bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced Breast Cancer and Breast Cancer Mortality in Randomized Controlled Trials on Mammography Screening
Authors: Autier Philippe , Héry Clarisse , Haukka Jari , Boniol Mathieu , Byrnes Graham
Published: November 2009

Purpose

We assessed changes in advanced cancer incidence and cancer mortality in eight randomized trials of breast cancer screening.

Patients and Methods

Depending on published data, advanced cancer was defined as cancer ≥ 20 mm in size (four trials), stage II+ (four trials), and ≥ one positive lymph node (one trial). For each trial, we obtained the estimated relative risk (RR) and 95% CI between the intervention and control groups, for both breast cancer mortality and diagnosis of advanced breast cancer. Using a meta-regression approach, log(RR-mortality) was regressed on log(RR-advanced cancer), weighting each trial by the reciprocal of the square of the standard error of log(RR) for mortality.

Results

RR for advanced breast cancer ranged from 0.69 (95% CI, 0.61 to 0.78) in the Swedish Two-County Trial to 0.97 (95% CI, 0.97 to 1.25) in the Canadian National Breast Screening Study-1 (NBSS-1) trial. Log(RR)s for advanced cancer were highly predictive of log(RR)s for mortality (R2= 0.95; P < .0001), and the linear regression curve had a slope of 1.00 (95% CI, 0.76 to 1.25) after fixing the intercept to zero. The slope changed only slightly after excluding the Two-County Trial and the Canadian NBSS-1 and NBSS-2 trials.

Conclusion

In trials on breast cancer screening, for each unit decrease in incidence of advanced breast cancer, there was an equal decrease in breast cancer mortality. Monitoring of incidence of advanced breast cancer may provide information on the current impact of screening on breast cancer mortality in the general population.
Melanoma Prognostic Model Using Tissue Microarrays and Genetic Algorithms
Authors: Gould Rothberg Bonnie E. , Berger Aaron J. , Molinaro Annette M. , Subtil Antonio , Krauthammer Michael O. , Camp Robert L. , Bradley William R. , Ariyan Stephan , Kluger Harriet M. , Rimm David L.
Published: November 2009

Purpose

As a result of the questionable risk-to-benefit ratio of adjuvant therapies, stage II melanoma is currently managed by observation because available clinicopathologic parameters cannot identify the 20% to 60% of such patients likely to develop metastatic disease. Here, we propose a multimarker molecular prognostic assay that can help triage patients at increased risk of recurrence.

Methods

Protein expression for 38 candidates relevant to melanoma oncogenesis was evaluated using the automated quantitative analysis (AQUA) method for immunofluorescence-based immunohistochemistry in formalin-fixed, paraffin-embedded specimens from a cohort of 192 primary melanomas collected during 1959 to 1994. The prognostic assay was built using a genetic algorithm and validated on an independent cohort of 246 serial primary melanomas collected from 1997 to 2004.

Results

Multiple iterations of the genetic algorithm yielded a consistent five-marker solution. A favorable prognosis was predicted by ATF2 ln(non-nuclear/nuclear AQUA score ratio) of more than –0.052, p21WAF1 nuclear compartment AQUA score of more than 12.98, p16INK4A ln(non-nuclear/nuclear AQUA score ratio) of ≤ −0.083, β-catenin total AQUA score of more than 38.68, and fibronectin total AQUA score of ≤ 57.93. Primary tumors that met at least four of these five conditions were considered a low-risk group, and those that met three or fewer conditions formed a high-risk group (log-rank P < .0001). Multivariable proportional hazards analysis adjusting for clinicopathologic parameters shows that the high-risk group has significantly reduced survival on both the discovery (hazard ratio = 2.84; 95% CI, 1.46 to 5.49; P = .002) and validation (hazard ratio = 2.72; 95% CI, 1.12 to 6.58; P = .027) cohorts.

Conclusion

This multimarker prognostic assay, an independent determinant of melanoma survival, might be beneficial in improving the selection of stage II patients for adjuvant therapy.
MicroRNAs in Cancer: Small Molecules With a Huge Impact
Authors: Iorio Marilena V. , Croce Carlo M.
Published: November 2009

Every cellular process is likely to be regulated by microRNAs, and an aberrant microRNA expression signature is a hallmark of several diseases, including cancer. MicroRNA expression profiling has indeed provided evidence of the association of these tiny molecules with tumor development and progression. An increasing number of studies have then demonstrated that microRNAs can function as potential oncogenes or oncosuppressor genes, depending on the cellular context and on the target genes they regulate. Here we review our current knowledge about the involvement of microRNAs in cancer and their potential as diagnostic, prognostic, and therapeutic tools.
Multimodality Screening of High-Risk Women: A Prospective Cohort Study
Authors: Weinstein Susan P. , Localio A. Russell , Conant Emily F. , Rosen Mark , Thomas Kathleen M. , Schnall Mitchell D.
Published: November 2009

Purpose

Mammography has been established as the primary imaging screening method for breast cancer; however, the sensitivity of mammography is limited, especially in women with dense breast tissue. Given the limitations of mammography, interest has developed in alternative screening techniques. This interest has led to numerous studies reporting mammographically occult breast cancers detected on magnetic resonance imaging (MRI) or ultrasound. In addition, digital mammography was shown to be more sensitive than film mammography in selected populations. Our goal was to prospectively compare cancer detection of digital mammography (DM), whole-breast ultrasound (WBUS), and contrast-enhanced MRI in a high-risk screening population previously screened negative by film screen mammogram (FSM).

