Prognostic implications of the co-detection of the urokinase plasminogen activator system and osteopontin in patients with non-small-cell lung cancer undergoing radiotherapy and correlation with gross tumor volume.

BACKGROUND: The urokinase plasminogen activator system (uPA, uPAR, PAI­1) is upregulated in cancer and high plasma levels are associated with poor prognosis. Their interaction with hypoxia-related osteopontin (OPN) which is also overexpressed in malignant tumors suggests potential clinical relevance. However, the prognostic role of the uPA system in the radiotherapy (RT) of non-small-cell lung cancer (NSCLC), particularly in combination with OPN, has not been investigated so far. METHODS: uPA, uPAR, PAI­1 and OPN plasma levels of 81 patients with locally advanced or metastasized NSCLC were prospectively analyzed by ELISA before RT and were correlated to clinical patient/tumor data and prognosis after RT. RESULTS: uPAR plasma levels were higher in M1; uPA and PAI­1 levels were higher in M0 NSCLC patients. uPAR correlated with uPA (p < 0.001) which also correlated with PAI­1 (p < 0.001). The prognostic impact of OPN plasma levels in the RT of NSCLC was previously reported by our group. PAI­I plasma levels significantly impacted overall (OS) and progression-free survival (PFS). Low PAI­1 levels were associated with a significantly reduced OS and PFS with a nearly 2­fold increased risk of death (p = 0.029) and tumor progression (p = 0.029). In multivariate analysis, PAI­1 levels remained an independent prognostic factor for OS and PFS with a 3­fold increased risk of death (p = 0.001). If PAI­1 plasma levels were combined with OPN or tumor volume, we found an additive prognostic impact on OS and PFS with a 2.5- to 3­fold increased risk of death (p = 0.01). CONCLUSION: Our results suggest that PAI-1 but not uPA and uPAR might add prognostic information in patients with advanced NSCLC undergoing RT. High pretreatment PAI-1 plasma levels were found predominantly in M0-stage patients and indicate a favorable prognosis as opposed to OPN where high plasma levels are associated with poor survival and metastasis. In combination, PAI-1 and OPN levels successfully predicted outcome and additively correlated with prognosis. These findings support the notion of an antidromic prognostic impact of OPN and PAI-1 plasma levels in the RT of advanced NSCLC.

Citizen approval of nudging interventions promoting healthy eating: the role of intrusiveness and trustworthiness.

BACKGROUND: Nudging interventions have lately been widely adopted by policy makers to increase the welfare of society and to help citizens make better choices. Hence, it has become important to understand the conditions under which they are approved. While most research has looked into whether professionals approve of nudging interventions, surprisingly the opinion of the target group has been widely ignored. This study investigated citizens' level of approval of nudging in the realm of healthy eating promotion, as well as its boundary conditions. METHODS: Participants (N = 1441) from the US and seven European countries were probed for their level of approval of nudges. Moreover, we investigated whether these levels of approval were dependent on the level of intrusiveness of the nudge and on the type and trustworthiness of the source (policy makers, experts, industry) implementing the nudge. RESULTS: People revealed moderate to high levels of approval with nudging across all countries. Intrusiveness and nudging approval were negatively associated. Nudges implemented by experts received more approval than those by policy makers. In general, approval increased with the trustworthiness of the source. CONCLUSIONS: These results provide information for European and American policy makers considering using nudging in their policy repertoire.

[Optical Coherence Tomography Angiography in Diagnosis and Post-Treatment Assessment of Hemangioblastomas in Hippel-Lindau Disease]. / Möglichkeiten der optischen Kohärenztomografie-Angiografie bei Diagnostik und postoperativer Verlaufskontrolle von Hämangioblastomen bei Von-Hippel-Lindau-Syndrom.

Background Optical coherence tomography angiography (OCTA) offers the possibility to visualize, non-invasively, blood vessels of the retina. In vascular tumors, especially hemangioblastomas in Hippel-Lindau disease, new information can be obtained with OCTA concerning structure of the tumor, tumor activity and treatment success. Patients Ten eyes of 10 patients with retinal hemangioblastoma in Hippel-Lindau disease were included. The age of the patients ranged from 19 years to 65 years (median 44 years). Results A total of 10 active and one inactive hemangioblastomas were examined with OCTA. In larger tumors, only the superficial blood flow could be visualized. Four hemangioblastomas were not treated due to their location near the optic nerve head. Six hemangioblastomas in the peripheral retina were treated with laser photocoagulation. In 4 eyes, a reduced blood flow could be shown directly after the treatment. The visualization of the perfusion was partially blocked after laser treatment. Conclusion OCTA enables innovative methods of pre- and postoperative assessment of retinal hemangioblastomas. It has the potential to give new information about the morphology, activity and effects of treatment. Prospective studies with longer follow-up are needed to evaluate the therapeutic relevance of this new imaging method.

