psychosis in general, and not in an analysis limited to schizophrenia, where all cognitive domains were associated with impaired insight to a similar degree.

Conclusions

Neuropsychological dysfunction, specifically impairment of set-shifting and error monitoring, contributes to poor insight in psychosis. Specific relations with different dimensions of insight and the putative role of metacognitive functions require further study.
Untreated illness and outcome of psychosis
Authors: Clarke Mary , Whitty Peter , Browne Stephen , McTigue Orfhlaith , Kamali Moayyad , Gervin Maurice , Kinsella Anthony , Waddington John L. , Larkin Conal , O'Callaghan Eadbhard
Published: August 2006

Background

There has been controversy as to whether early intervention in psychosis
can improve the outcome of the disorder.

Aims

To establish if there is an association between duration of untreated
psychosis and the 4-year outcome of persons with a first episode of
psychosis.

Method

Prospective naturalistic follow-up study of the outcome of consecutive
first presentations with DSM–IV psychosis attending a community-based
psychiatric service.

Results

A longer duration of untreated psychosis was associated with a
significantly poorer functional and symptomatic outcome 4 years later.
For schizophrenia and schizophreniform disorder, each increment in
duration of untreated psychosis was associated with a 7.8 point decrease
in global functioning and an increase in positive symptoms scores by 1.9
points.

Conclusions

This study extends the findings of short-term follow-up studies by
confirming an association between duration of untreated psychosis and
‘midterm’ outcome.
Grey matter correlates of minor physical anomalies in the ÆSOP
first-episode psychosis study
Authors: Dean K. , Fearon P. , Morgan K. , Hutchinson G. , Orr K. , Chitnis X. , Suckling J. , Mallet R. , Leff J. , Jones P. B. , Murray R. M. , Dazzan P.
Published: August 2006

Background

Minor physical anomalies are more prevalent among people with psychosis.
This supports a neurodevelopmental aetiology for psychotic disorders,
since these anomalies and the brain are both ectodermally derived.
However, little is understood about the brain regions implicated in this
association.

Aims

To examine the relationship between minor physical anomalies and grey
matter structure in a sample of patients with first-episode
psychosis.

Method

Sixty patients underwent assessment of minor physical anomalies with the
Lane scale. High-resolution magnetic resonance images and voxel-based
methods of image analysis were used to investigate brain structure in
these patients.

Results

The total anomalies score was associated with a grey matter reduction in
the prefrontal cortex and precuneus and with a grey matter excess in the
basal ganglia, thalamus and lingual gyrus.

Conclusions

Minor physical anomalies in a sample of patients with first-episode
psychosis are associated with regional grey matter changes. These
regional changes may be important in the pathogenesis of psychotic
disorder.
Cognitive impairment in bipolar II disorder
Authors: Torrent Carla , Martínez-Arán Anabel , Daban Claire , Sánchez-Moreno Jose , Comes Mercè , Goikolea José Manuel , Salamero Manel , Vieta Eduard
Published: August 2006

Background

Persistent impairments in neurocognitive function have been described in
bipolar disorder.

Aims

To compare the cognitive performance of patients with bipolar II disorder
with that of patients with bipolar I disorder and a healthy control
group.

Method

The study included 71 euthymic patients with bipolar disorder (38 bipolar
I, 33 bipolar II), who were compared on clinical and neuropsychological
variables (e.g. executive function, attention, verbal and visual memory)
and contrasted with 35 healthy controls on cognitive performance.

Results

Compared with controls, both bipolar groups showed significant deficits
in most cognitive tasks including working memory (Digit Span Backwards,
P=0.002) and attention (Digit Span Forwards,
P=0.005; Trail Making Test,
P=0.001). Those with type II disorders had an
intermediate level of performance between the bipolar I group and the
control group in verbal memory (P < 0.005) and
executive functions (Stroop interference task,
P=0.020).

Conclusions

Cognitive impairment exists in both subtypes of bipolar disorder,
although more so in the bipolar I group. The best predictors of poor
psychosocial functioning in bipolar II disorder were subclinical
depressive symptoms, early onset of illness and poor performance on a
measure related to executive function.
Internet information-seeking in mental health
Authors: Powell John , Clarke Aileen
Published: August 2006

Background

A major use of the internet is for health information-seeking. There has
been little research into its use in relation to mental health.