Methods

During a 2-year period, 609 asymptomatic high-risk women with nonactionable FSM examinations presented for a prospective multimodality screening consisting of DM, WBUS, and MRI. The FSM examinations were reinterpreted by study radiologists. Patients had benign or no suspicious findings on clinical examination. The cancer yield by modality was evaluated.

Results

Twenty cancers were diagnosed in 18 patients (nine ductal carcinomas in situ and 11 invasive breast cancers). The overall cancer yield on a per-patient basis was 3.0% (18 of 609 patients). The cancer yield by modality was 1.0% for FSM (six of 597 women), 1.2% for DM (seven of 569 women), 0.53% for WBUS (three of 567 women), and 2.1% for MRI (12 of 571 women). Of the 20 cancers detected, some were only detected on one imaging modality (FSM, n = 1; DM, n = 3; WBUS, n = 1; and MRI, n = 8).

Conclusion

The addition of MRI to mammography in the high-risk group has the greatest potential to detect additional mammographically occult cancers. The incremental cancer yield of WBUS and DM is much less.
Unique Localization of Circulating Tumor Cells in Patients With Hepatic Metastases
Authors: Jiao Long R. , Apostolopoulos Christos , Jacob Jimmy , Szydlo Richard , Johnson Natalia , Tsim Nicole , Habib Nagy A. , Coombes R. Charles , Stebbing Justin
Published: November 2009

Purpose

There are few data on the impact of immediate and differing surgical interventions on circulating tumor cells (CTCs), nor their compartmentalization or localization in different anatomic vascular sites.

Patients and Methods

CTCs from consecutive patients with colorectal liver metastases were quantified before and immediately after open surgery, laparoscopic resection, open radiofrequency ablation (RFA), or percutaneous RFA. For individuals undergoing open surgery, either hepatic resections or open RFA, CTCs were examined in both systemic and portal circulation by measuring CTCs in samples derived from the peripheral vein, an artery, the hepatic portal vein, and the hepatic vein.

Results

A total of 29 consecutive patients with colorectal liver metastases with a median age of 55 years (range, 30 to 88 years) were included. CTCs were localized to the hepatic portosystemic macrocirculation with significantly greater numbers than in the systemic vasculature. Surgical procedures led to a statistically significant fall in CTCs at multiple sites measured. Conversely, RFA, either open or percutaneous, was associated with a significant increase in CTCs.

Conclusion

Surgical resection of metastases, but not RFA, immediately decreases CTC levels. In patients with colorectal liver metastases, CTCs appear localized to the hepatic (and pulmonary) macrocirculations. This may explain why metastases in sites other than the liver and lungs are infrequently observed in cancer.
Glucocorticoids in Vivo Induce Both Insulin Hypersecretion and Enhanced Glucose Sensitivity of Stimulus-Secretion Coupling in Isolated Rat Islets
Authors: Rafacho Alex , Marroquí Laura , Taboga Sebastião R. , Abrantes Júlia L. F. , Silveira Leonardo R. , Boschero Antonio C. , Carneiro Everardo M. , Bosqueiro José R. , Nadal Angel , Quesada Ivan
Published: October 2009

Although glucocorticoids are widely used as antiinflammatory agents in clinical therapies, they may cause serious side effects that include insulin resistance and hyperinsulinemia. To study the potential functional adaptations of the islet of Langerhans to in vivo glucocorticoid treatment, adult Wistar rats received dexamethasone (DEX) for 5 consecutive days, whereas controls (CTL) received only saline. The analysis of insulin release in freshly isolated islets showed an enhanced secretion in response to glucose in DEX-treated rats. The study of Ca2+ signals by fluorescence microscopy also demonstrated a higher response to glucose in islets from DEX-treated animals. However, no differences in Ca2+ signals were found between both groups with tolbutamide or KCl, indicating that the alterations were probably related to metabolism. Thus, mitochondrial function was explored by monitoring oxidation of nicotinamide dinucleotide phosphate autofluorescence and mitochondrial membrane potential. Both parameters revealed a higher response to glucose in islets from DEX-treated rats. The mRNA and protein content of glucose transporter-2, glucokinase, and pyruvate kinase was similar in both groups, indicating that changes in these proteins were probably not involved in the increased mitochondrial function. Additionally, we explored the status of Ca2+-dependent signaling kinases. Unlike calmodulin kinase II, we found an augmented phosphorylation level of protein kinase Cα as well as an increased response of the phospholipase C/inositol 1,4,5-triphosphate pathway in DEX-treated rats. Finally, an increased number of docked secretory granules were observed in the β-cells of DEX animals using transmission electron microscopy. Thus, these results demonstrate that islets from glucocorticoid-treated rats develop several adaptations that lead to an enhanced stimulus-secretion coupling and secretory capacity.
Carbohydrate-Responsive Gene Expression in the Adipose Tissue of Rats
Authors: Shankar Kartik , Harrell Amanda , Kang Ping , Singhal Rohit , Ronis Martin J. J. , Badger Thomas M.
Published: October 2009

