Prognostic importance of anaemia in HIV type-1-infected patients starting antiretroviral therapy: collaborative analysis of prospective cohort studies

BACKGROUND: In HIV type-1-infected patients starting highly active antiretroviral therapy (HAART), the prognostic value of haemoglobin when starting HAART, and of changes in haemoglobin levels, are not well defined. METHODS: We combined data from 10 prospective studies of 12,100 previously untreated individuals (25% women). A total of 4,222 patients (35%) were anaemic: 131 patients (1.1%) had severe (<8.0 g/dl), 1,120 (9%) had moderate (male 8.0-<11.0 g/dl and female 8.0- < 10.0 g/dl) and 2,971 (25%) had mild (male 11.0- < 13.0 g/ dl and female 10.0- < 12.0 g/dl) anaemia. We separately analysed progression to AIDS or death from baseline and from 6 months using Weibull models, adjusting for CD4+ T-cell count, age, sex and other variables. RESULTS: During 48,420 person-years of follow-up 1,448 patients developed at least one AIDS event and 857 patients died. Anaemia at baseline was independently associated with higher mortality: the adjusted hazard ratio (95% confidence interval) for mild anaemia was 1.42 (1.17-1.73), for moderate anaemia 2.56 (2.07-3.18) and for severe anaemia 5.26 (3.55-7.81). Corresponding figures for progression to AIDS were 1.60 (1.37-1.86), 2.00 (1.66-2.40) and 2.24 (1.46-3.42). At 6 months the prevalence of anaemia declined to 26%. Baseline anaemia continued to predict mortality (and to a lesser extent progression to AIDS) in patients with normal haemoglobin or mild anaemia at 6 months. CONCLUSIONS: Anaemia at the start of HAART is an important factor for short- and long-term prognosis, including in patients whose haemoglobin levels improved or normalized during the first 6 months of HAART.

Habitat fragmentation and adaptation: a reciprocal replant-transplant experiment among 15 populations of Lychnis flos-cuculi

1. Habitat fragmentation and variation in habitat quality can both affect plant performance, but their effects have rarely been studied in combination. We thus examined plant performance in response to differences in habitat quality for a species subject to habitat fragmentation, the common but declining perennial herb Lychnis flos-cuculi. 2. We reciprocally transplanted plants between 15 fen grasslands in north-east Switzerland and recorded plant performance for 4 years. 3. Variation between the 15 target sites was the most important factor and affected all measures of plant performance in all years. This demonstrates the importance of plastic responses to habitat quality for plant performance. 4. Plants from smaller populations produced fewer rosettes than plants from larger populations in the first year of the replant-transplant experiment. 5. Plant performance decreased with increasing ecological difference between grassland of origin and target grassland, indicating adaptation to ecological conditions. In contrast, plant performance was not influenced by microsatellite distance and hardly by geographic distance between grassland of origin and target grassland. 6. Plants originating from larger populations were better able to cope with larger ecological differences between transplantation site and site of origin. 7. Synthesis: In addition to the direct effects of target grasslands, both habitat fragmentation, through reduced population size, and adaptation to habitats of different quality, contributed to the performance of L. flos-cuculi. This underlines that habitat fragmentation also affects species that are still common. Moreover, it suggests that restoration projects involving L. flos-cuculi should use plant material from large populations living in habitats similar to the restoration site. Finally, our results bring into question whether plants in small habitat remnants will be able to cope with future environmental change.

Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal

BACKGROUND: The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy. METHODS: We analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together to form a "rare ADEs" category. RESULTS: During a median follow-up period of 43 months (interquartile range, 19-70 months), 2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-Hodgkin's lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84-22.35) and progressive multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70-14.92). Three groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped confidence intervals: severe (non-Hodgkin's lymphoma and progressive multifocal leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55-9.48]), moderate (cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76-3.13]), and mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08-2.00]). CONCLUSIONS: In the combination antiretroviral therapy era, mortality rates subsequent to an ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in clinical end point trials, prognostic studies, and patient management.

