Indirect partial volumetry in breast cancer-related lymphoedema: Distribution of oedema and clinical-diagnostic implications.

INTRODUCTION AND OBJECTIVES: Currently, the assessment of lymphoedema related to breast cancer (BCRL) is performed through the global perimeter volumetry. We implemented an additional system with partial measures (hand, forearm, and upper arm) that allows us to approximate the segmental distribution of oedema. We used this measurement tool to determine the oedema distribution and its evolution, as well as its possible impact on clinical assessment. METHODS: We carried out a retrospective observational study of the patients referred to our service with suspected BCRL. INCLUSION CRITERIA: Unilateral breast cancer, availability of global and partial digital medical record, and follow-up for a minimum of 24 months. Of the 210 selected patients, 190 were considered affected (≥10% excess volume). We analysed at three time points (initial, final, and peak involvement) the oedema distribution and segmental predominance and its relationship with the evolutionary course and the severity of the process. We subsequently examined, at the initial timepoint, the concordance of the global assessment with the partial assessment for the clinical classification of the 210 patients in the initial sample. RESULTS: The BCRL oedema was characteristically irregular, with the forearm being the most affected segment and the hand the least affected (RM ANOVA: p<0.001). The irregularity was related to its severity (χ2: p<0.001) and the evolutionary course (Student t-test: p<0.005 for the hand). Overall, disagreement of 46.67% was observed between the clinical classification of the global and partial assessment. CONCLUSIONS: This work supports the need to add partial volumetry to the commonly used global assessment.

Real-life cost-effectiveness of benralizumab in patients with severe asthma.

BACKGROUND: Availability of clinically effective and cost-effective treatments for severe asthma would be beneficial to patients and national healthcare systems. The aim of this study was to evaluate clinical outcomes and healthcare expenditure after incorporating benralizumab into the standard treatment of refractory eosinophilic asthma. METHODS: This was a cross-sectional multicentre study of consecutive patients with refractory eosinophilic asthma who received treatment with benralizumab during at least 12 months. Patient follow-up was performed in specialised severe asthma units. The main effectiveness parameters measured were: the avoidance of one asthma exacerbation, a 3-point increase in the asthma control test (ACT) score, and the difference in utility scores (health-related quality of life) between a 1-year baseline treatment and 1-year benralizumab treatment. The health economic evaluation included direct costs and incremental cost-effectiveness ratios (ICERs). RESULTS: After 1 year of treatment with benralizumab, patients with refractory eosinophilic asthma showed an improvement in all the effectiveness parameters analysed: improvement of asthma control and lung function, and decrease in the number of exacerbations, oral corticosteroid (both as corticosteroid courses and maintenance therapy), and inhaled corticosteroid use. The total annual cost per patient for the baseline and benralizumab treatment periods were €11,544 and €14,043, respectively, reflecting an increase in costs due to the price of the biological agent but a decrease in costs for the remaining parameters. The ICER was €602 per avoided exacerbation and €983.86 for every 3-point increase in the ACT score. CONCLUSIONS: All the pharmacoeconomic parameters analysed show that treatment with benralizumab is a cost-effective option as an add-on therapy in patients with refractory eosinophilic asthma.

Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling.