Although obesity is often associated with high-fat diets, it can develop from a variety of meal patterns. Excessive intake of simple carbohydrates is one consistent eating behavior leading to obesity. However, the impact of overconsumption of diets with high carbohydrate to fat ratios (C/F) on body composition and global adipose tissue gene expression remains unclear. We used total enteral nutrition to evaluate the effects of caloric intake and C/F on body weight gain and development of obesity. Female Sprague Dawley rats were fed diets with either low C/F or high C/F (HC) (reflecting a 19.5-fold increase in C/F) at two levels of caloric intake: 187 or 220 kcal/kg3/4 · d (15% excess) for 4 wk. At the end of the study period, rats fed HC diets had about 20% higher body weight at either caloric intake compared with rats fed low C/F diets (P < 0.05). Body composition (assessed by nuclear magnetic resonance, computerized tomography, and adipose tissue weights) revealed higher percent fat mass (P < 0.05) in HC rats. Obesity was associated with increased serum resistin, leptin, fasting hyperinsulinemia, and insulin resistance after an oral glucose challenge (P < 0.05). Microarray analyses of adipose tissues revealed HC diets led to changes in 270 and 464 transcripts at 187 and 220 kcal/kg3/4 · d intakes. Genes regulating glucose transport, glycolysis, fatty acid and triglyceride biosynthesis, desaturation and elongation, adipogenesis, and adipokines were affected by HC diets. These results suggest that C/F and interactions with excessive caloric intake per se may regulate body composition and play important roles in the development of obesity and metabolic syndrome.
Thermoelastohydrodynamics of grease-lubricated concentrated point contacts
Authors: Karthikeyan B K , Teodorescu M , Rahnejat H , Rothberg S J
Published: November 2009

Isothermal and thermoelastohydrodynamic lubrication (TEHL) analyses of grease lubricated bearings are presented. A grease plug flow is formed in the conjunction that, with no shear at the boundaries with the solid surfaces, adheres to them in the region of high pressures under isothermal conditions. The elastohydrodynamic lubrication grease pressure distribution conforms fairly closely to that of its base oil alone, with the exception of inlet trail and pressure spike regions. The dependency of film thickness on speed (rolling viscosity) and load parameters for the base oil agrees with previously reported findings of the research community. For grease there are subtle differences with the base oil film thickness load and speed dependencies. However, it is clear that extrapolated oil film thickness formulae for oils can be used reasonably for the prediction of grease films, at least as a first approximation. The results presented agree well with optical interferometric measurements reported in the literature for grease-lubricated contacts at low temperatures and low surface velocities. TEHL analysis shows breakdown of the plug flow and significant reduction in film thickness, which can lead to changes in the regime of lubrication to mixed or boundary conditions.
Variations in the effect of incarceration on community gonorrhoea rates, Guilford County, North Carolina, 2005–2006
Authors: Porter K A , Thomas J C , Emch M E
Published: November 2009

Community incarceration rates have been shown to be associated with rates of HIV and sexually transmitted diseases (STDs). Mechanisms underlying this association include transmission by recently released inmates and community disruption resulting from the absence of incarcerated individuals. We studied the 2006 rates of gonorrhoea at the census tract level in Guilford County, North Carolina (NC) with the previous year's incarceration rates as the exposure of interest. We replicated an analysis conducted in Durham, NC, but unlike in Durham found no meaningful association. When terms were added to the model to allow for a non-linear effect, incarceration levels were associated with rates of gonorrhoea ( P < 0.05), indicating the effect of incarceration on gonorrhoea rates differs based on the level of incarceration. Using a spatial model, we found evidence that the association varies across the county. The association between incarceration and gonorrhoea varies by the rate of incarceration and geographically.
eTriage – a novel, web-based triage and booking service: enabling timely access to sexual health clinics
Authors: Jones R , Menon-Johansson A , Waters A M , Sullivan A K
Published: November 2009

In recent years, the sexual health of the nation has risen in profile. We face increasing demands and targets, in particular the 48-hour waiting time directive, and as a result clinic access has become a priority. eTriage is a novel, secure, web-based service designed specifically to increase access to our clinics. It has proved a popular booking method, providing access to 10% of all appointments across the Directorate within six months of introduction. KC60 analyses revealed that the majority of users (58%) underwent asymptomatic screening with the remainder having some degree of pathology. There was a greater percentage prevalence of human papilloma virus, chlamydia, non-specific urethritis, gonorrhoea, herpes and trichomonas in the eTriage population when compared with the general clinic population. A notes review illustrated a high degree of concordance between data entered on eTriage registration and clinical review (97%). A patient survey revealed high levels of patient satisfaction with the service. As an adjunct to our existing booking services, eTriage has served to increase patient choice and has proved itself to be a safe, efficient and effective means of improving patient access.
HIV-associated oral plasmablastic lymphoma and role of adherence to highly active antiretroviral therapy
Authors: Francischini E , Martins F M , Braz-Silva P H , Magalhães M H C G , Ortega K L
Published: November 2009

Plasmablastic lymphoma (PBL) is an HIV-associated non-Hodgkin's lymphoma that primarily affects the oral cavity. We describe the case of an HIV patient with a lesion in the maxilla that lasted four months. He was diagnosed with PBL and received highly active antiretroviral therapy as well as chemotherapy and local radiotherapy. The lesion regressed after the third cycle of chemotherapy. The patient interrupted antiretroviral treatment and the lesion recurred. The immune reconstitution secondary to the use of antiretroviral therapy seems to participate in the regression of PBL and maintains the remission of the tumour, but it might not be enough to prevent the development of PBL.
Herpes zoster of the nipple: rapid DNA-based diagnosis by the loop-mediated isothermal amplification method
Authors: Watanabe D , Kuhara T , Ishida N , Takama H , Tamada Y , Matsumoto Y
Published: November 2009