Feasibility and safety of same-day home discharge after radiofrequency catheter ablation

Interventional cardiology in a day-case setting might reduce logistic constraints on hospital resources. However, in contrast with coronary angioplasty, few data support the feasibility and safety of radiofrequency catheter ablation (RCA). The aim of this prospective, multicenter cohort study was to evaluate the feasibility and safety of RCA in 1,342 patients (814 men; mean age 57 +/- 17 years) considered eligible for ambulatory RCA, according to specific set of criteria, for common atrial flutter (n = 632), atrioventricular nodal reentrant tachycardia (n = 436), accessory pathways (n = 202), and atrial tachycardia (n = 72). Patients suitable for early discharge (4 to 6 hours after uncomplicated RCA) were scheduled for 1-month follow-up. Predictive factors for delayed complications were studied by multivariate analysis. Of the 1,342 enrolled patients, 1,270 (94.6%) were discharged the same day and followed for 1 month; no deaths occurred, and the readmission rate was 0.79% (95% confidence interval 0.30% to 1.27%). Six patients had significant puncture complications, 2 presented with symptomatic delayed pulmonary embolism, and 2 had new onset of poorly tolerated atrial flutter. None of these complications was life threatening. Multivariate analysis did not identify any significant independent predictors for delayed complications. In conclusion, these data suggest that same-day discharge after uncomplicated RCA for routine supraventricular arrhythmias is safe and may be applicable in clinical practice. This approach is known to be associated with significant patient satisfaction and cost savings and can be considered a first-line option in most patients who undergo routine ablation procedures.

Comparison of drug retention rates and causes of drug discontinuation between anti-tumor necrosis factor agents in rheumatoid arthritis

OBJECTIVE: Tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of severe rheumatoid arthritis (RA), yet drug discontinuation is common. The aim of this study was to compare treatment retention rates and specific causes of anti-TNF discontinuation in a population-based RA cohort. METHODS: All patients treated with etanercept, infliximab, or adalimumab within the Swiss Clinical Quality Management RA cohort between 1997 and 2006 were included in the study. Causes of treatment discontinuation were broadly categorized as adverse events (AEs) or nontoxic causes, and further subdivided into specific categories. Specific causes of treatment interruption were analyzed using a Cox proportional hazards model and adjusted for potential confounders. RESULTS: A total of 2,364 anti-TNF treatment courses met the inclusion criteria. Treatment discontinuation was reported 803 times: 309 with etanercept, 249 with infliximab, and 245 with adalimumab. Drug inefficacy represented the largest single cause of treatment discontinuation (55.8% of cases). The median time of receiving anti-TNF therapy was 37 months, but discontinuation rates differed between the 3 anti-TNF agents (P < 0.001), with shorter retention rates for infliximab (hazard ratio [HR] 1.24, 99% confidence interval [99% CI] 1.01-1.51). The specific causes of treatment discontinuation revealed an increased risk of AEs with infliximab (HR 1.4, 99% CI 1.003-1.96), mostly due to an increased risk of infusion or allergic reactions (HR 2.11, 99% CI 1.23-3.62). Other discontinuation causes were equally distributed between the anti-TNF agents. CONCLUSION: In this population, infliximab was associated with higher overall discontinuation rates compared with etanercept and adalimumab, which is mainly due to an increased risk of infusion or allergic reactions.

Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene

CONTEXT: Thyroid transcription factor 1 (TITF1/NKX2.1) is expressed in the thyroid, lung, ventral forebrain, and pituitary. In the lung, TITF1/NKX2.1 activates the expression of genes critical for lung development and function. Titf/Nkx2.1(-/-) mice have pituitary and thyroid aplasia but also impairment of pulmonary branching. Humans with heterozygous TITF1/NKX2.1 mutations present with various combinations of primary hypothyroidism, respiratory distress, and neurological disorders. OBJECTIVE: The objective of the study was to report clinical and molecular studies of the first patient with lethal neonatal respiratory distress from a novel heterozygous TITF1/NKX2.1 mutation. Participant: This girl, the first child of healthy nonconsanguineous French-Canadian parents, was born at 41 wk. Birth weight was 3,460 g and Apgar scores were normal. Soon after birth, she developed acute respiratory failure with pulmonary hypertension. At neonatal screening on the second day of life, TSH was 31 mU/liter (N <15) and total T(4) 245 nmol/liter (N = 120-350). Despite mechanical ventilation, thyroxine, surfactant, and pulmonary vasodilators, the patient died on the 40th day. RESULTS: Histopathology revealed pulmonary tissue with low alveolar counts. The thyroid was normal. Sequencing of the patient's lymphocyte DNA revealed a novel heterozygous TITF1/NKX2.1 mutation (I207F). This mutation was not found in either parent. In vitro, the mutant TITF-1 had reduced DNA binding and transactivation capacity. CONCLUSION: This is the first reported case of a heterozygous TITF1/NKX2.1 mutation leading to neonatal death from respiratory failure. The association of severe unexplained respiratory distress in a term neonate with mild primary hypothyroidism is the clue that led to the diagnosis.