BACKGROUND: The incidence of esophageal adenocarcinoma (EAC) is rapidly rising and has a 5-year survival rate of <20%. Beyond TNM (tumor-node-metastasis) staging, no reliable risk stratification tools exist and no large-scale studies have profiled circulating tumor DNA (ctDNA) at relapse in EAC. Here we analyze the prognostic potential of ctDNA dynamics in EAC, taking into account clonal hematopoiesis with indeterminate potential (CHIP). PATIENTS AND METHODS: A total of 245 samples from 97 patients treated with neoadjuvant chemotherapy and surgery were identified from the prospective national UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium data set. A pan-cancer ctDNA panel comprising 77 genes was used. Plasma and peripheral blood cell samples were sequenced to a mean depth of 7082× (range 2196-28 524) and ctDNA results correlated with survival. RESULTS: Characteristics of the 97 patients identified were as follows: 83/97 (86%) male, median age 68 years (SD 9.5 years), 100% cT3/T4, 75% cN+. EAC-specific drivers had higher variant allele fractions than passenger mutations. Using stringent quality criteria 16/79 (20%) were ctDNA positive following resection; recurrence was observed in 12/16 (75%) of these. As much as 78/97 (80%) had CHIP analyses that enabled filtering for CHIP variants, which were found in 18/78 (23%) of cases. When CHIP was excluded, 10/63 (16%) patients were ctDNA positive and 9/10 of these (90%) recurred. With correction for CHIP, median cancer-specific survival for ctDNA-positive patients was 10.0 months versus 29.9 months for ctDNA-negative patients (hazard ratio 5.55, 95% confidence interval 2.42-12.71; P = 0.0003). Similar outcomes were observed for disease-free survival. CONCLUSIONS: We demonstrate in a large, national, prospectively collected data set that ctDNA in plasma following surgery for EAC is prognostic for relapse. Inclusion of peripheral blood cell samples can reduce or eliminate false positives from CHIP. In future, post-operative ctDNA could be used to risk stratify patients into high- and low-risk groups for intensification or de-escalation of adjuvant chemotherapy.

Do immature and mature sibling oocytes recovered from stimulated cycles have the same reproductive potential?

RESEARCH QUESTION: How can laboratory and clinical outcomes of spontaneously, early maturing germinal-vesicle oocytes and sibling in-vivo-matured (metaphase II [MII]) oocytes be quantified and compared? DESIGN: A prospective, non-randomized intra-cohort study of oocytes from women aged 38 years or younger, with six or fewer MII oocytes and four or more germinal vesicles retrieved. No indication was identified for genetic tests or oocyte or embryo cryopreservation. The study was carried out at IVIRMA-Valencia. Early maturing germinal vesicles were selected for reproductive purposes. In vitro- and in-vivo MII oocytes were fertilized. After time-lapse culture, hatching blastocysts from germinal vesicles were biopsied for aneuploidy screening and vitrified. Laboratory and clinical outcomes were compared according to oocyte origin. RESULTS: Almost 70% of germinal vesicles had matured early and spontaneously, and had comparable in vitro-outcomes and morphokinetics to sibling in vivo-matured oocytes. Fifty per cent of biopsied blastocysts were euploid. Germinal-vesicle rescue increased the number of MII oocytes per cycle to 3.9, finally adding one extra-blastocyst per cycle. A live birth confirmed the feasibility of this approach. Further data, however, are needed to quantify its real contribution to standard intracytoplasmic sperm injection cycles. Nevertheless, 40% of patients obtained either an immediate advantage (reduction of cancellation rate) or long-term benefit (availability of extra blastocysts of attempts). CONCLUSIONS: Germinal-vesicle rescue can be considered as a complementary approach when folliculometry (expected) and number of MII (observed) are unequal.

Molecular signatures that can be transferred across different omics platforms.

MOTIVATION: Molecular signatures for treatment recommendations are well researched. Still it is challenging to apply them to data generated by different protocols or technical platforms. RESULTS: We analyzed paired data for the same tumors (Burkitt lymphoma, diffuse large B-cell lymphoma) and features that had been generated by different experimental protocols and analytical platforms including the nanoString nCounter and Affymetrix Gene Chip transcriptomics as well as the SWATH and SRM proteomics platforms. A statistical model that assumes independent sample and feature effects accounted for 69-94% of technical variability. We analyzed how variability is propagated through linear signatures possibly affecting predictions and treatment recommendations. Linear signatures with feature weights adding to zero were substantially more robust than unbalanced signatures. They yielded consistent predictions across data from different platforms, both for transcriptomics and proteomics data. Similarly stable were their predictions across data from fresh frozen and matching formalin-fixed paraffin-embedded human tumor tissue. AVAILABILITY AND IMPLEMENTATION: The R-package 'zeroSum' can be downloaded at https://github.com/rehbergT/zeroSum . Complete data and R codes necessary to reproduce all our results can be received from the authors upon request. CONTACT: rainer.spang@ur.de.

[Pharmacoeconomic study of the treatment of advanced Parkinson's disease]. / Estudio farmacoeconomico del tratamiento de la enfermedad de Parkinson avanzada.