Aims

To investigate the prevalence of internet use for mental health
information-seeking and its relative importance as a mental health
information source.

Method

General population survey. Questions covered internet use, past
psychiatric history and the 12-item General Health Questionnaire.

Results

Eighteen per cent of all internet users had used the internet for
information related to mental health. The prevalence was higher among
those with a past history of mental health problems and those with
current psychological distress. Only 12% of respondents selected the
internet as one of the three most accurate sources of information,
compared with 24% who responded that it was one of the three sources they
would use.

Conclusions

The internet has a significant role in mental health information-seeking.
The internet is used more than it is trusted.
Physical vulnerability and fatal self-harm in the
elderly
Authors: Eddleston Michael , Dissanayake Mathisha , Sheriff M. H. Rezvi , Warrell David A. , Gunnell David
Published: August 2006

Although the high rate of suicide in elderly people is conventionally
explained as being due to greater intent to die, we have noted elderly Sri
Lankans dying after relatively mild poisoning. Using data from cases of
yellow oleander poisoning, we investigated the effect of age on outcome in
1697 patients, controlling for gender and amount ingested. In fully adjusted
models, people over 64 years old were 13.8 (95% CI 3.6–53.0) times more
likely to die than those less than 25 years old. The high number of suicides
in elderly people globally is likely to be due, in part, to the difficulty
they face in surviving the effects of both the poisoning and its
treatment.
Vagus nerve stimulation in chronic treatment-resistant
depression
Authors: Corcoran Ciaran D. , Thomas Philip , Phillips Jack , O'Keane Veronica
Published: August 2006

We evaluated the efficacy and safety of vagus nerve stimulation therapy in
the treatment of 11 patients with chronic treatment-resistant depression.
Mood was evaluated at frequent intervals over the year following
implantation. All measures of depression, including the Hamilton Rating
Scale for Depression reduced significantly. The response and remission rates
were 55% and 27% respectively at 1 year. Side-effects were common, and some
were severe.
Attitudes of mental health practitioners to the Hippocratic Oath: tradition and modernity in psychiatry
Authors: Marzanski Marek , Coupe Tim , Musunuri Padmapriya
Published: August 2006

Aims and Method

To establish whether psychiatrists believe that medicine should be practised according to the principles of the Hippocratic Oath, an anonymised postal questionnaire survey was conducted of all medical staff at the Caludon Centre, an 80-bed in-patient mental health unit in Coventry.

Results

Thirty-three respondents (82.5%) believed that medicine should be practised according to the Oath. Support for the 15 separate statements derived from the Oath varied considerably.

Clinical Implications

The principles of the Oath remain an important guide to the ethical basis of medical practice for most medical staff surveyed.
Psychiatric admission booking: audit of the impact of a standardised admission form
Authors: Dinniss Stephen , Dawe Jocelyn , Cooper Michael
Published: August 2006

Aims and Method

We used a complete audit cycle to assess the quality and completeness of current admission bookings by junior doctors and whether the introduction of a standardised admission form led to improvements.

Results

Following the introduction of the standardised form significant improvements were found in almost all areas, including the recording of basic data, history, mental state, physical examination, risk assessments and diagnosis.

Clinical Implications

The introduction of a standardised admission form improved the completeness of information obtained. The form may also be used as an educational tool and to assist trainees preparing for examinations.
Diary from Sri Lanka's east coast: settling in
Authors: Rose Nick
Published: August 2006

In the early morning, speeding between green shimmering fields of paddy, a line of soldiers comes into view. They are strung along the road, languidly prodding piles of rubbish with metal tridents, checking for claymore mines that may have been planted overnight. Arriving at the rural hospital, I settle down to supervise the young medical officer running the new mental health clinic. I concentrate on developing her clinical skills. I give her plenty of feedback, highlighting things done well, areas to work on, that sort of thing. We have discussions about assessment issues, risk, appropriate treatment strategies, family involvement, working with local belief systems, thinking critically. I also supervise her in training the community workers who attend with the patient and family; it is almost unheard of for a patient to come alone.
Why people are often reluctant to see a psychiatrist
Authors: Morgan Graham
Published: August 2006