A 28-year-old Japanese man presented with grouped erosions and vesicles on an erythematous base affecting the right areola and the surrounding skin. A Tzanck smear from the vesicle revealed giant cells. An initial clinical diagnosis of mammary herpes simplex was considered but to explore the differential diagnosis, viral DNA was amplified by the loop-mediated isothermal amplification (LAMP) method. DNA replication was observed only in varicella zoster virus LAMP mixture, and this confirmed a diagnosis of herpes zoster. The patient was treated with 3000 mg of daily oral valacyclovir for seven days. After antiviral treatment, the lesion had healed and the pain had resolved completely.
Coping with Uncertainties in Technological Learning
Authors: Ma Tieju
Published: October 2009

To date, optimization models of endogenous technological change commonly deal with uncertainty in technological learning with risk-factor methods, i.e., by adding expected risk costs resulting from overestimating technological learning rates into an objective function with a subjective risk factor. This paper argues that another way of coping with the uncertainty, risk-constrained methods that have been ignored in existing literatures, could be more practicable (at least as a supplement) for decision support. With a simplified model, this paper explores technology development paths generated by two risk-constrained methods, and compares the two risk-constrained methods with a risk-factor method. Our study shows that comparing with the risk-factor method, the two risk-constrained methods also generate an S-shaped technology diffusion pattern, which accords with historical observations, and they can result in earlier as well as later adoption of an advanced but currently expensive technology, depending on different combinations of uncertainty levels of the technology learning rate and the upper limit on the expected risk cost. Another finding of our research is that two totally different technology development paths can both be optimal solutions, which implies that with early policy interventions there is the possibility that an economy could be led to a low-carbon economy with little additional cost.
Late spinal subdural haematoma after spinal anaesthesia for total hip replacement
Authors: Moussallem C. D. , El-Yahchouchi C. A. , Charbel A. C. , Nohra G.
Published: October 2009

We present a case of delayed presentation of a subdural haematoma causing cauda equina syndrome which occurred 96 hours after a spinal anaesthetic had been administered for an elective total hip replacement in an 86-year-old man. The patient had received low-molecular-weight heparin anticoagulation which had been delayed until 12 hours postoperatively. No other cause of the haemorrhage could be identified.
Selective soft-tissue release for recurrent or residual deformity after conservative treatment of idiopathic clubfoot
Authors: Park S.-S. , Kim S. W. , Jung B.-S. , Lee H. S. , Kim J. S.
Published: October 2009

We reviewed the results of a selective à la carte soft-tissue release operation for recurrent or residual deformity after initial conservative treatment for idiopathic clubfoot by the Ponseti method. Recurrent or residual deformity occurred in 13 (19 feet) of 33 patients (48 feet; 40%). The mean age at surgery was 2.3 years (1.3 to 4) and the mean follow-up was 3.6 years (2 to 5.3). The mean Pirani score had improved from 2.8 to 1.1 points, and the clinical and radiological results were satisfactory in all patients. However, six of the 13 patients (9 of 19 feet) had required further surgery in the form of tibial derotation osteotomy, split anterior tibialis tendon transfer, split posterior tibialis transfer or a combination of these for recurrent deformity.

We concluded that selective soft-tissue release can provide satisfactory early results after failure of initial treatment of clubfoot by the Ponseti method, but long-term follow-up to skeletal maturity will be necessary.
Ten-year follow-up of the non-porous Allofit cementless acetabular component
Authors: Zenz P. , Stiehl J. B. , Knechtel H. , Titzer-Hochmaier G. , Schwagerl W.
Published: October 2009

Cementless acetabular fixation has demonstrated superior long-term durability in total hip replacement, but most series have studied implants with porous metal surfaces. We retrospectively evaluated the results of 100 consecutive patients undergoing total hip replacement where a non-porous Allofit component was used for primary press-fit fixation.

This implant is titanium alloy, grit-blasted, with a macrostructure of forged teeth and has a biradial shape. A total of 81 patients (82 hips) were evaluated at final follow-up at a mean of 10.1 years (8.9 to 11.9). The Harris Hip Score improved from a mean 53 points (23 to 73) pre-operatively to a mean of 96 points (78 to 100) at final review. The osseointegration of all acetabular components was radiologically evaluated with no evidence of loosening. The survival rate with revision of the component as the endpoint was 97.5% (95% confidence interval 94 to 100) after 11.9 years. Radiolucency was found in one DeLee-Charnley zone in four acetabular components. None of the implants required revision for aseptic loosening. Two patients were treated for infection, one requiring a two-stage revision of the implant. One femoral stem was revised for osteolysis due to the production of metal wear debris, but the acetabular shell did not require revision.

