Quality of life during and after adjuvant anthracycline-taxane-based chemotherapy with or without Gemcitabine in high-risk early breast cancer: results of the SUCCESS A trial.

PURPOSE: In high-risk early breast cancer, adjuvant taxane-Gemcitabine combinations result in a recurrence-free survival similar to single-agent taxanes. However, haematologic toxicities and need for dose reductions are more frequent in combinations. Which option ultimately provides a better quality of life (QoL) is unknown. We compared the QoL curves before, during, and up to one year after three cycles of Fluorouracil-epirubicin-cyclophosphamide followed by three cycles of Docetaxel-Gemcitabine or Docetaxel. METHODS: Overall, 3691 women with recent R0-resection of a primary epithelial breast cancer participated in the nationwide SUCCESS A clinical trial. The centres sent QoL questionnaires of the European Organisation for Research and Treatment of Cancer before and up to 15 months after randomisation to Docetaxel-Gemcitabine versus Docetaxel. Multilevel analysis by chemotherapy arm estimated the QoL time curves, questionnaire return, and dropout. RESULTS: The combination caused one-point higher global QoL (95% confidence ±1; p = 0.05) and 1.1 lower odds of adherence to the outcome (95% confidence 1.0-1.1; p = 0.23) than the monotherapy. In both groups, a 10-point decrease during therapy preceded a 16-point increase after chemotherapy (p < 0.001). The secondary QoL outcomes showed transient superiority of the combination at the end of chemotherapy. Discontinuation from chemotherapy and its reasons were equal in both groups. CONCLUSIONS: While patients perceive a one-point QoL difference as meaningless, a six-point increase is clinically relevant for them. That is, both regimens cause the same relevant long-term QoL improvement. With the similar recurrence-free survival, the lower toxicity, and the shorter chemotherapy duration in mind, taxanes without Gemcitabine are the preference. This challenges previous recommendations supporting combinations.

Bilateral taste disorders in patients with Ramsay Hunt syndrome and Bell palsy.

OBJECTIVE: Ramsay Hunt syndrome (RHS) and Bell palsy (BP) are typically known as facial nerve motor syndromes and are primarily unilateral. The aim of this study was to challenge this assertion, because both conditions are also known to be associated with viruses that typically affect several nerves. METHODS: Ten participants with RHS, 12 with BP, all clinically unilateral, and 12 healthy controls were prospectively enrolled. Electrogustometric thresholds were measured bilaterally in the areas of the chorda tympani, the glossopharyngeal, and the major petrosal nerve. Also bilaterally, the taste function was tested using chemogustometry with different tastant concentrations. Again bilaterally, the morphology of the mucosa and the vessels of the anterior fungiform papillae were examined by contact endoscopy. Statistically, RHS and BP participants were compared with the healthy controls, and the paretic sides of RHS and BP were compared pairwise with their mobile sides. RESULTS: Electrogustometrically, perception was reduced bilaterally in RHS (10-19dB, p < 0.001) and BP (3-5dB, p = 0.011-0.030) in all 3 innervation areas. Chemogustometrically, it was also reduced bilaterally in RHS (20-70%) and BP (8-50%). Papillary atrophies were increased 100% in RHS (p = 0.001) and BP (p < 0.001). They were more increased on the paretic side in RHS (30%, p = 0.078) and BP (83%, p < 0.001). INTERPRETATION: In these 2 clinically unilateral conditions, the gustatory perception and morphology are bilaterally affected, more in RHS and more on the paretic side. BP, known as an isolated motor condition, appears to be a cranial polyneuritis. A bilateral examination and therapeutic gustatory monitoring might follow these observations in evidence-based practice. Ann Neurol 2018;83:807-815.

Anxiety and its predictive value for pain and regular analgesic intake after lumbar disc surgery - a prospective observational longitudinal study.