INTRODUCTION: When oral or transdermal drug therapy in Parkinson's disease becomes less effective, there are three therapies using assisted devices that can reduce motor and non-motor complications: subcutaneous apomorphine infusion pump (SAIP), continuous levodopa/carbidopa duodenal infusion (LDI) and deep brain stimulation (DBS). AIM: Conduct a comparative pharmacoeconomic analysis of the use of SAIP, with LDI and DBS. As a secondary objective arises discuss the profile of the ideal candidate for each of the technicals. PATIENTS AND METHODS: Information on life years gained and quality adjusted life years (QALY) according to Hoehn and Yahr scale was obtained, as well as data on costs and resource use for each of the alternatives. The perspective of the analysis was the National Health System and the time horizon was 5 years for costs and patient´s lifetime for utilities. Outcome measures used were life years gained and QALYs, and incremental cost/utility ratio for comparison. RESULTS: Cost/utility ratio was obtained for each option: 31,956 euros/QALY for DBS, 38,249 euros/QALY for SAIP, and 75,206 euros/QALY for LDI. CONCLUSIONS: Our results allow us to add information about effectiveness of different treatments, as these are presented in gain of years lived in full health (QALY). Data obtained contribute to decision making that determine planning and management of each case, without forgetting patient and neurologist preferences, as well as budgetary limitations.

TITLE: Estudio farmacoeconomico del tratamiento de la enfermedad de Parkinson avanzada.Introduccion. Cuando el tratamiento farmacologico oral o transdermico de la enfermedad de Parkinson pierde eficacia, se dispone de tres terapias mediante dispositivos asistidos que pueden reducir las complicaciones motoras y no motoras: la apomorfina en infusion subcutanea (ASBI), la bomba de infusion duodenal continua de levodopa/carbidopa (IDL) y la estimulacion cerebral profunda (ECP). Objetivo. Efectuar un analisis farmacoeconomico comparativo del uso de ASBI con IDL y ECP; como objetivo secundario, discutir el perfil del candidato ideal para cada una de las tecnicas. Pacientes y metodos. Se extrajo informacion sobre datos de años de vida ganados y años de vida ganados ajustados por calidad (AVAC) segun la escala de Hoehn y Yahr, e informacion sobre costes y consumo de recursos para cada alternativa. La perspectiva del analisis fue la del Sistema Nacional de Salud, y el horizonte temporal fue de cinco años para los costes y toda la vida del paciente para las utilidades. Las medidas de resultado utilizadas fueron los años de vida ganados y AVAC, y en su comparacion se uso la ratio coste-utilidad incremental. Resultados. El coste-utilidad obtenido para cada opcion fue: 31.956 euros/AVAC para la ECP, 38.249 euros/AVAC para la ASBI y 75.206 euros/AVAC para la IDL. Conclusiones. Los resultados permiten evaluar la efectividad y utilidad de los diferentes tratamientos para la enfermedad de Parkinson avanzada, pues se presentan en ganancias de años vividos en plena salud. Los datos obtenidos contribuyen a la toma de decisiones que determinen la planificacion y gestion de cada caso, sin olvidar las preferencias del paciente y del neurologo, asi como las limitaciones presupuestarias.

Anastomic urethroplasty in bulbar urethral stricture. 13 years experience in a department of urology. / Uretroplastia anastomótica en el manejo de estenosis de uretra bulbar. Experiencia de 13 años en un Servicio de Urología.