This study demonstrates that a non-porous titanium acetabular component with adjunct surface fixation offers an alternative to standard porous-coated implants.
Neurological deficit after surgical enucleation of schwannomas of the upper limb
Authors: Park M. J. , Seo K. N. , Kang H. J.
Published: October 2009

We evaluated 56 patients for neurological deficit after enucleation of a histopathologically confirmed schwannoma of the upper limb. Immediately after the operation, 41 patients (73.2%) had developed a new neurological deficit: ten of these had a major deficit such as severe motor or sensory loss, or intolerable neuropathic pain. The mean tumour size had been significantly larger in patients with a major neurological deficit than in those with a minor or no deficit. After a mean 25.4 months (12 to 85), 39 patients (70%) had no residual neurological deficit, and the other 17 (30%) had only hypoaesthesia, paraesthesiae or mild motor weakness.

This study suggests that a schwannoma in the upper limb can be removed with an acceptable risk of injury to the nerve, although a transient neurological deficit occurs regularly after the operation. Biopsy is not advised. Patients should be informed pre-operatively about the possibility of damage to the nerve: meticulous dissection is required to minimise this.
Regio-, stereo-, and enantioselective reactions of carbon acids catalyzed by recoverable organic catalysts bearing ionic liquid moieties
Authors: Zlotin Sergey G. , Kryshtal Galina V. , Zhdankina Galina M. , Kucherenko Alexander S. , Bogolyubov Andrei V. , Siyutkin Dmitriy E.
Published: October 2009

Organic compounds bearing specific ionic liquid (IL) moieties, in particular, bulky organic cations and fluorinated organic or inorganic anions, catalyze many important reactions of carbon acids involving carbanions and enols as reactive species, such as aldol, Michael, and dichlorocyclopropanation reactions. Many of these catalysts are at least comparable to traditional phase-transfer catalysts (PTCs) with halide anions or organocatalysts based on amino acid derivatives. Furthermore, they enjoy the advantage of being readily recoverable and hence are available for multiple recycling in chemical reactions.
Introduction
Authors: Fuss Eric , Trips Carola
Published: November 2009

This volume is concerned with questions raised by two apparently conflicting observations on the inventory of expressions (and in particular, lexical items) in natural languages. On the one hand, it is widely assumed that the rules of grammar include so-called blocking constraints, which prohibit the co-existence of forms that are identical in meaning, but differ in form. On the other hand, it can be shown that many natural languages exhibit examples of non-blocking and at least some degree of linguistic variation involving exactly this type of (morphological) doublets which can be said to compete for realizing one and the same meaning. In the following we are going to introduce the different types of blocking that are discussed in the literature as well as non-blocking effects to set the contributions in this volume in their context.
A phase-based approach to Scandinavian definiteness marking
Authors: Heck Fabian , Müller Gereon , Trommer Jochen
Published: November 2009

We propose a syntactic approach to apparent blocking effects in the realization of definiteness marking in the Scandinavian languages. The claim is that the differences in definiteness marking can be attributed to a requirement that a definiteness feature ([DEF], a property of N) must be located at the left edge of the DP phase in order to be PIC-accessible for probes outside of the DP. As a result, [DEF] can be spelled out on N if N is the only element within DP and [DEF] is therefore part of DP’s edge domain (giving rise to suffixal marking). In contrast, the presence of an (overt) adjectival modifier (at the left edge of DP) requires feature movement of [DEF] to D, which is then realized as a prenominal article (with additional spell-out of the lower copy of [DEF] in Swedish). The paper also addresses the (slightly different) behavior of definiteness marking in the context of relative clauses and certain issues pertaining to the interpretation of the different strategies.
(Non-)Blocking in the voice system
Authors: Kallulli Dalina
Published: November 2009

This paper deals with (non-) blocking phenomena arising in the context of morphological voice marking patterns, such as active versus passive (as in e.g. Latin), or active versus non-active (as in e.g. Albanian and Modern Greek). Starting from the observation that across languages with voice (or voice-related) marking non-blocking effects arise only with unaccusatives (specifically, with so-called “alternating unaccusatives”), but not for instance with passives or reflexives, the paper presents a variety of facts that converge in showing that this situation is due to a difference in the respective featural make-up of passives and unaccusatives. The central claim that is defended is that the passive morphology is being reanalysed as a morpheme that relates not just to an [–external argument] feature, but to a [+activity] feature (in the sense of Kallulli 2007) in a predicate structure (here: v
0) also containing a [–external argument] feature.
Cytotoxic T lymphocyte antigen-4 Ala17 polymorphism is a genetic marker of autoimmune adrenal insufficiency: Italian association study and meta-analysis of European studies
Authors: Brozzetti Annalisa , Marzotti Stefania , Tortoioli Cristina , Bini Vittorio , Giordano Roberta , Dotta Francesco , Betterle Corrado , De Bellis Annamaria , Arnaldi Giorgio , Toscano Vincenzo , Arvat Emanuela , Bellastella Antonio , Mantero Franco , Falorni Alberto
Published: November 2009

Objective

Cytotoxic T lymphocyte antigen-4 (CTLA4) gene polymorphism has been associated with human autoimmune diseases, but discordant data are available on its association with autoimmune Addison's disease (AAD). We tested the human leukocyte antigen (HLA)-independent association of CTLA4+49 (A/G) (Ala 17) and/or CTLA4 CT60 (A/G) polymorphism with AAD.

Design

DNA samples from 180 AAD patients and 394 healthy control subjects from continental Italy were analyzed, and association statistical analyses and meta-analysis of published studies were performed.

Methods

TaqMan minor groove binder chemistry assays and PCR fragment length polymorphism assays were used.