The Highland Users Group (HUG) is a collective advocacy group run through 13 branches spread throughout the Scottish Highlands. It has over 360 members and has two tasks: (a) to speak out about the lives of its members in order to press for changes to improve their lives and (b) to raise awareness of mental ill health in an attempt to challenge the stigma and discrimination that users face. Our work has been recognised as being of a consistently high quality, both locally and nationally within Scotland.
Satisfaction with a research mentoring scheme for specialist registrars
Authors: Winter Nicole , Rathod Shanaya , Gregoire Alain
Published: August 2006

Aims and Method

Following the introduction of a new research mentoring process, a survey was conducted of Wessex specialist registrars' views on research training.

Results

Of 34 respondents, 26 (76.5%) had agreed a plan with a research mentor and 31 (91.2%) were making good use of their research day for specified purposes. Of 24 trainees undertaking research, 21 (87.5%) felt adequately supported, 20 (83.3%) were interested in their research, 16 (66.7%) enjoyed it and 21 (87.5%) gained research knowledge/skills.

Clinical Implications

Agreeing a research training plan with a mentor, coupled with regularly reviewed support and supervision through a newly developed mentoring process, was associated with high levels of trainee satisfaction. Compared with a previous survey, these results indicate considerable improvement in research training.
Rewarming Rates in Urban Patients with Hypothermia: Prediction of Underlying Infection
Authors: Delaney Kathleen A. , Vassallo Susi U. , Larkin Gregory L. , Goldfrank Lewis R.
Published: August 2006

Background:
In the urban setting, hypothermia is commonly associated with illness or intoxication, with death often secondary to infection.

Objectives:
To evaluate factors that affect the rewarming rate (RWR) and the ability of the RWR and other clinical markers to predict the presence or absence of underlying infection in an adult urban population.

Methods:
This was a prospective observational study of hypothermic patient visits to a large emergency department. Serial temperatures were obtained during rewarming to construct rewarming curves. Rewarming modalities selected by emergency physicians were correlated with admission temperatures. Univariate associates of RWR and infection were assessed.

Results:
The authors identified 96 patient visits. The median temperature was 89.5°F (31.9°C; range, 73.0°F to 95.0°F [22.8°C to 35.0°C]). Thirteen patients had temperatures of < 80.0°F (26.0°C). Seven died within 14 hours of presentation; six, of infection. No patient experienced ventricular fibrillation. Potential candidate predictors of infection from a multivariate analysis were a RWR of < 1.80°F (1.0°C) per hour and a serum albumin of < 2.7 g/dL. Rapid rewarming was associated with the absence of infection and a temperature below 86.0°F (30.0°C). In patients without significant underlying illness, rewarming rates appeared to be independent of the modality of rewarming.

Conclusions:
Rewarming rates reflect intrinsic capacity for thermogenesis. Increased RWRs were associated with the absence of infection. The achievement of normothermia did not prevent death in infected patients. Initiation of invasive rewarming in urban patients with hypothermia who have not had hypothermic cardiac arrest may be unwarranted. Management of this population should emphasize support, detection, and treatment of underlying illness.
Lymph Node Status and TS Gene Expression Are Prognostic Markers in Stage II/III Rectal Cancer After Neoadjuvant Fluorouracil-Based Chemoradiotherapy
Authors: Liersch Torsten , Langer Claus , Ghadimi B. Michael , Kulle Bettina , Aust Daniela E. , Baretton Gustavo B. , Schwabe Wolfgang , Häusler Peter , Becker Heinz , Jakob Christiane
Published: August 2006

Purpose

According to the CAO/ARO/AIO-94 trial of the German Rectal Cancer Study Group, preoperative combined fluorouracil (FU) -based long-term chemoradiotherapy (CT/RT) is recommended for patients with International Union Against Cancer (UICC) stage II/III rectal cancer. However, despite the local benefit of neoadjuvant treatment, the overall prognostic value remains uncertain in comparison with adjuvant CT/RT. Furthermore, the prognostic value of molecular biomarkers, such as thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), all of which are involved in the FU metabolism, is unknown in neoadjuvant settings. We assessed the impact of standardized preoperative CT/RT and intratumoral TS, TP, and DPD levels on patient outcome.

