How to do (or not to do) Measuring health worker motivation in surveys in low- and middle-income countries.

A health system's ability to deliver quality health care depends on the availability of motivated health workers, which are insufficient in many low income settings. Increasing policy and researcher attention is directed towards understanding what drives health worker motivation and how different policy interventions affect motivation, as motivation is key to performance and quality of care outcomes. As a result, there is growing interest among researchers in measuring motivation within health worker surveys. However, there is currently limited guidance on how to conceptualize and approach measurement and how to validate or analyse motivation data collected from health worker surveys, resulting in inconsistent and sometimes poor quality measures. This paper begins by discussing how motivation can be conceptualized, then sets out the steps in developing questions to measure motivation within health worker surveys and in ensuring data quality through validity and reliability tests. The paper also discusses analysis of the resulting motivation measure/s. This paper aims to promote high quality research that will generate policy relevant and useful evidence.

[Successful therapy with etanercept in relapsing polychondritis]. / Erfolgreiche Therapie mit Etanercept bei rezidivierender Polychondritis.

Relapsing polychondritis is a rare autoimmune disease associated with inflammation and destruction of cartilage and connective tissue.We report on a patient with a severe form of this disease that had a progressive and complicated course despite administration of a number of disease-modifying anti-rheumatic drugs.Finally, therapy with the TNF-alpha-antagonist etanercept was initiated, which led to a considerable decrease in disease activity. This case is further evidence for the efficiency of TNF-alpha-antagonists in relapsing polychondritis.

[Comparison of patients with psoriasis vulgaris vs. psoriatic arthritis with regard to the reported quality of life]. / Vergleich von Patienten mit Psoriasis vulgaris vs. Psoriasis-Arthritis im Hinblick auf die berichtete Lebensqualität.

The present study investigates possible differences in quality of life impairment of patients with psoriasis vulgaris and psoriatic arthritis. One hundred and sixteen patients who were admitted for inpatient rehabilitation to the Fachklinik Bad Bentheim were asked to fill in a self-assessment questionnaire. This questionnaire comprised the SF-12, the German version of the Health Assessment Questionnaire, questions regarding the occupational and the social situation as well as additional questions for identification of specific disease-related burden. Altogether, both groups exhibited impairments of the quality of life. As was to be expected, the arthritis patients suffered from considerably more functional impairment than the patients who only had skin involvement. Interestingly, however, the psychic burden attributable to the disease is equal in patients with isolated skin involvement in comparison to patients with additional arthritis. Summarizing, a different proportion between the extent of psychic and physical impairment is found in the two groups, which might be due to a different pattern of coping with the disease. Taking this aspect into account is imperative when assessing the severity of the disease.

[Foreign body in proximal ureter after selective embolisation of a renal artery]. / Fremdkörpermaterial im proximalen Ureter nach selektiver Nierenarterienembolisation.

Colic attacks by a foreign body in the urinary tract are very rare and mostly follow iatrogenic manipulation. This case report focuses on ureteric colic thought to result from radiological embolisation material. It is of practical interest because embolisation of prolonged bleeding after endourological procedures is widely done.An 80-year-old woman with a long history of nephrolithiasis underwent percutaneous nephrolithotomy. She suffered from a continuous, transfusion-obligatory bleeding. The source of bleeding was treated with embolisation by coiling. About 2 years later, the patient presented with persistent pain on the right abdominal side and urinary obstruction. A dislocation of the coils into the ureteropelvic junction was diagnosed. After primary ureteral stenting, the foreign body was removed via ureterotomy.

Interobserver-variability of lung nodule volumetry considering different segmentation algorithms and observer training levels.