Results

Frequency of allele G of CTLA4+49 was significantly increased among AAD patients (40% alleles) than among healthy controls (27% alleles; P<0.0001). CTLA4 CT60 polymorphism was associated with AAD only in the heterozygous A/G individuals. The frequency of +49 AG+GG genotypes was significantly higher among AAD patients than among healthy control subjects, in both a co-dominant (P<0.0001) and G dominant model (P<0.0001). CTLA4+49 allele G was significantly associated with disease risk in both patients with isolated AAD and in patients with autoimmune polyendocrine syndrome. Multivariate logistic regression analysis showed that CTLA4+49 allele G was positively associated with AAD (P<0.0001, odds ratio (OR)=2.43, 95% confidence interval=1.54–3.86) also after correction for DRB1*03-DQA1*0501-DQB1*0201, DRB1*04-DQA1*0301-DQB1*0302, and sex. Meta-analysis of five studies revealed a significant association of CTLA4+49 allele G with AAD (P<0.0001) with an overall OR of 1.48 (1.28–1.71).

Conclusions

The CTLA4+49 polymorphism is strongly associated with genetic risk for AAD, independently from the well-known association with HLA class II genes.
Increased suppression of serum ghrelin concentration by hyperinsulinemia in women with anorexia nervosa
Authors: Karczewska-Kupczewska Monika , Strączkowski Marek , Adamska Agnieszka , Nikołajuk Agnieszka , Otziomek Elżbieta , Górska Maria , Kowalska Irina
Published: November 2009

Context

Ghrelin is a peptide secreted mainly by the stomach, which has the ability to stimulate appetite and food intake. Serum ghrelin concentration decreases rapidly after a meal, probably because of the concurrent increase in serum insulin. Anorexia nervosa (AN) is an eating disorder, which is characterized by high serum ghrelin concentration; however, the regulation of circulating ghrelin by insulin in this disorder remains unclear.

Objective

To estimate serum ghrelin concentration in the fasting state and after hyperinsulinemia in women with AN.

Design and participants

We examined 19 women with AN, 26 lean healthy women, and 25 women who were overweight or obese. Serum ghrelin concentration was measured in the fasting state and after euglycemic hyperinsulinemic clamp.

Results

Insulin sensitivity was similar in AN and normal-weight women, and was markedly decreased in the obese subjects. In the fasting state, serum ghrelin was higher in AN group than in other groups (normal-weight, P=0.017; obese, P=0.0001) and in normal-weight women than in obese women (P=0.044). Hyperinsulinemia resulted in a marked decrease in serum ghrelin in AN (P<0.0001) and normal-weight women (P=0.002). The fall in serum ghrelin was higher in AN group than in other groups (normal-weight, P=0.0008; obese, P=0.0001), and was related to insulin sensitivity (r=0.24, P<0.05). In multiple regression analysis, only fasting serum ghrelin and the presence of AN were independent predictors of this fall.

Conclusions

Women with AN have an increased suppression of serum ghrelin by hyperinsulinemia. This phenomenon might lead to an increased and more rapid feeling of satiety in AN.
Detection, Validation, and Downstream Analysis of Allelic Variation in Gene Expression
Authors: Ciobanu Daniel C , Lu Lu , Mozhui Khyobeni , Wang Xusheng , Jagalur Manjunatha , Morris John A , Taylor William L , Dietz Klaus , Simon Perikles , Williams Robert W
Published: November 2009

Common sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control—or cis modulation—rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alternative transcripts, combined with eQTL maps and selective gene resequencing, revealed that between 17 and 25% of apparent cis modulation is caused by SNPs that overlap probes rather than by genuine quantitative differences in mRNA levels. This estimate climbs to 40–50% when qualitative differences between isoform variants are included. We have developed an analytical approach to filter differences in expression and improve the yield of genuine cis-modulated transcripts to ∼80%. This improvement is important because the resulting variation can be successfully used to study downstream consequences of altered expression on higher-order phenotypes. Using a systems genetics approach we show that two validated cis-modulated genes, Stk25 and Rasd2, are likely to control expression of downstream targets and affect disease susceptibility.
Seizure Sensitivity Is Ameliorated by Targeted Expression of K+–Cl− Cotransporter Function in the Mushroom Body of the Drosophila Brain
Authors: Hekmat-Scafe Daria S , Mercado Adriana , Fajilan Adriel A , Lee Ann W , Hsu Richard , Mount David B , Tanouye Mark A
Published: November 2009

The kccDHS1 allele of kazachoc (kcc) was identified as a seizure-enhancer mutation exacerbating the bang-sensitive (BS) paralytic behavioral phenotypes of several seizure-sensitive Drosophila mutants. On their own, young kccDHS1 flies also display seizure-like behavior and demonstrate a reduced threshold for seizures induced by electroconvulsive shock. The product of kcc shows substantial homology to KCC2, the mammalian neuronal K+–Cl− cotransporter. The kccDHS1 allele is a hypomorph, and its seizure-like phenotype reflects reduced expression of the kcc gene. We report here that kcc functions as a K+–Cl− cotransporter when expressed heterologously in Xenopus laevis oocytes: under hypotonic conditions that induce oocyte swelling, oocytes that express Drosophila kcc display robust ion transport activity observed as a Cl−-dependent uptake of the K+ congener 86Rb+. Ectopic, spatially restricted expression of a UAS-kcc+ transgene was used to determine where cotransporter function is required in order to rescue the kccDHS1 BS paralytic phenotype. Interestingly, phenotypic rescue is largely accounted for by targeted, circumscribed expression in the mushroom bodies (MBs) and the ellipsoid body (EB) of the central complex. Intriguingly, we observed that MB induction of kcc+ functioned as a general seizure suppressor in Drosophila. Drosophila MBs have generated considerable interest especially for their role as the neural substrate for olfactory learning and memory; they have not been previously implicated in seizure susceptibility. We show that kccDHS1 seizure sensitivity in MB neurons acts via a weakening of chemical synaptic inhibition by GABAergic transmission and suggest that this is due to disruption of intracellular Cl− gradients in MB neurons.
Sen1p Performs Two Genetically Separable Functions in Transcription and Processing of U5 Small Nuclear RNA inSaccharomyces cerevisiae
Authors: Finkel Jonathan S , Chinchilla Karen , Ursic Doris , Culbertson Michael R
Published: November 2009