Patients and Methods

Forty patients with rectal cancer pretherapeutic UICC stage II/III, receiving preoperative FU-based CT/RT (CAO/ARO/AIO-94 trial) followed by standardized surgery, including total mesorectal excision, were investigated. Downsizing, downstaging, tumor regression, as well as TS, TP, and DPD gene expression of post-treatment surgical specimens were correlated with disease-free survival (DFS) and overall survival (OS).

Results

Significant downsizing (P < .001) and downstaging (P = .001) were achieved with preoperative CT/RT. During a median follow-up of 49 months (95% CI, 43 to 58 months), the cancer recurrence rate was 28.2%. DFS and OS were significantly increased in patients with downstaging (P < .001 and P = .003, respectively), compared with patients without downstaging. All patients who developed cancer recurrence had a persistent positive lymph node status after preoperative CT/RT (P < .001) and a significantly higher TS gene expression (P = .035) compared with those patients without recurrence.

Conclusion

Persistent positive lymph node status and high intratumoral TS expression after preoperative CT/RT are predictive of an unfavorable prognosis in rectal cancer UICC stage II/III.
Risk of Cardiovascular Mortality in Prostate Cancer Patients in the Rotterdam Randomized Screening Trial
Authors: Otto Suzie J. , Schröder Fritz H. , de Koning Harry J.
Published: August 2006

Purpose

To estimate the risk of cardiovascular disease (CVD) mortality in prostate cancer patients in the Rotterdam section of European Randomized Study of Screening for Prostate Cancer, in both arms, and to compare this with the risk in the general population.

Methods

Standardized mortality ratios (SMRs) of cardiovascular mortality for 2,211 prostate cancer patients were calculated including analyses for treatment subgroups (surgery, radiotherapy, watchful waiting, and hormone therapy). Cardiovascular mortality was defined as death as a result of all CVD and as a result of coronary heart disease, acute myocardial infarction, other diseases of the heart, and cerebrovascular accidents. The prevalence of self-reported comorbidities at entry of the trial was evaluated as well.

Results

After a mean follow-up of 5.5 years, 258 prostate cancer patients (12%) had died. The SMR of all-cause mortality was 0.90 (95% CI, 0.79 to 1.01). The risk for cardiovascular mortality was low compared with that in the general population; the SMRs varied between 0.37 and 0.49. Low cardiovascular mortality risks were also seen within each treatment subgroup. CVD was the most frequently self-reported comorbidity at entry and prostate cancer patients undergoing radical prostatectomy reported the lowest rates (24%) compared with those receiving other therapies (40% to 42%).

Conclusion

Although some self-selection has occurred, prostate cancer treatment did not increase the risk of dying as a result of cardiovascular causes in our cohort. The risk was significantly lower for all primary treatment modalities, suggesting that less emphasis should be put on CVD as a contraindication for aggressive (surgical) treatment for prostate cancer patients.
Randomized Multicenter Trial of Hyperthermic Isolated Limb Perfusion With Melphalan Alone Compared With Melphalan Plus Tumor Necrosis Factor: American College of Surgeons Oncology Group Trial Z0020
Authors: Cornett Wendy R. , McCall Linda M. , Petersen Rebecca P. , Ross Merrick I. , Briele Henry A. , Noyes R. Dirk , Sussman Jeffrey J. , Kraybill William G. , Kane John M. , Alexander H. Richard , Lee Jeffrey E. , Mansfield Paul F. , Pingpank James F. , Winchester David J. , White Richard L. , Chadaram Vijaya , Herndon James E. , Fraker Douglas L. , Tyler Douglas S.
Published: August 2006

Purpose

To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-α) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma.

Patients and Methods

Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-α during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status.