OBJECTIVE: The aim of this study was to investigate the interobserver variability of CT based diameter and volumetric measurements of artificial pulmonary nodules. A special interest was the consideration of different measurement methods, observer experience and training levels. MATERIALS AND METHODS: For this purpose 46 artificial small solid nodules were examined in a dedicated ex-vivo chest phantom with multislice-spiral CT (20 mAs, 120 kV, collimation 16 mm x 0.75 mm, table feed 15 mm, reconstructed slice thickness 1mm, reconstruction increment 0.7 mm, intermediate reconstruction kernel). Two observer groups of different radiologic experience (0 and more than 5 years of training, 3 observers each) analysed all lesions with digital callipers and 2 volumetry software packages (click-point depending and robust volumetry) in a semi-automatic and manually corrected mode. For data analysis the variation coefficient (VC) was calculated in per cent for each group and a Wilcoxon test was used for analytic statistics. RESULTS: Click-point robust volumetry showed with a VC of <0.01% in both groups the smallest interobserver variability. Between experienced and un-experienced observers interobserver variability was significantly different for diameter measurements (p=0.023) but not for semi-automatic and manual corrected volumetry. A significant training effect was revealed for diameter measurements (p=0.003) and semi-automatic measurements of click-point depending volumetry (p=0.007) in the un-experienced observer group. CONCLUSIONS: Compared to diameter measurements volumetry achieves a significantly smaller interobserver variance and advanced volumetry algorithms are independent of observer experience.

Lack of genetic association of the three more common polymorphisms of CARD15 with psoriatic arthritis and psoriasis in a German cohort.

OBJECTIVE: To determine whether the three common independent sequence variants of the putative pleiotropic non-MHC autoimmune gene CARD15 influence disease susceptibility in large German cohorts of patients with psoriatic arthritis and psoriasis vulgaris, before and after stratification to HLA-C. METHODS: DNA was obtained from 375 patients with psoriatic arthritis, 281 patients with psoriasis vulgaris without joint involvement, and 376 controls. The three variants of the CARD15 gene (R702W, G908R, leu1007fsinsC), and two single nucleotide polymorphisms of the HCR gene (HCR-325, HCR-2327) for HLA-C stratification were genotyped using allelic discrimination Taqman assays. RESULTS: No significant differences in genotype frequencies were observed between controls and either the psoriatic arthritis or the psoriasis vulgaris patient population, even after stratification to HLA-C in both patient cohorts, or to the type of joint involvement within the psoriatic arthritis group. CONCLUSIONS: The lack of genetic association between the most common Crohn's disease alleles of the CARD15 gene and psoriatic joint disease on large cohorts of white patients does not support a recently claimed role for CARD15 as the first non-MHC susceptibility gene in the pathogenesis of psoriatic arthritis, but confirms and extends previous studies in the case of psoriasis vulgaris.

A molecular link between stem cell regulation and floral patterning in Arabidopsis.

The homeotic gene AGAMOUS (AG) has dual roles in specifying organ fate and limiting stem cell proliferation in Arabidopsis flowers. We show that the floral identity protein LEAFY (LFY), a transcription factor expressed throughout the flower, cooperates with the homeodomain protein WUSCHEL (WUS) to activate AG in the center of flowers. WUS was previously identified because of its role in maintaining stem cell populations in both shoot and floral meristems. The unsuspected additional role of WUS in regulating floral homeotic gene expression supports the hypothesis that floral patterning uses a general meristem patterning system that was present before flowers evolved. We also show that AG represses WUS at later stages of floral development, thus creating a negative feedback loop that is required for the determinate growth of floral meristems.

Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon.

BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a terminal ileum and colon who have functional short-bowel syndrome with severe malabsorption of wet weight (>1.5 kg/day) and energy (>2.3 MJ/day) and no postprandial secretion of GLP-2. METHODS: Balance studies were performed before and after treatment with GLP-2, 400 microg subcutaneously twice a day for 35 days, in 8 patients (4-17 years from last bowel resection; 6 with Crohn's disease). Four patients received home parenteral nutrition (mean residual jejunum, 83 cm), and 4 did not (mean ileum resection, 106 cm). Biopsy specimens were taken from jejunal/ileal stomas, transit was measured by scintigraphy, and body composition was measured by dual-energy x-ray absorptiometry. RESULTS: Treatment with GLP-2 improved the intestinal absorption of energy 3.5% +/- 4.0% (mean +/- SD) from 49.9% to 53.4% (P = 0.04), wet weight 11% +/- 12% from 25% to 36% (P = 0.04), and nitrogen 4.7% +/- 5.4% from 47.4% to 52.1% (P = 0.04). Body weight increased 1.2 +/- 1.0 kg (P = 0.01), lean body mass increased 2.9 +/- 1.9 kg (P = 0.004), fat mass decreased 1.8 +/- 1.3 kg (P = 0.007), and 24-hour urine creatinine excretion increased (P = 0.02). The time to 50% gastric emptying of solids increased 30 +/- 16 minutes from 89 to 119 minutes (P < 0.05). Small bowel transit time was not changed. Crypt depth and villus height were increased in 5 and 6 patients, respectively. CONCLUSIONS: Treatment with GLP-2 improves intestinal absorption and nutritional status in short-bowel patients with impaired postprandial GLP-2 secretion in whom the terminal ileum and the colon have been resected.