Vascular endothelial growth factors, angiogenesis, and survival in human ileal enterochromaffin cell carcinoids

BACKGROUND AND AIMS: Well-differentiated neuro-endocrine ileal carcinoids are composed of serotonin-producing enterochromaffin (EC) cells. Life expectancy is determined by metastatic spread to the liver because medical treatment options are still very limited. Selective inhibition of angiogenesis or lymphangiogenesis might prevent tumour growth and metastatic spread. We examined the role of the vascular endothelial growth factors (VEGFs) A, B, C, D, and their receptors (VEGFRs) 1, 2, 3 in angiogenesis and lymphangiogenesis of ileal EC cell carcinoids with and without liver metastases. METHODS: The expression of various VEGFs and VEGFRs was determined by quantitative real-time RT-PCR in healthy mucosa, primary tumour, lymph node metastases and liver metastases of 25 patients with ileal EC cell carcinoids. Microvessel density (MVD) was determined by CD-31 staining in primary tumours and lymphatic vessel density (LVD) by LYVE-1 staining. VEGF expression levels, MVD, LVD, and patients' survival time were correlated using logistic regression and Kaplan-Meier survival analysis. RESULTS: VEGF-A was highly expressed with no difference between normal mucosa and tumours. VEGF-B and -D as well as VEGFR-1 and -2 expression levels were significantly increased in the tumours when compared to normal mucosa. Patients with liver metastasis, however, had a significantly lower expression of the factors A, B, and C and the receptors 2 and 3. MVD in primary tumours positively correlated with the expression of VEGF ligands and their receptors, except for VEGF-D. LVD did not correlate with any VEGF ligand or receptor. Interestingly, low expression levels of VEGF-B were associated with poor survival. CONCLUSION: Patients with more aggressive metastatic spreading had relatively decreased expression levels of VEGF ligands and receptors. Thus, anti-angiogenic therapy may not be a suitable target in metastatic ileal EC cell carcinoids.

Tree phenology and carbon dioxide fluxes - use of digital photography for process-based interpretation at the ecosystem scale

Vegetation phenology is an important indicator of climate change and climate variability and it is strongly connected to biospheric–atmospheric gas exchange. We aimed to evaluate the applicability of phenological information derived from digital imagery for the interpretation of CO2 exchange measurements. For the years 2005–2007 we analyzed seasonal phenological development of 2 temperate mixed forests using tower-based imagery from standard RGB cameras. Phenological information was jointly analyzed with gross primary productivity (GPP) derived from net ecosystem exchange data. Automated image analysis provided reliable information on vegetation developmental stages of beech and ash trees covering all seasons. A phenological index derived from image color values was strongly correlated with GPP, with a significant mean time lag of several days for ash trees and several weeks for beech trees in early summer (May to mid-July). Leaf emergence dates for the dominant tree species partly explained temporal behaviour of spring GPP but were also masked by local meteorological conditions. We conclude that digital cameras at flux measurement sites not only provide an objective measure of the physiological state of a forest canopy at high temporal and spatial resolutions, but also complement CO2 and water exchange measurements, improving our knowledge of ecosystem processes.