Results

The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-α arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-α arm, and one disease progression–related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-α arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-α arm (P = .435 and P = .890, respectively).

Conclusion

In locally advanced extremity melanoma treated with HILP, the addition of TNF-α to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-α plus melphalan was associated with a higher complication rate.
Disadvantage of Men Living Alone Participating in Radiation Therapy Oncology Group Head and Neck Trials
Authors: Konski Andre A. , Pajak Thomas F. , Movsas Benjamin , Coyne James , Harris Jonathan , Gwede Clement , Garden Adam , Spencer Sharon , Jones Christopher , Watkins-Bruner Deborah
Published: August 2006

Purpose

This study evaluated whether males without partners were disadvantaged for survival in Radiation Therapy Oncology Group (RTOG) head and neck cancer clinical trials.

Methods

Patients treated on three RTOG trials were studied. The Cox proportional hazards model was used to determine if sex and the interaction between sex and marital/partner status were independent prognostic variables for overall survival controlling for Karnofsky performance status, tumor stage, nodal stage, primary site, and protocol treatment.

Results

A total of 1,901 patients (1,509 men) were entered onto the three RTOG trials, with 1,822 (1,438 men) analyzable patients. Prognostic variables independent of disease-related variables for survival in multivariate analyses restricted to men were age, marital/partner status, and income.

Conclusion

The apparent disadvantage of unpartnered men is striking, even after controlling for disease and other demographic variables. Possible explanations could easily be tested in observational studies, leading to evaluation of simple interventions to improve their outcome.
Predictors of Recurrence in Patients With T2 and Early T3, N0 Adenocarcinoma of the Rectum Treated by Surgery Alone
Authors: Nissan Aviram , Stojadinovic Alexander , Shia Jinru , Hoos Axel , Guillem Jose G. , Klimstra David , Cohen Alfred M. , Minsky Bruce D. , Paty Philip B. , Wong W. Douglas
Published: August 2006

Purpose

Treatment of rectal cancer with neoadjuvant radiotherapy has been shown to reduce local recurrence and improve overall survival. The role of chemoradiotherapy in patients with T2, N0 and early T3, N0 rectal cancer, treated by radical surgery with total mesorectal excision, remains controversial. The aim of this study was to identify predictors of recurrence in this group of patients to enhance treatment selection.

Patients and Methods

One hundred patients with primary T2-3, N0 adenocarcinoma of the rectum, uniformly treated by surgery alone, were studied. The pathology slides available for 97 patients were rereviewed. Three patients with incomplete data sets were excluded. Clinical and survival data were obtained from a prospective computerized database and updated from hospital and office charts. The study end points were disease-free survival, disease-specific survival (DSS), time to pelvic recurrence (PR), and distant recurrence.

Results

Complete follow-up was available for all study patients. Median follow-up was 79.5 months (range, 57.7 to 105.9 months). During this time period 30 patients (31.9%) died as a result of disease and 64 patients (68.1%) remained alive and disease free. Five-year DSS was 73%. The cumulative risk for PR was 8% at 5 years and 10% at 8 years. Lymphovascular invasion, preoperative serum carcinoembryonic antigen (CEA > 5 ng/mL) level, and age older than 70 years were all associated with adverse outcome.

Conclusion

Patients with T2-3, N0 rectal cancers and either lymphovascular invasion or elevated CEA levels have reduced survival and a higher incidence of PR, and should be considered for future randomized trials.
Pooled Analysis of Safety and Efficacy of Oxaliplatin Plus Fluorouracil/Leucovorin Administered Bimonthly in Elderly Patients With Colorectal Cancer
Authors: Goldberg Richard M. , Tabah-Fisch Isabelle , Bleiberg Harry , de Gramont Aimery , Tournigand Christophe , Andre Thierry , Rothenberg Mace L. , Green Erin , Sargent Daniel J.
Published: August 2006

Purpose

Oxaliplatin, fluorouracil, and leucovorin are commonly used to treat advanced and resected colorectal cancer. This analysis compares the safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly (FOLFOX4) in patients age younger than and at least 70 years.