The survival characteristics of dense sickle cells.

Sickle red blood cells (RBCs) become depleted of potassium, leading to dehydration and abnormally elevated cellular density. The increased sickling that results is important for both hemolysis and vasocclusion. In this study, sickle cells were subjected to high-speed centrifugation, and the bottom 15% were isolated. This procedure removed light cells and to a variable degree enriched cells that were denser than normal to produce a high-density-enriched (HDE) population of sickle cells. Autologous HDE cells from 3 subjects were labeled with biotin and re-infused. The following determinations were performed: (1) the survival and density changes of HDE cells; (2) the amount of fetal hemoglobin (HbF) in labeled cells after magnetic isolation; (3) the percentage of labeled F cells; (4) the percentage of labeled cells displaying external phosphatidylserine (PS). For patients with 3.5%, 4.5%, and 24% HbF in the HDE RBCs, the circulation half-time was 40, 80, and 180 hours, respectively. The percentage of HbF (measured in all 3 subjects) and of F cells (measured in 2 subjects) in labeled RBCs increased with time after re-infusion, indicating that HDE F cells have longer in vivo survival than HDE non-F cells. The percentage of PS(+), biotin-labeled HDE cells showed no consistent increase or decrease with time after re-infusion. These data provide evidence that HDE sickle cells, especially those that do not contain HbF, have a very short in vivo survival, and that the percentage of PS(+) cells in a re-infused HDE population does not change in a consistent manner as these cells age in the circulation.

The novel peptide HEADY specifies apical fate in a simple radially symmetric metazoan.

One of the first steps in animal development is axis formation, during which an uneven distribution of signals and/or transcription factors results in the establishment of polarity in the embryo. Hydra, one of the simplest metazoan animals, shows characteristics of a permanent embryo. Even adult polyps have a striking capacity to regenerate, suggesting that molecular mechanisms underlying de novo pattern formation are permanently active and self regulatory. Here we show that HEADY, a short, amidated peptide, plays a central role in the specification of apical fate in this simple metazoan. The HEADY gene, whose transcripts accumulate at the apical organizing center, is required for specification of apical fate, as disruption of HEADY function by dsRNA mediated interference (RNAi) results in severe defects in head formation. Conversely, an instructive role of HEADY in head specification is demonstrated by the application of synthetic HEADY peptide, which induces formation of secondary axes with head morphology. Thus, the HEADY peptide acts as developmental switch to pattern the apical-basal axis of Hydra, providing a first insight into how initial asymmetry is specified in lower metazoan animals.

Epidermal growth factor activates reproductive behavior independent of ovarian steroids in female rodents.

Sex steroids exert profound influence on neural development and function through activation of intranuclear receptors. However, during sexual differentiation and at onset of puberty, intracerebral estrogen (E) availability is subsequent to these effects. The potent mitogen epidermal growth factor (EGF) activates estrogen receptor (ER)-dependent transcription in cultured cells in the absence of exogenous E. Since reproductive behavior in female rodents is the result of E-dependent transcriptional activity and protein synthesis, lordosis serves as a well established in vivo model for probing cellular and molecular mechanisms of steroid receptor-dependent behavior. Here we demonstrate that EGF can signal through the classical E receptor (ERalpha) to alter in vivo function in rodent central nervous system. EGF and EGF receptor ligands induced lordosis in a dose- and time-dependent manner in the absence of steroid treatment in ovariectomized rats and mice. Using antisense oligonucleotides, pharmacological and antibody blockade, and mutant mice, we also report that this behavioral responsiveness is mediated through ERalpha by specific stimulation of membrane-bound EGF receptors and EGF receptor-specific tyrosine kinase rather than by direct ligand activation of the ERalpha. Of biological significance, delayed onset of puberty and the absence of synchronization between reproductive behavior and ovulation was detected in intact mutant Wa-2 mice that express a naturally occurring point mutation in the EGF receptor. To our surprise, EGF-mediated behavior was independent of progesterone (P) and progesterone receptor (PR) since antiprogestins, PR antisense oligonucleotides, and targeted disruption of PR in ovariectomized transgenic mice failed to impede the display of lordosis after EGF. Finally, we also found that another growth factor, insulin-like growth factor-1, which provokes ER-dependent transcription in vitro, activates mating behavior in a similar E-independent manner. Thus, growth factor mediation of ER-targeted function may be a universal feature in the rodent central nervous system, raising critical questions about the role of growth factors in mediating ER-dependent processes in development and reproduction.