UNLABELLED: Urethral stenosis is a common disease in the clinical practice of urology, with a major impact on the quality of life of patients. The anastomotic urethroplasty is a technique with very precise indications usually membranous or bulbar urethra stenosis with a length of 3 cm or up to 7 cm when it is secondary to urethral disruptions (no stenosis) after pelvic trauma. OBJECTIVE: We review anastomotic urethroplasty performed in our department between 2002 and 2015. METHODS: A retrospective, descriptive and inferential analysis on 107 patients out of 482 treated with Anastomotic urethroplasty by urethral strictures at the Urology Department of the Hospital "Virgen de la Victoria" (Malaga) from January 2002 to September 2015, establishing effectiveness and safety of the technique, as well as factors that might influence the results. The main diagnostic method was retrograde urethrography and voiding cystourethrography in 100% of patients undergoing surgery, using voiding uroflowmetry for subsequent monitoring. The definition of success was a postoperative flowmetry with Qmax>15 ml/s, and in case of lower flow, we perform a cystoscopy to verify recurrence of stenosis or exclude other pathology. RESULTS: The median age was 42 years, with a mean follow up of 59 months. The length of stenosis valued by retrograde urethrography and voiding cystourethrography was in 91.6% of cases of >1 cm and <2 cm. The most common etiology was idiopathic in 72.9%, followed by iatrogenic with 15.9%. Regarding the location, it was observed that the area most often affected was the bulbar urethra with 82.2%, with the membranous urethra in second place. In 77.6% of patients anastomotic urethroplasty was the initial treatment, followed in frequency by direct vision internal urethrotomy 9.3%. In the case of comorbidities associated with treatment with anastomotic urethroplasty it was observed that only Diabetes Mellitus had a tendency to statistical significance, with p=0.092, not demonstrating such significance in the case of hypertension or when the subject presented Diabetes Mellitus together with hypertension. Finally, the intervention was successful in 102 cases (95.3%), with only 5 cases (4.7%) where it failed, 4 of them treated with a new Anastomotic urethroplasty, with resolution of the stricture. CONCLUSIONS: Anastomotic urethroplasty is the treatment of choice for short bulbar urethral stricture, with high success rate and low complication rate, as well as low recurrence of these.

[Quality of life of patients with asthma on beclomethasone/formoterol. Cost-utility analysis]. / Calidad de vida del paciente asmático con beclometasona/formoterol. Análisis de coste-utilidad.

AIM: To perform a cost-utility analysis on asthmatic patients on beclomethasone/formoterol fixed combination in Primary Health Care. Material and methods Non-probability sampling was used to select a group of asthmatic patients with moderate/severe persistent severity (GEMA 2009), treated with beclomethasone/formoterol fixed combination, over 18 years, had given their informed consent. The study observation period was 6 months. The variables studied were: age, sex, duration of disease, health resources used, analysis of health related quality of life by EQ-5D and SF-36, and the specific Asthma Quality of Life Questionnaire. For the qualitative variables, the frequency and percentages were calculated, and for the quantitative variables, the mean, SD and 95% CI. Chi-square, Student t-test and ANOVA were used for statistical inference. Comparisons were made with a statistical significance of 0.05. RESULTS: Of the 64 patients that completed the study, 59.4% were female. The mean age was 49 years, and mean disease duration was 93 months. For asthma control, 53% of patients had a prescription pattern of one/12h. All health related quality of life scales were modified with respect to the baseline and the differences were statistically significant. Our patients had a better health related quality of life than Spanish asthma cohort. The incremental cost utility beclomethasone/formoterol versus usual treatment option was € 6,256/QALY.

Randomized clinical trial of nutritional counseling for malnourished hospital patients. / Ensayo clínico aleatorizado del asesoramiento nutricional en pacientes desnutridos hospitalizados.

INTRODUCTION: Malnutrition is associated with an increased risk of mortality and morbidity, longer hospital stays and general loss of quality of life. The aim of this study is to assess the impact of dietary counseling for malnourished hospital patients. PATIENTS AND METHODS: Prospective, randomized, open-label study of 106 hospital patients with malnutrition (54 in the control group and 52 in the intervention group). The intervention group received dietary counseling, and the control group underwent standard treatment. We determined the patients' nutritional state (body mass index, laboratory parameters, malnutrition universal screening tool), degree of dependence (Barthel index), quality of life (SF-12), degree of satisfaction (CSQ-8), the number and length of readmissions and mortality. RESULTS: The patients who underwent the "intervention" increased their weight at 6 months, while the controls lost weight (difference in body mass index, 2.14kg/m(2); p<.001). The intervention group had better results when compared with the control group in the Malnutrition Universal Screening Tool scores (difference, -1.29; p<.001), Barthel index (difference, 7.49; p=.025), SF-12 (difference, 13.72; p<.001) and CSQ-8 (difference, 4.34, p<.001) and required fewer readmissions (difference, -0.37; p=.04) and shorter stays for readmissions (difference, -6.75; p=.035). Mortality and laboratory parameters were similar for the 2 groups. CONCLUSIONS: Nutritional counseling improved the patients' nutritional state, quality of life and degree of dependence and decreased the number of hospital readmissions.