Loss of function of PGAP1 as a cause of severe encephalopathy identified by Whole Exome Sequencing: Lessons of the bioinformatics pipeline.

We evaluated a multiple consanguineous Turkish family with two children, a boy and a girl, affected by severe encephalopathy, hypotonia, microcephaly and retinal dystrophy by a combination of linkage analysis and Whole Exome Sequencing (WES). We analyzed the sequence data by two different bioinformatics pipelines which did not differ in overall processing strategy but involved differences in software used, minor allele frequency (MAF) thresholds and reference data sets, the usage of in-house control exomes and filter settings to prioritize called variants. Assuming autosomal recessive mode of inheritance, only homozygous variants present in both children were considered. The resulting variant lists differed partially (nine variants identified by both pipelines, ten variants by only one pipeline). Major reasons for this discrepancy were different filters for MAF and different variant prioritizations. Combining the variant lists with the results of linkage analysis and further prioritization by expression data and prediction tools, an intronic homozygous splice variant (c.1090-2A>G; IVS9-2A>G; p.?) in PGAP1 (Post-GPI Attachment To Proteins 1) was identified and validated by cDNA analysis. PGAP1 ensures the first step of maturation of GPI (glycosylphosphatidylinositol)-anchor proteins. Recently, a homozygous loss-of-function mutation in PGAP1 has been reported in one family with two children affected by a similar phenotype. The present report not only illustrates the possible influence of specific filtering settings on the results of WES but also confirms PGAP1 as a cause of severe encephalopathy.

Craniofrontonasal syndrome in a male due to chromosomal mosaicism involving EFNB1: further insights into a genetic paradox.

Craniofrontonasal syndrome (CFNS) is an X-linked disorder caused by inactivating mutations in the gene for ephrin-B1 (EFNB1). Paradoxically it shows a more severe phenotype in females than in males. As a result of X inactivation cell populations with and without EFNB1 expression are found in EFNB1+/- females. This is thought to initiate a process termed cellular interference which may be responsible for the phenotype in females. We present a boy with severe clinical features of CFNS. In ∼42% of his blood cells we found a supernumerary ring X chromosome containing EFNB1 but lacking XIST. Mosaicism for cell populations with different levels of EFNB1 expression can explain the severe phenotype of this patient. In vitro experiments in Xenopus tissue showed that cells overexpress ephrinB1 cluster and sort out from wild-type cells. Our report provides further evidence that cellular interference contributes to the paradoxical inheritance pattern of CFNS.

Pseudoautosomal inheritance of Léri-Weill syndrome: what does it mean?

The short stature homeobox (SHOX) gene is located in the pseudoautosomal region 1 of both sex chromosomes. Haploinsufficiency of SHOX leads to different phenotypes ranging from isolated short stature to Léri-Weill syndrome characterized by short stature, mesomelia and Madelung deformity. We describe a family with a SHOX deletion originally located on the Y chromosome and transmitted from father to daughter by crossover during meiosis. The male index patient presented with short stature, mesomelia and mild Madelung deformity. His father had a normal height but slightly disproportionate short legs. The sister of the index patient presented with marked Madelung deformity and normal height. A deletion of the SHOX gene was identified in the male index patient, his father and his sister. Metaphase fluorescence in situ hybridization (FISH) analyses showed a deletion of the SHOX gene on the Y chromosomes of the index patient and his father, and on the X chromosome of his sister, indicating that a meiotic crossover of the SHOX gene region between the X and Y chromosomes had occurred. The pseudoautosomal region 1 is a known recombination 'hot spot' in male meiosis. Published genetic maps indicate high recombination frequency of ∼40% for SHOX in male meiosis leading to pseudoautosomal inheritance.

Mortality after radiotherapy or surgery in the treatment of early stage non-small-cell lung cancer: a population-based study on recent developments.