Patients and Methods

This retrospective analysis included 3,742 colorectal cancer patients (614 age ≥ 70) from four clinical trials testing FOLFOX4 in the adjuvant, first-, and second-line settings. End points included grade ≥ 3 adverse events, response rate (in advanced disease), progression or relapse-free survival, dose-intensity, and overall survival in the studies with mature survival data.

Results

Grade ≥ 3 hematologic toxicity (neutropenia [43% v 49%; P = .04] and thrombocytopenia [2% v 5%; P = .04]) were significantly higher in older patients. Older age was not associated with increased rates of severe neurologic adverse events, diarrhea, nausea/vomiting, infection, overall incidence of grade ≥ 3 toxicity (63% v 67%; P = .15), or 60-day mortality (1.1% v 2.3%; P = .20). The relative benefit of FOLFOX4 versus control did not differ by age for response rate, progression or recurrence free-survival (hazard ratio, 0.70 for FOLFOX4 v control for age < 70, 0.65 for age ≥ 70; P = .42), or overall survival (hazard ratio, 0.77 age < 70, 0.82 age ≥ 70; P = .79). Dose-intensity did not differ by age at cycles 1, 3, 6, or 12.

Conclusion

FOLFOX4 maintains its efficacy and safety ratio in selected elderly patients with colorectal cancer. Its judicious use should be considered without regard to patient age, although scant data are available among patients older than 80 years.
Depletion of the co-chaperone CDC-37 reveals two modes of PAR-6 cortical association inC. elegansembryos
Authors: Beers Melissa , Kemphues Kenneth
Published: August 2006

PAR proteins play roles in the establishment and maintenance of polarity in many different cell types in metazoans. In C. elegans, polarity established in the one-cell embryo determines the anteroposterior axis of the developing animal and is essential to set the identities of the early blastomeres. PAR-1 and PAR-2 colocalize at the posterior cortex of the embryo. PAR-3, PAR-6 and PKC-3 (aPKC) colocalize at the anterior cortex of the embryo. A process of mutual exclusion maintains the anterior and posterior protein domains. We present results indicating that a homolog of the Hsp90 co-chaperone Cdc37 plays a role in dynamic interactions among the PAR proteins. We show that CDC-37 is required for the establishment phase of embryonic polarity; that CDC-37 reduction allows PAR-3-independent cortical accumulation of PAR-6 and PKC-3; and that CDC-37 is required for the mutual exclusion of the anterior and posterior group PAR proteins. Our results indicate that CDC-37 acts in part by maintaining PKC-3 levels and in part by influencing the activity or levels of other client proteins. Loss of the activities of these client proteins reveals that there are two sites for PAR-6 cortical association, one dependent on CDC-42 and not associated with PAR-3,and the other independent of CDC-42 and co-localizing with PAR-3. We propose that, in wild-type embryos, CDC-37-mediated inhibition of the CDC-42-dependent binding site and PAR-3-mediated release of this inhibition provide a key mechanism for the anterior accumulation of PAR-6.
Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm
Authors: Lindsley R. Coleman , Gill Jennifer G. , Kyba Michael , Murphy Theresa L. , Murphy Kenneth M.
Published: August 2006

Formation of mesoderm from the pluripotent epiblast depends upon canonical Wnt/β-catenin signaling, although a precise molecular basis for this requirement has not been established. To develop a robust model of this developmental transition, we examined the role of Wnt signaling during the analogous stage of embryonic stem cell differentiation. We show that the kinetics of Wnt ligand expression and pathway activity in vitro mirror those found in vivo. Furthermore, inhibition of this endogenous Wnt signaling abrogates the functional competence of differentiating ES cells, reflected by their failure to generate Flk1+ mesodermal precursors and subsequent mature mesodermal lineages. Microarray analysis at various times during early differentiation reveal that mesoderm- and endoderm-associated genes fail to be induced in the absence of Wnt signaling, indicating a lack of germ layer induction that normally occurs during gastrulation in vivo. The earliest genes displaying Wnt-dependent expression, however, were those expressed in vivo in the primitive streak. Using an inducible form of stabilized β-catenin, we find that Wnt activity, although required, does not autonomously promote primitive streak-associated gene expression in vitro. Our results suggest that Wnt signaling functions in this model system to regulate the thresholds or stability of responses to other effector pathways and demonstrate that differentiating ES cells represent a useful model system for defining complex regulatory interactions underlying primary germ layer induction.
BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites
Authors: Miura Shigeto , Davis Shannon , Klingensmith John , Mishina Yuji
Published: August 2006