The chronology of the earliest Upper Palaeolithic in northern Iberia: New insights from L'Arbreda, Labeko Koba and La Viña.

Since the late 1980s, northern Iberia has yielded some of the earliest radiocarbon dated Aurignacian assemblages in Western Europe, probably produced by anatomically modern humans (AMHs). This is at odds with its location furthest from the likely eastern entry point of AMHs, and has also suggested to some that the Châtelperronian resulted from cultural transfer from AMHs to Neanderthals. However, the accuracy of the early chronology has been extensively disputed, primarily because of the poor association between the dated samples and human activity. Here, we test the chronology of three sites in northern Iberia, L'Arbreda, Labeko Koba and La Viña, by radiocarbon dating ultrafiltered collagen from anthropogenically modified bones. The published dates from Labeko Koba are shown to be significant underestimates due to the insufficient removal of young contaminants. The early (c.44 ka cal BP [thousands of calibrated years before present]) Aurignacian chronology at L'Arbreda cannot be reproduced, but the reason for this is difficult to ascertain. The existing chronology of La Viña is found to be approximately correct. Together, the evidence suggests that major changes in technocomplexes occurred contemporaneously between the Mediterranean and Atlantic regions of northern Iberia, with the Aurignacian appearing around 42 ka cal BP, a date broadly consistent with the appearance of this industry elsewhere in Western Europe.

[Cost-effectiveness analysis of fixed dose antihypertensive drugs]. / Análisis coste-eficacia de los antihipertensivos en dosis fijas.

OBJECTIVE: The aim of this study is to compare the efficiency of different fixed-dose combinations of renin-angiotensin-aldosterone system (RAAS) blockers and calcium channel blockers, to use it as a guide to assist the rational prescribing in antihypertensive therapy. METHODS: The efficacy of each drug was obtained from intervention studies randomized, double-blind, made with these combinations and a utility-cost modeling from the model proposed and used by NICE. The perspective of our analysis is the National Health System and the time horizon is long enough to achieve therapeutic goals. MAIN OUTCOME MEASURES: Cost per mmHg reduction in BP, percentage of reduction necessary to achieve the therapeutic goals for hypertension control and cost, and finally quantity and quality of life gained with these treatments in patients with hypertension, diabetes. RESULTS: We studied three fixed-dose combinations: amlodipine/olmesartán, amlodipine/valsartan and manidipine/delapril. The cost per mmHg systolic BP ranged from 24.93 to 12.34 €/mmHg, and diastolic BP ranged from 34.24 to 18.76 €/mmHg, depending on the drug used. For an initial value of 165mmHg systolic BP the most efficient treatment to achieve the therapeutic goal of hypertension control (<140mmHg) is manidipine/delapril with a cost of 67.76 €. The use of these drugs to control diabetic and hypertensive patients resulted in all cases being cost-effective (more effective and lower cost compared to "no treatment"). Manidipine/delapril showed the best relation cost-utility (1,970 €/QALY (quality-adjusted life year)) followed by amlodipine/olmesartan and amlodipine/valsartan (2,087 and 2,237 €/QALY, respectively).

[Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin]. / Langzeitwirkung von Dapagliflozin bei Typ-2-Diabetikern unter hoch dosierter Insulintherapie.