BACKGROUND: Stereotactic body radiotherapy (SBRT) can achieve high tumour control with limited toxicity for inoperable early stage non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: The German Epidemiologic Cancer Registries from the Robert-Koch Institute were assessed. Periods according to the availability of SBRT were: (1) 2000-2003 (pre-SBRT); (2) 2004-2007 (interim); and (3) 2007-2014 (broad availability of SBRT). To assess the association of cancer-related parameters with mortality, hazard ratios (HR) from Cox proportional hazards models were computed. To evaluate the change of treatment-related mortality, we performed interaction analyses and the relative excess risk due to interaction (RERI, additive scale) was computed. RESULTS: A total of 16,292 patients with UICC stage I NSCLC diagnosed between 2000 and 2014 were analysed. Radiotherapy utilization increased from 5% in pre-SBRT era to 8.8% after 2007. In univariate analyses, survival in the whole cohort improved only marginally when 2000-2003 is compared to 2004-2007 (HR 0.92, 95% CI 0.85-1.01) or 2008-2014 (HR 0.93, 95% CI 0.86-1.01). Comparing surgery/radiotherapy, mortality in the radiotherapy group started from a 3.5-fold risk in 2000-2003 to 2.6 after 2007. The interaction analysis revealed a stronger improvement for radiotherapy (multiplicative scale for 2000-2003 vs. > 2007: 0.74, 95% CI 0.58-0.94). On an additive scale, treatment × period interaction revealed an RERI for 2000-2003 vs. > 2007 of - 1.18 (95% CI - 1.8, - 0.55). CONCLUSIONS: Using population-based data, we observed a survival improvement in stage I lung cancer over time. With an increasing utilization of radiotherapy, a stronger improvement occurred in patients treated with radiotherapy when compared to surgery.

[Scleral melting after cyclophotocoagulation]. / Skleraeinschmelzung nach Zyklophotokoagulation.

We report on a case of a scleral melting as a rare but severe complication of transscleral cyclophotocoagulation. The tissue defect was successfully repaired by tectonic keratoplasty.

ATP-dependent Ca2+ uptake and Ca2+-dependent protein phosphorylation in basolateral liver plasma membranes.

ATP-dependent Ca2+ uptake was measured in vesicles of rat liver cell basolateral plasma membranes. Nucleotide-dependent uptake was specific for ATP and observed at pH 7.0 and 7.4/7.5 but not at pH 8.0. ATP-dependent Ca2+ transport was only observed in the presence of Mg2+. Kinetic analysis of ATP-dependent transport revealed an apparent Km in the submicromolar region. Addition of calmodulin and trifluoperazine had no effect on ATP-dependent uptake. A Ca2+-dependent, phosphorylated intermediate with the apparent molecular weight of 135,000 could be demonstrated in the basolateral plasma membranes. Phosphorylated intermediates with apparent molecular weights of 200,000 and 110,000 were demonstrated in microsomes and appeared to contaminate 'basolateral' membrane protein phosphorylation. The results suggest that a 135,000 molecular weight protein is a Ca2+-ATPase and the enzymatic expression of the liver cell basolateral membrane Ca2+ pump.

A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group study.

PURPOSE: From 1979 to 1984, 356 eligible patients with advanced or recurrent endometrial carcinoma no longer amenable to therapy with surgery, radiotherapy, or progestins were treated with doxorubicin alone or doxorubicin in combination with cyclophosphamide. PATIENTS AND METHODS: Patients were randomized to receive doxorubicin 60 mg/m2 intravenously (i.v.) with or without cyclophosphamide 500 mg/m2 i.v. every 3 weeks for eight drug courses. All patients had received prior therapy with progestins with subsequent progression of disease. No patients had received prior therapy with cytotoxic drugs. Of 356 patients, 300 had measurable disease. RESULTS: Among 132 patients treated with doxorubicin alone, there were seven complete responses (5%), 22 partial responses (17%), 73 with stable disease (55%), and 30 with increasing disease within 2 months of study entry (23%). For the 144 patients who received the combination, there were 18 complete responses (13%), 25 partial responses (17%), 75 with stable disease (52%), and 26 with increasing disease (18%). The median progression-free interval for those patients who received doxorubicin alone was 3.2 months, while it was 3.9 months for those who received the combination. The median survival duration for doxorubicin patients was 6.7 months, while it was 7.3 months for the combination patients. None of the unadjusted estimates of treatment differences are statistically significant. Prognostic features that had an impact on outcome included one factor associated with an increased likelihood of response (presence of measurable lung metastases) and four features associated with a poorer survival (poor performance status [PS] of 2 or 3, high pathologic grade, and presence of liver metastases or other intraabdominal disease). If these features are taken into account in multivariate analyses, there is no statistically significant evidence for differences in response rates (relative odds of response, 1.58; P = .06, one-tailed test), and survival duration is slightly longer in the combination regimen (17% reduction in death rate; P = .048). CONCLUSION: The combination of doxorubicin plus cyclophosphamide thus appears to offer a small advantage over doxorubicin alone in the management of endometrial carcinoma at the expense of more frequent and severe myelosuppression and gastrointestinal toxicity.