The Saccharomyces cerevisiae SEN1 gene codes for a nuclear-localized superfamily I helicase. SEN1 is an ortholog of human SETX (senataxin), which has been implicated in the neurological disorders ataxia-ocular apraxia type 2 and juvenile amyotrophic lateral sclerosis. Pleiotropic phenotypes conferred by sen1 mutations suggest that Sen1p affects multiple steps in gene expression. Sen1p is embedded in a protein–protein interaction network involving direct binding to multiple partners. To test whether the interactions occur independently or in a dependent sequence, we examined interactions with the RNA polymerase II subunit Rpb1p, which is required for transcription, and Rnt1p, which is required for 3′-end maturation of many noncoding RNAs. Mutations were identified that impair one of the two interactions without impairing the other interaction. The effects of the mutants on the synthesis of U5 small nuclear RNA were analyzed. Two defects were observed, one in transcription termination and one in 3′-end maturation. Impairment of the Sen1p–Rpb1p interaction resulted in a termination defect. Impairment of the Sen1p–Rnt1p interaction resulted in a processing defect. The results suggest that the Sen1p–Rpb1p and Sen1p–Rnt1p interactions occur independently of each other and serve genetically separable purposes in targeting Sen1p to function in two temporally overlapping steps in gene expression.
Genetic Screen inDrosophila melanogasterUncovers a Novel Set of Genes Required for Embryonic Epithelial Repair
Authors: Campos Isabel , Geiger Jennifer A , Santos Ana Catarina , Carlos Vanessa , Jacinto Antonio
Published: November 2009

The wound healing response is an essential mechanism to maintain the integrity of epithelia and protect all organisms from the surrounding milieu. In the “purse-string” mechanism of wound closure, an injured epithelial sheet cinches its hole closed via an intercellular contractile actomyosin cable. This process is conserved across species and utilized by both embryonic as well as adult tissues, but remains poorly understood at the cellular level. In an effort to identify new players involved in purse-string wound closure we developed a wounding strategy suitable for screening large numbers of Drosophila embryos. Using this methodology, we observe wound healing defects in Jun-related antigen (encoding DJUN) and scab (encoding Drosophila αPS3 integrin) mutants and performed a forward genetics screen on the basis of insertional mutagenesis by transposons that led to the identification of 30 lethal insertional mutants with defects in embryonic epithelia repair. One of the mutants identified is an insertion in the karst locus, which encodes Drosophila βHeavy-spectrin. We show βHeavy-spectrin (βH) localization to the wound edges where it presumably exerts an essential function to bring the wound to normal closure.
Synthesis and Characterization of Highly Transparent Sol-Gel Glass for Photovoltaic Applications
Authors: Shanmugam Mariyappan , Baroughi Mahdi Farrokh , Yan XingZhong , Galipeau David
Published: November 2009

Room temperature sol-gel synthesis and optical characterization of highly transparent silica glass for photovoltaic (PV) applications is presented in this paper. Tetraethyl orthosilicate (TEOS), Ethanol, Hydrochloric acid (HCl) and deionized water were used as precursors in the volumetric ratio of 4:4.3:0.1:3.2 ml. Silica glass of thickness in the range of 0.5-1 cm were obtained with an average transmittance of 93% and absorption coefficient (α) of 0.08 cm−1 in a wide wavelength window of 350-1100 nm. Application of the developed sol-gel silica glass on solar ray concentration, anti-reflective coating (ARC) and effect of surface passivation on silicon wafers were examined. Carrier lifetime of the sol-gel silica passivated silicon substrate was 16 s and the calculated surface recombination velocity of the was 2200 cm/sec. Very low value of α, high transparency in a wide spectral window and effective surface passivation on silicon suggest that sol-gel processed silica glass can be a potential cost effective candidate for different PV applications.
Hepatic Toxicities Associated with the Use of Preoperative Systemic Therapy in Patients with Metastatic Colorectal Adenocarcinoma to the Liver
Authors: Cleary James M. , Tanabe Kenneth T. , Lauwers Gregory Y. , Zhu Andrew X.
Published: October 2009