BACKGROUND: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin. OBJECTIVE: To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs. DESIGN: A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231). SETTING: 126 centers in Europe and North America from 30 April 2008 to 19 November 2009. PATIENTS: 808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs. INTERVENTION: Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer-generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks. MEASUREMENTS: The primary outcome was change in hemoglobin A1c from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods. RESULTS: 800 patients were analyzed. After 24 weeks, mean hemoglobin A1c decreased by 0.79 % to 0.96 % with dapagliflozin compared with 0.39 % with placebo (mean difference, -0.40 % [95 % CI, -0.54 % to -0.25 %] in the 2.5-mg group, -0.49 % [CI, -0.65 % to -0.34 %] in the 5-mg group, and -0.57 % [CI, -0.72 % to -0.42 %] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, -7.60 U [CI, -10.32 to -4.87 U] in the 2.5-mg group, -6.28 U [CI, -8.99 to -3.58 U] in the 5-mg group, and -6.82 U [CI, -9.56 to -4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, -1.35 kg [CI, -1.90 to -0.80 kg] in the 2.5-mg group, -1.42 kg [CI, -1.97 to -0.88 kg] in the 5-mg group, and -2.04 kg [CI, -2.59 to -1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6 % vs. 51.8 %), events suggesting genital infection (9.0 % vs. 2.5 %), and events suggesting urinary tract infection (9.7 % vs. 5.1 %). LIMITATION: Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety. CONCLUSION: Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus.

[Statistical Process Control (SPC) can help prevent treatment errors without increasing costs in radiotherapy]. / El control estadístico de proceso puede ayudar a prevenir los errores de tratamiento sin aumentar los costes en radioterapia.

PURPOSE: Statistical Process Control (SPC) was applied to monitor patient set-up in radiotherapy and, when the measured set-up error values indicated a loss of process stability, its root cause was identified and eliminated to prevent set-up errors. MATERIALS AND METHODS: Set up errors were measured for medial-lateral (ml), cranial-caudal (cc) and anterior-posterior (ap) dimensions and then the upper control limits were calculated. Once the control limits were known and the range variability was acceptable, treatment set-up errors were monitored using sub-groups of 3 patients, three times each shift. These values were plotted on a control chart in real time. RESULTS: Control limit values showed that the existing variation was acceptable. Set-up errors, measured and plotted on a X chart, helped monitor the set-up process stability and, if and when the stability was lost, treatment was interrupted, the particular cause responsible for the non-random pattern was identified and corrective action was taken before proceeding with the treatment. CONCLUSION: SPC protocol focuses on controlling the variability due to assignable cause instead of focusing on patient-to-patient variability which normally does not exist. Compared to weekly sampling of set-up error in each and every patient, which may only ensure that just those sampled sessions were set-up correctly, the SPC method enables set-up error prevention in all treatment sessions for all patients and, at the same time, reduces the control costs.

A protein encoded by a new family of mobile elements from Euryarchaea exhibits three domains with novel folds.

We present here the 2.6A resolution crystal structure of the pT26-6p protein, which is encoded by an ORF of the plasmid pT26-2, recently isolated from the hyperthermophilic archaeon, Thermococcus sp. 26,2. This large protein is present in all members of a new family of mobile elements that, beside pT26-2 include several virus-like elements integrated in the genomes of several Thermococcales and Methanococcales (phylum Euryarchaeota). Phylogenetic analysis suggested that this protein, together with its nearest neighbor (organized as an operon) have coevolved for a long time with the cellular hosts of the encoding mobile element. As the sequences of the N and C-terminal regions suggested a possible membrane association, a deletion construct (739 amino acids) was used for structural analysis. The structure consists of two very similar beta-sheet domains with a new topology and a five helical bundle C-terminal domain. Each of these domains corresponds to a unique fold that has presently not been found in cellular proteins. This result supports the idea that proteins encoded by plasmid and viruses that have no cellular homologues could be a reservoir of new folds for structural genomic studies.

A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion.