Endogenous catecholamine levels in chronic heart failure. Relation to the severity of hemodynamic abnormalities.

Plasma free epinephrine, norepinephrine, and dopamine concentrations were determined in 48, 63, and 45 patients, respectively, with overt congestive heart failure, and compared with those in 26 patients with stable angina but without heart failure. Systemic hemodynamic values were determined to assess the severity of heart failure. Arterial epinephrine levels were not different between patients with heart failure (73 +/- 92 pg/ml) and patients without heart failure (55 +/- 73 pg/ml). In patients with congestive heart failure, norepinephrine (665 +/- 510 pg/ml, mean +/- SD) and dopamine (407 +/- 405 pg/ml) levels were significantly higher than in patients with stable angina without heart failure (norepinephrine 184 +/- 136 pg/ml, p less than 0.001, and dopamine 197 +/- 259 pg/ml, p less than 0.02). However, in patients with congestive heart failure, the plasma norepinephrine levels did not correlate with cardiac index (r = 0.21, p = NS), pulmonary capillary wedge pressure (r = 0.11, p = NS), mean arterial pressure (r = 0.11, p = NS), or systemic vascular resistance (r = 0.18, p = NS). Similarly, there was no correlation between dopamine levels and the hemodynamic abnormalities in patients with congestive heart failure. These findings suggest that although endogenous norepinephrine and dopamine levels are frequently elevated in patients with heart failure, reflecting enhanced sympathetic activity, catecholamine levels do not reflect the severity of heart failure.

Psychosocial impact of predictive testing for Huntington disease on support persons.

Although a support person is required by many centers during the predictive testing protocol for Huntington disease (HD), little is known about the psychosocial impact of predictive testing on persons serving in this role. Eighteen adults who were support persons during predictive HD testing in one HD testing center completed a semi-structured interview to describe their experiences. Participants also completed the Impact of Events Scale (IES) to assess perceptions of emotional distress regarding predictive testing and the State Anxiety Scale of the State Trait Anxiety Inventory (STAI) to assess anxiety regarding the interview. State anxiety scores were similar to normative values for working adults. Although support persons for individuals with a positive gene test scored higher on all measures of the IES than those who were support persons for persons with negative gene mutation results, these differences were not statistically significant. Support persons identified aspects of the protocol that did not fit their needs, perceived the testing process as extending into subsequent caregiving responsibilities when the test was positive, and were uninformed regarding specific caregiving issues for family members with the gene mutation. The impact of the testing experience appeared to be most intense for those support persons who were at-risk offspring of probands. Findings suggest that individual assessment of support person needs may allow more focused counseling of support persons during predictive genetic HD testing. Collaboration with health care providers may facilitate symptom management following testing.

The masking role of the sodium pump and chloride ions on the effect of carbachol in- and outside the endplate region of rat diaphragm muscle.

The effect of carbachol (10(-3)M) on the membrane potential of rat diaphragm muscle fibres near and remote from the endplate has been investigated by means of a microelectrode technique. In the endplate region a rather slow depolarization was observed followed by spontaneous repolarization. Outside the endplate region similar, but smaller, responses could be measured. In a muscle part separated from the endplate zone, carbachol had no depolarizing effect. Inhibition of the sodium pump by ouabain (10(-4)M) or potassium-free medium not changing the membrane potential itself, allowed carbachol to exert a depolarizing effect on this endplate-free membrane, while in endplate-free regions continuous with the endplate-zone the depolarizations already observed were enhanced. In low chloride solutions carbachol also had a depolarizing effect on endplate-free muscle membrane. It is concluded from these experiments that a direct effect of cholinergic drugs on endplate-free muscle membrane of rat diaphragm is counteracted by the sodium pump in combination with passive chloride movements. The results are discussed in the context of known receptor densities and chloride effects.

Empower children to develop healthful eating habits.

Controlling a child's eating habits is counterproductive. By allowing children to make decisions about what and how much to eat, parents empower children to self-regulate their eating. The parent's role is to offer a variety of healthful foods, oversee the planning and assembly of meals, and set the schedule for meals and snacks. The child's responsibility is to decide what, how much, and even whether to eat.

Dietary intake and symptoms of anorexia nervosa in female university dancers.