Upper airway collapsibility in habitual snorers and sleep apneics: evaluation with drug-induced sleep endoscopy.

Increased upper airway collapsibility has been suspected of being involved in the pathogenesis of sleep-related diseases. It is assumed that patients with severe obstructive sleep apnea syndrome (OSAS) show a stronger collapse of the upper airway compared with habitual snorers. It was the objective of this study to analyze the patterns of upper airway collapse in habitual snorers and patients with OSAS and to correlate these results with data from polysomnography. Endoscopy was carried out during drug-induced sleep (with propofol) and collapsibility was analyzed at two major levels (palatal and tongue base). A total of 207 habitual snorers and 117 patients with OSAS underwent endoscopy after overnight polysomnography in our sleep laboratory. In 95% of cases we were able to induce snoring during drug-induced sleep. The collapsibility in the area of the base of the tongue correlated with higher values of the respiratory disturbance index (RDI) as recorded by standard polysomnography. Patients with OSAS showed significantly stronger collapsibility compared with snorers. The difference was more evident at the tongue-base level. We found no significant correlation between the applied CPAP pressure and collapsibility in patients with OSAS. These results show that collapsibility at the tongue-base level is a factor relevant in sleep-related breathing disorders.

[Pharyngolaryngoscopic findings in patients with obstructive sleep apnea syndrome and primary snoring]. / Pharyngolaryngoskopische Befunde bei Patienten mit obstruktivem Schlafapnoesyndrom und primärem Schnarchen.

BACKGROUND AND OBJECTIVE: The localization of an upper airway collapse in snorers and patients suffering from obstructive sleep apnea was a subject frequently discussed in the last few years. Pharyngolaryngoscopy during sleep or drug-induced sleep allows evaluation of upper airway conditions. PATIENTS/METHODS: A total of 324 patients suffering from snoring or obstructive sleep apnea underwent flexible pharyngolaryngoscopy while awake and under propofol-induced sedation in the course of routine diagnostic procedures in the sleeping lab. In this study, the results of pharyngolaryngoscopy are compared to results of the Müller maneuver and polysomnographic recordings. The therapeutic consequences of this additional investigation are discussed. RESULTS: In 95% of cases snoring was observed during drug-induced sleep. A significant discrepancy was seen between results of the endoscopy while being awake (Müller maneuver) and during drug-induced sleep. The degree of collapse differed significantly in the area of the base of the tongue. Severe collapse was seen much more often with pharyngoscopy during drug-induced sleep compared to the results during the Müller maneuver. CONCLUSIONS: The collapsibility in the area of the base of the tongue correlated with higher results in the RDI (respiratory disturbance index) registered with standard polysomnography. Snoring and upper airway collapse were easily surveyed, and the pharyngolaryngoscopy during propofol-induced sleep proved to be a simple, safe, readily controllable and effective supplementary diagnostic device for the diagnosis and treatment of obstructive sleep apnea and snoring.

Silencing of developmental genes in Hydra.

Numerous developmental control genes have been isolated in a variety of organisms by either homology cloning or system-specific strategies. Functional genetic tests, however, are available for only a few model organisms and particularly are missing in a number of animals that occupy key positions for understanding the evolution of development and gene function. Double-stranded RNA-mediated interference (RNAi) opens a way to perform functional studies in such "nongenetic" organisms. Here we show that RNAi can be used to test the function of developmental genes in the cnidarian Hydra, a classical model for developmental studies. Introduction of double-stranded RNA corresponding to the head-specific gene ks1 caused strong depletion of ks1 transcripts. ks1 loss-of-function polyps exhibited severe defects in head formation, indicating an important role of ks1 in Hydra head development. Our results demonstrate for the first time efficient gene silencing in Hydra. RNAi provides an entry point for a variety of functional studies and a direct approach for analyzing the hierarchy of regulatory genes in Hydra, which until now has not been amenable to loss-of-function genetics.