OBJECTIVE: To compare changes in weight in obese patients who received long-acting octreotide (octreotide LAR) at one of three dose levels (20, 40, or 60 mg) or placebo over 6 months and to identify the lowest dose of octreotide LAR that safely achieved optimal weight loss. DESIGN: Randomized, double-blind, placebo-controlled trial of octreotide LAR at three dose levels. PATIENTS: A total of 172 adults (28 men and 144 women) with at least moderate obesity (body mass index (BMI) range 30-65 kg/m2) and evidence of insulin hypersecretion were enrolled. Patients were predominantly either Caucasian (50.0%) or African American (45.3%). The mean age (38 +/- 11 year), weight (110.7 +/- 23 kg), and BMI (39.8 +/- 6.5 kg/m2) were similar across the four treatment groups. MEASUREMENTS: Efficacy measures included weight, BMI, fasting serum glucose; triglycerides; percentage of total body fat and abdominal fat as measured by dual-energy X-ray absorptiometry; skin fold thickness; waist-to-hip circumference; leptin; percentage of carbohydrates, fat, and protein ingested; nutritional evaluation (including dietary analysis--3-day food record); quality of life (QoL; using the Impact of Weight on Quality of Life-Lite); Beck Depression Inventory; and Carbohydrate Craving Questionnaire. Safety measures included medical history, vital signs, physical examinations, hematology, blood chemistries, thyroid function tests, hemoglobin A1c, gallbladder ultrasound, electrocardiograms, and adverse events. RESULTS: After 6 months of treatment, patients receiving 40 or 60 mg of octreotide LAR experienced statistically significant weight loss compared to baseline, with mean differences from placebo in percent weight change of -1.98 and -1.87%, respectively. This finding was accompanied by statistically significant mean decreases in BMI compared to baseline, that is, a mean decrease of 0.73 and 0.79 kg/m2 for the 40 and 60 mg treatment arms, respectively. The observed weight loss was progressive during the 6-month treatment in the two higher dose groups. The lowest dose to reach statistical significance in weight loss after 6 months' treatment was 40 mg. Post hoc analysis revealed a 3.5-3.8% weight loss at month 6 in the two higher dose groups among Caucasian patients having insulin secretion greater than the median of the cohort, defined as CIR(gp) (corrected insulin response at the glucose peak) > or = 1.43. There were no statistically significant changes in QoL scores, body fat, leptin concentration, Beck Depression Inventory, or macronutrient intake. Mean changes of blood glucose AUC(0-180 min) during an oral glucose tolerance test in patients taking octreotide LAR were 39-40 mg/dl h higher than those on placebo. A total of 7-21% of the patients taking octreotide LAR reached a 5% or greater decrease in body weight from Baseline, compared to 11% for the placebo group. This was not statistically significant. The most common adverse events included diarrhea, headache, cholelithiasis, nausea, and abdominal pain. CONCLUSION: Octreotide LAR given at 40 or 60 mg resulted in statistically significant weight loss. A post hoc analysis stratifying patients by race and CIR(gp) indicated that Caucasian patients with the greater degree of insulin hypersecretion appeared to derive the most benefit from treatment. The observed safety profile was consistent with the known effects of octreotide from previous studies.

Oxidative stress and airway inflammation in severe exacerbations of COPD.

BACKGROUND: A study was undertaken to assess both oxidative stress and inflammation in the lungs of patients with chronic obstructive pulmonary disease (COPD) during severe and very severe exacerbations compared with those with stable COPD, healthy smokers, and non-smokers. Two sites within the lungs were compared: the large airways (in sputum) and the peripheral airways (by bronchoalveolar lavage (BAL)). METHODS: BAL fluid cell numbers and levels of tumour necrosis factor (TNFalpha) and interleukin (IL)-8 were measured as markers of airway inflammation and glutathione (GSH) levels as a marker of antioxidant status. Nuclear translocation of the pro-inflammatory transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) were also measured by electromobility shift assay in BAL fluid leucocytes and lung biopsy samples. RESULTS: Influx of inflammatory cells into the peripheral airways during exacerbations of COPD was confirmed. Increased IL-8 levels were detected in BAL fluid from patients with stable COPD compared with non-smokers and healthy smokers, with no further increase during exacerbations. In contrast, IL-8 levels in the large airways increased during exacerbations. GSH levels were increased in the BAL fluid of smokers (444%) and patients with stable COPD (235%) compared with non-smokers and were reduced during exacerbations (severe 89.2%; very severe 52.3% compared with stable COPD). NF-kappaB DNA binding in BAL leucocytes was decreased in healthy smokers compared with non-smokers (41.3%, n = 9, p<0.001) but did not differ in COPD patients, whereas AP-1 DNA binding was significantly decreased during exacerbations of COPD. CONCLUSION: There is evidence of increased oxidative stress in the airways of patients with COPD that is increased further in severe and very severe exacerbations of the disease. This is associated with increased neutrophil influx and IL-8 levels during exacerbations.