Colorectal cancer patients with isolated liver metastasis are potentially cured with surgical resection. Recent advances in systemic chemotherapy have increased the ability to convert unresectable metastatic liver lesions to resectable lesions. The cost in toxicity of these therapeutic advances is increasingly being recognized. Numerous reports have demonstrated an association between irinotecan and steatohepatitis as well as between oxaliplatin and sinusoidal dilation. In this review, we summarize the current clinical experience with these hepatic toxicities and discuss the role they play in determining postoperative morbidity. We also review emerging safety data regarding the use of bevacizumab and cetuximab. Finally, we give specific clinical examples of how multidisciplinary teams can best manage patients receiving preoperative chemotherapy for potentially resectable liver metastases.
Environmental risk assessment of human pharmaceuticals in the European Union: A case study with the β-blocker atenolol
Authors: Küster Anette , Alder Alfredo C , Escher Beate I , Duis Karen , Fenner Kathrin , Garric Jeanne , Hutchinson Thomas H , Lapen David R , Péry Alexandre , Römbke Jörg , Snape Jason , Ternes Thomas , Topp Ed , Wehrhan Anne , Knacker Thomas
Published: November 2009

β-Adrenergic receptor blockers (β-blockers) are applied to treat high blood pressure, ischemic heart disease, and heart rhythm disturbances. Due to their widespread use and limited human metabolism, β-blockers are widely detected in sewage effluents and surface waters. β-Adrenergic receptors have been characterized in fish and other aquatic animals, so it can be expected that physiological processes regulated by these receptors in wild animals may be affected by the presence of β-blockers. Because ecotoxicological data on β-blockers are scarce, it was decided to choose the β-blocker atenolol as a case study pharmaceutical within the project ERAPharm. A starting point for the assessment of potential environmental risks was the European guideline on the environmental risk assessment of medicinal products for human use. In Phase I of the risk assessment, the initial predicted environmental concentration (PEC) of atenolol in surface water (500 ng L−1) exceeded the action limit of 10 ng L−1. Thus, a Phase II risk assessment was conducted showing acceptable risks for surface water, for groundwater, and for aquatic microorganisms. Furthermore, atenolol showed a low potential for bioaccumulation as indicated by its low lipophilicity (log KOW = 0.16), a low potential for exposure of the terrestrial compartment via sludge (log KOC = 2.17), and a low affinity for sorption to the sediment. Thus, the risk assessment according to Phase II-Tier A did not reveal any unacceptable risk for atenolol. Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm. A 2-generation reproduction test with the waterflea Daphnia magna resulted in the most sensitive no-observed-effect concentration (NOEC) of 1.8 mg L−1. However, even with this NOEC, a risk quotient of 0.003 was calculated, which is still well below the risk threshold limit of 1. Additional studies confirm the outcome of the environmental risk assessment according to EMEA/CHMP (2006). However, atenolol should not be considered as representative for other β-blockers, such as metoprolol, oxprenolol, and propranolol, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies. Integr Environ Assess Manag 2010;6:514–523. © 2009 SETAC
The chironomid acute toxicity test: Development of a new test system
Authors: Weltje Lennart , Rufli Hans , Heimbach Fred , Wheeler James , Vervliet-Scheebaum Marco , Hamer Michael
Published: November 2009

This paper describes the basis for a water-only acute chironomid toxicity test guideline using first-instar larvae. The method is based on the OECD test guidelines for the acute Daphnia sp. immobilization test and the long-term tests with Chironomus sp., reflecting the common test procedures currently used by the European agrochemical industry. Development of this guideline proposal is important under the European Plant Protection Products Directive (91/414/EEC), under which an insect species may be required to be tested, particularly for certain insecticides, for which Daphnia sp. may not be representative of the sensitivity of nontarget aquatic invertebrates. Chironomus sp. is a freshwater insect currently used in different international test guidelines. Because their ready availability as a test organism, with culturing conditions and certain test methods already established, Chironomus sp. is regarded as a suitable additional freshwater invertebrate species for regulatory testing. Integr Environ Assess Manag 2010;6:301–307. © 2009 SETAC
No‐Till Sequential Cropping of Summer and Fall Annual Forage Species Compared with Grassland
Authors: Basweti E. A. , Turk P. J. , Rayburn E. B. , Bryan W. B.
Published: October 2009

Summer (SAS) and fall annual species (FAS) can supplement animal forage requirements during times of slow growth of cool‐season perennials. A 2‐yr experiment was conducted in a perennial grassland (G) at the Reedsville Experimental Farm of West Virginia University to determine herbage accumulation (HA) and quality of two summer and two fall crops (in factorial combination) grown on the same land. The summer crops were sudangrass [Sorghum bicolor (L.) Moench] or pearl millet [Pennisetum glaucum (L.) R. Br.], and the fall crops were triticale (×Triticosecale spp.) or a mixture of annual ryegrass (Lolium multiflorum Lam.) and turnip (Brassica rapa L.). Two methods, burning and glyphosate application, were used to control existing vegetation before seeding annual forages. Three levels of N (0, 50, and 100 kg ha−1) were applied to each sequence of crops on two occasions for a total of 0, 100, and 200 kg ha−1 yr−1. On a 12‐mo basis, G out‐produced (at 0 and 100 kg N ha−1) or equaled (at 200 kg N ha−1) all combinations of SAS and FAS. Sudangrass produced the most herbage mass in summer and was of lower quality than pearl millet and G. Species established after glyphosate and receiving high N application produced more herbage mass than those established after burning or with lower rates of N. Pearl millet seeded after burning failed to establish. Grassland (2543 kg ha−1) and the mixture of annual ryegrass and turnip (2608 kg ha−1) out‐produced triticale (1778 kg ha−1) in fall.