Bmpr1a encodes the BMP type IA receptor for bone morphogenetic proteins (BMPs), including 2 and 4. Here, we use mosaic inactivation of Bmpr1a in the epiblast of the mouse embryo (Bmpr-MOREembryos) to assess functions of this gene in mesoderm development. Unlike Bmpr1a-null embryos, which fail to gastrulate, Bmpr-MOREembryos initiate gastrulation, but the recruitment of prospective paraxial mesoderm cells to the primitive streak is delayed. This delay causes a more proximal distribution of cells with paraxial mesoderm character within the primitive streak, resulting in a lateral expansion of somitic mesoderm to form multiple columns. Inhibition of FGF signaling restores the normal timing of recruitment of prospective paraxial mesoderm and partially rescues the development of somites. This suggests that BMP and FGF signaling function antagonistically during paraxial mesoderm development.
Gata3 participates in a complex transcriptional feedback network to regulate sympathoadrenal differentiation
Authors: Moriguchi Takashi , Takako Nakano , Hamada Michito , Maeda Atsuko , Fujioka Yuki , Kuroha Takashi , Huber Reuben E. , Hasegawa Susan L. , Rao Arvind , Yamamoto Masayuki , Takahashi Satoru , Lim Kim-Chew , Engel James Douglas
Published: August 2006

Gata3 mutant mice expire of noradrenergic deficiency by embryonic day (E) 11 and can be rescued pharmacologically or, as shown here, by restoring Gata3 function specifically in sympathoadrenal (SA) lineages using the human DBH promoter to direct Gata3 transgenic expression. In Gata3-null embryos, there was significant impairment of SA differentiation and increased apoptosis in adrenal chromaffin cells and sympathetic neurons. Additionally, mRNA analyses of purified chromaffin cells from Gata3 mutants show that levels of Mash1, Hand2 and Phox2b(postulated upstream regulators of Gata3) as well as terminally differentiated SA lineage products (tyrosine hydroxylase, Th, and dopamineβ-hydroxylase, Dbh) are markedly altered. However, SA lineage-specific restoration of Gata3 function in the Gata3 mutant background rescues the expression phenotypes of the downstream, as well as the putative upstream genes. These data not only underscore the hypothesis that Gata3 is essential for the differentiation and survival of SA cells, but also suggest that their differentiation is controlled by mutually reinforcing feedback transcriptional interactions between Gata3, Mash1, Hand2 and Phox2b in the SA lineage.
Loss of cyclin D1 impairs cerebellar development and suppresses medulloblastoma formation
Authors: Pogoriler Jennifer , Millen Kathleen , Utset Manuel , Du Wei
Published: August 2006

Medulloblastoma, the most common malignant brain tumor of childhood, is believed to derive from immature granule neuron precursors (GNPs) that normally proliferate in the external granule layer before exiting the cell cycle and migrating to their mature location in the inner granule layer. In this study, we examined the expression of D type cyclins in GNPs during cerebellar development and showed that GNPs in early development expressed only cyclin D1, whereas later GNPs expressed both cyclins D1 and D2. Coinciding with the period of cyclin D1-only expression, Ccnd1-/- mice showed reduced proliferation of GNPs and impaired growth of the cerebellum. Interestingly, removal of cyclin D1 was sufficient to drastically reduce the incidence of medulloblastoma in Ptch1+/- mice, despite the fact that these tumors showed upregulation of both cyclins D1 and D2. We showed that cyclin D1 has an earlier role in tumorigenesis: in the absence of cyclin D1, the incidence and overall volume of `preneoplastic' lesions were significantly decreased. We propose a model that links a role of cyclin D1 in normal GNP proliferation with its early role in tumorigenesis.