This study was designed to measure and evaluate the dietary intake and symptoms of anorexia nervosa in female university dancers (no. = 21) and a control group of female university non-dancers (no. = 29). Three-day food records were analyzed for calories, protein, vitamin A, vitamin C, thiamin, riboflavin, niacin, calcium, phosphorus, and iron. Symptoms of anorexia nervosa were determined through the use of an objective questionnaire, the Eating Attitudes Test (EAT). The percent of subjects who consumed less than two-thirds of the Recommended Dietary Allowance (RDA) for energy was significantly higher in the dance group (28.6% vs. 10.3%, p less than .005). Seventy percent of the total study population consumed less than two-thirds of the RDA for at least one nutrient, and 24% consumed less than two-thirds of the RDA for three or more nutrients. Thirty-three percent of the dancers and 13.8% of the controls scored in the range symptomatic of anorexia nervosa on the EAT, a difference that was statistically significant (p less than .005). The results indicate that both female university dancers and female university students may be at risk for nutrient deficiency and anorexia nervosa.

Developing a critical pathway for orientation.

A direct correlation exists between job satisfaction and employee retention with an organized and compassionate orientation process for new employees on a nursing unit. It is generally recognized that preceptorship/mentoring is the most desirable orientation modality; however, situations occasionally require orientees to work with several preceptors with varying levels of proficiency. A program based upon a framework designated "critical pathway" was established in a coronary care unit and a cardiac progressive care unit to organize orientation information into weekly segments, with each week's content building upon the previous week's information. Because the critical pathway clearly delineates the orientation content, all necessary information is imparted to the orientee in an organized fashion without omitting pertinent details. Problems with orientation are documented as variances on the critical pathway, and are discussed between the preceptor and orientee during weekly evaluation sessions. This article reports the procedure for developing a critical pathway for orientation using the critical pathway concept, which is adapted from the nursing case management practice model.

Fluorescence of Blastomyces and other fungi in Papanicolaou-stained pulmonary cytology preparations: comparison with light microscopy.

In this study, 152 Papanicolaou-stained pulmonary cytologic smears from 15 known cases of pulmonary fungal infection were randomly mixed with 194 control pulmonary smears. All slides were examined for fungi by three observers, first by light microscopy and then by fluorescent microscopy. The results of the light and fluorescent microscopy were compared. It was concluded that when both methods were used for fungal detection, the yield of positive results was higher.

[Gender identity disorders as a symptom of psychosis, schizophrenia in particular]. / Genderidentiteitsstoornissen als bijverschijnsel van psychose, in het bijzonder schizofrenie.

In the Netherlands it has recently become possible for transsexual patients to receive hormonal treatment from the onset of puberty. Until the age of 16, pubertal development can be prevented with luteinizing hormone-releasing hormone (LHRH) agonists. From 16 years of age onwards, gender adjustment can be initiated by administration of hormones of the opposite sex. Surgical treatment can be offered once the patient reaches 18 years of age. Although such treatment will only be initiated with reticence and after a long phase of intense diagnostic screening, the question arises whether a clear differentiation can be made between pure gender identity disorders and secondary transsexual feelings that are part of an ongoing psychopathological development, such as schizophrenia. The potential diagnostic confusion is illustrated by a case history of a male schizophrenic patient. This patient had been treated hormonally for transsexualism for years before acute psychotic decompensation occurred. Neuroleptic treatment of the psychosis rapidly reduced the psychotic symptoms. In retrospect, the patient regards his transsexual period as a 'mistake'. Delusions about one's physical appearance and the urge to drastically change the way one looks appear to be relatively common in patients suffering from schizophrenia.

The DIAL-log study 1: Profiling the experience of people with dementia.

Between July 1996 and December 1997 telephone helpline staff from the Alzheimer's Disease Society (ADS) in London, and six participating ADS regions in England and one in Northern Ireland, documented calls from people with dementia who contacted the service. Each call was recorded as soon as practicable after its completion on a Dementia Information and Advice Line (DIAL) log form (DIAL-log). Sixty-four calls were recorded in this way and 62 completed DIAL-logs were included in the study findings. Analysis of the data was undertaken via SPSS 6.1 for Windows. This article, the first of two, introduces the background to the study and notes that callers reported memory loss and forgetfulness as the most frequently noticed first signs of dementia. The study aims and limitations are also outlined in this first article. The second article will detail the main findings and the challenges that the DIAL-log study may provide for future dementia care practice and research.

The DIAL-log study. 2: Support in the early stages of dementia.

In the previous article (Vol 8(6): 387-93) the background information and study aims/limitations of the Dementia Information and Advice Lines (DIAL-log) project were outlined. This article introduces the main findings of the project and suggests that the transition into dementia is experienced through rising degrees of uncertainty and anxiety. People with the early experience of dementia also requested strategies for coping with memory loss and uncertainty over the meaning and purpose of memory testing. Building on the main findings of the project, the article concludes with a five-stage framework to help shape future research and service support.