Literarisiertes Leben und gelebte Literatur - Interferenzen von Autobiographie, Briefkultur und galantem Roman um 1700

Der Beitrag untersucht Interferenzen von Literatur und Leben in höfischen Selbstzeugnissen um 1700. Am Beispiel einer autobiographischen Schlüsselerzählung von Aurora von Königsmarck wird zum einen gezeigt, wie die eigene Lebensgeschichte literarisch überformt in einer typischen galanten Erzählung dargeboten wird. An einem zweiten Beispiel, dem Briefwechsel zwischen Sophie Dorothea von Hannover und Graf Philipp von Königsmarck, lässt sich zum anderen erkennen, dass eben diese literarischen Muster aus dem Bereich der Galanterie wiederum Vorbilder für ganz reale Lebensentwürfe werden konnten. Der galante Diskurs um 1700 erweist sich als ein Diskurs, der der Verwischung der Grenzen zwischen Literatur und Leben Vorschub leistet. Dabei verstärken sich die selbstreflexiven Züge des frühneuzeitlichen Rollen-Ichs, was einerseits Handlungsspielräume neu eröffnet, andererseits von den Diskursteilnehmern eine komplexere Form von Fremd- und Selbstbeobachtung erfordert und sich deshalb als riskant erweist.

Planung und Risikobewertung projektspezifischer Produktionsnetzwerke

Bei Einzel‐ und Kleinserienfertigung müssen sowohl langfristige Kooperationspartner als auch auftrags-spezifische, internationale Partner und Lieferanten in die Produktion komplexer Investitionsgüter einbezogen werden. Zunehmend sind kleine und mittlere Unternehmen (KMU) herausgefordert nicht nur technische Komponenten zu liefern, sondern die komplette Projektplanung zu realisieren. Im Forschungsprojekt „PIP“ soll ein Verfahren entwickelt werden, das gerade KMU des Maschinen- und Anlagenbaus bei der aufwandsmi-nimierten Partner- und Lieferantenauswahl sowie der Einschätzung möglicher Projektrisiken unterstützt. Der vorliegende Artikel beschreibt Rahmenbedingungen beim Aufbau projektspezifischer Produktionsnetzwerke sowie Lösungsansätze zu deren verbesserter Planung und Risikobewertung.

Subclinical thyroid dysfunction and functional capacity among elderly

Background: Subclinical thyroid dysfunction is common among older people and has been associated with decreased functional capacity but with conflicting data. The aim of this study was to assess the association between subclinical thyroid dysfunction and functional capacity in an elderly population. Methods: We included 5182 participants with a mean age of 75.2 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Self-reported functional capacity was assessed using the Barthel Index (BI) and the Instrumental Activities of Daily Living (IADL) scores at baseline and during follow-up. Participants with subclinical hyperthyroidism (n=65) and subclinical hypothyroidism (n=173) were compared to euthyroid participants (n=4944). The association between persistent subclinical thyroid dysfunction and functional capacity and decline was also investigated. Results: At baseline, compared to euthyroid participants (BI 19.73±SE 0.06; IADL 13.52±0.02), there was no difference in functional capacity for participants with subclinical hyperthyroidism (BI 19.60±0.09; IADL 13.51±0.12, p>0.05) or subclinical hypothyroidism (BI 19.82±0.06; IADL 13.55±0.08, p>0.05). Over a mean 3.2-year follow-up period, there was no association between thyroid function and annual decline of either BI or IADL (p>0.05). No association was found between persistent subclinical thyroid dysfunction and functional capacity at baseline or during follow-up (p>0.05). Results were similar after excluding participants with a maximum BI and/or IADL score at baseline. Conclusion: Among well-functioning community-dwelling elderly, we found no evidence that subclinical thyroid dysfunction contributes to decreased functional capacity.

A unified nomenclature of NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER family members in plants

Members of the plant NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER (NRT1/PTR) family display protein sequence homology with the SLC15/PepT/PTR/POT family of peptide transporters in animals. In comparison to their animal and bacterial counterparts, these plant proteins transport a wide variety of substrates: nitrate, peptides, amino acids, dicarboxylates, glucosinolates, IAA, and ABA. The phylogenetic relationship of the members of the NRT1/PTR family in 31 fully sequenced plant genomes allowed the identification of unambiguous clades, defining eight subfamilies. The phylogenetic tree was used to determine a unified nomenclature of this family named NPF, for NRT1/PTR FAMILY. We propose that the members should be named accordingly: NPFX.Y, where X denotes the subfamily and Y the individual member within the species.