A head-activator binding protein is present in hydra in a soluble and a membrane-anchored form.

The neuropeptide head activator plays an important role for proliferation and determination of stem cells in hydra. By affinity chromatography a 200 kDa head-activator binding protein, HAB, was isolated from the multiheaded mutant of Chlorohydra viridissima. Partial amino acid sequences were used to clone the HAB cDNA which coded for a receptor with a unique alignment of extracellular modules, a transmembrane domain, and a short carboxy-terminal cytoplasmic tail. A mammalian HAB homologue with identical alignment of these modules is expressed early in brain development. Specific antibodies revealed the presence of HAB in hydra as a transmembrane receptor, but also as secreted protein, both capable of binding head activator. Secretion of HAB during regeneration and expression in regions of high determination potential hint at a role for HAB in regulating the concentration and range of action of head activator.

Head-specific gene expression in Hydra: complexity of DNA- protein interactions at the promoter of ks1 is inversely correlated to the head activation potential.

To gain insight into the molecular mechanisms that direct position-dependent gene expression in the simple and evolutionarily old metazoan Hydra, we have examined DNA-protein interactions in the 1.5-kb cis regulatory region of the head-specific gene ks1. In vitro footprinting and gel-retardation techniques have been used to map the location of all protein-binding sites. To our surprise, we found substantially more proteins binding to ks1 promoter elements in nuclear extract from basal (gastric) than from apical (head- and tentacle-formation zone) cells. One of these proteins is the homeobox protein Cnox-2. In the head regeneration-deficient mutant reg-16, an increased level of nuclear protein binds to ks1 promoter elements. Treatment of polyps with the ks1-inducing phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) resulted in reduced binding of nuclear proteins to the ks1 cis regulatory region. As activation of ks1 transcription is correlated with the absence of nuclear proteins binding to the ks1 promoter, we propose that the majority of these proteins act as transcriptional repressors. In this view, the gradient of head activation along the Hydra body axis is caused by a decreasing amount of inhibitory factors, rather than an increasing amount of activators, toward the head. Thus, inhibitory mechanisms might have played a crucial role in regulating position-dependent gene activation during early metazoan evolution.

Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors.

A series of substituted 4-anilinoquinazolines and related compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that a narrow structure-activity relationship (SAR) existed for the bicyclic ring system, with quinazolines, quinolines, and cinnolines having activity and with quinazolines and quinolines generally being preferred. Substitution of the aniline was investigated and clearly indicated that small lipophilic substituents such as halogens or methyl were preferred at the C-4' position. Small substituents such as hydrogen and fluorine are preferred at the C-2' position. Introduction of a hydroxyl group at the meta position of the aniline produced the most potent inhibitors of Flt and KDR tyrosine kinases activity with IC(50) values in the nanomolar range (e.g. 10, 12, 13, 16, and 18). Investigation of the quinazoline C-6 and C-7 positions indicates that a large range of substituents are tolerated at C-7, whereas variation at the C-6 is more restricted. At C-7, neutral, basic, and heteroaromatic side chains led to very potent compounds, as illustrated by the methoxyethoxy derivative 13 (IC(50) < 2 nM). Our inhibitors proved to be very selective inhibitors of Flt and KDR tyrosine kinase activity when compared to that associated with the FGF receptor (50- to 3800-fold). Observed enzyme profiles translated well with respect to potency and selectivity for inhibition of growth factor stimulated proliferation of human umbilical vein endothelial cells (HUVECs). Oral administration of selected compounds to mice produced total plasma levels 6 h after dosing of between 3 and 49 microM. In vivo efficacy was demonstrated in a rat uterine oedema assay where significant activity was achieved at 60 mg/kg with the meta hydroxy anilinoquinazoline 10. Inhibition of growth of human tumors in athymic mice has also been demonstrated: compound 34 inhibited the growth of established Calu-6 lung carcinoma xenograft by 75% (P < 0.001, one tailed t-test) following daily oral administration of 100 mg/kg for 21 days.