BACKGROUND: Ongoing pain after surgery is a major problem and influences recovery and the quality of life of the patient. Associations between anxiety and their impact on postoperative pain after herniated disc surgery have been reported, but the results are inconsistent. The aim of the present longitudinal study was to evaluate the predictive value of preoperative anxiety for postoperative ongoing pain and prolonged analgesic intake after herniated disc surgery. METHODS: 106 patients with lumbar disc herniation were evaluated in the study. Anxiety was measured with the Generalized Anxiety Disorder 7-Item Scale (GAD-7) before surgery. Pain intensity was assessed on a numeric rating scale (NRS) at baseline, 6-weeks and 6-months after surgery. Regression analysis was performed to identify independent predictors of pain and regular utilization of analgesics up to 6 months after surgery while controlling for confounding variables. RESULTS: 42.5% of the patients were rated as anxiety cases (sum scores GAD-7 > 5), mean scores of anxiety showed mild to moderate symptom severity, and 43% suffered from chronic pain before surgery. Six months after surgery, 55.6% of the patients indicated pain levels of 4/10 (NRS) or higher and about 40% still took pain medication on a regular basis, regardless of their preoperative classification as anxiety-case (37.7% and 41.5%). The preoperative pain level was statistically significant for ongoing postsurgical pain in all four analyses (p < 0.001). With binary logistic regression analyses, preoperative pain intensity, but neither demographic factors nor preoperative anxiety, was identified as predictor for postoperative pain and need for analgesic medication up to 6 months after lumbar disc surgery. CONCLUSION: We found no evidence for the presence of anxiety before disc surgery being a prognostic factor for ongoing pain and regular postoperative intake of analgesics. Only preoperative pain intensity was predictive for increased pain and continued need for analgesic medication up to 6 months after lumbar disc surgery. TRIAL REGISTRATION: Clinicaltrials.gov NCT01488617 . Registered 6 December 2011.

Anterior segment dysgenesis associated with Williams-Beuren syndrome: a case report and review of the literature.

BACKGROUND: Williams-Beuren syndrome is characterized by mild mental retardation, specific neurocognitive profile, hypercalcemia during infancy, distinctive facial features and cardiovascular diseases. We report on complete ophthalmologic, sonographic and genetic evaluation of a girl with a clinical phenotype of Williams-Beuren syndrome, associated with unilateral anterior segment dysgenesis and bilateral cleft of the soft and hard palate. These phenotypic features have not been linked to the haploinsufficiency of genes involved in the microdeletion. CASE PRESENTATION: A term born girl presented at the initial examination with clouding of the right cornea. On ultrasound biomicroscopy the anterior chamber structures were difficult to differentiate, showing severe adhesions from the opacified cornea to the iris with a kerato-irido-lenticular contact to the remnant lens, a finding consistent with Peters' anomaly. Genetic analyses including FISH confirmed a loss of the critical region 7q11.23, usually associated with the typical Williams-Beuren syndrome. Microsatellite analysis showed a loss of about 2.36 Mb. CONCLUSIONS: A diagnosis of Williams-Beuren syndrome was made based on the microdeletion of 7q11.23. The unique features, including unilateral microphthalmia and anterior segment dysgenesis, were unlikely to be caused by the microdeletion. Arguments in favor of the latter are unilateral manifestation, as well as the fact that numerous patients with deletions of comparable or microscopically visible size have not shown similar manifestations.

Skeletal muscle-specific expression of a utrophin transgene rescues utrophin-dystrophin deficient mice.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease usually resulting in death of patients by their early twenties. In contrast, mice lacking dystrophin (Dmd(mdx)), appear physically normal despite their underlying muscle pathology. Mice deficient for both dystrophin and the dystrophin-related protein, utrophin, (Dmd(mdx);Utrn-/- mice) die between 6 and 20 weeks of age suffering from severe muscle weakness with joint contractures, pronounced growth retardation and kyphosis, suggesting that dystrophin and utrophin play complementary roles. The exact cause of death in these mice was not determined. Here we show that expression of a truncated utrophin transgene solely within the skeletal muscle of these mutants prevents premature death and the development of any clinical phenotype. In the absence of full-length dystrophin and utrophin, the presence of truncated utrophin also decreases muscle fibre regeneration, relocalizes the dystrophin protein complex to the sarcolemma and re-establishes a normal expression pattern of developmental muscle proteins. These data suggest that Dmd(mdx);Utrn-/- mice succumb to a skeletal muscle defect and that their reduced lifespan is not due to cardiac or neurogenic components. The phenotypic rescue observed demonstrates that the Dmd(mdx);Utrn-/- mice are an ideal model for testing gene delivery protocols for the expression of utrophin or dystrophin in skeletal muscle. To determine the cause of death of the Dmd(mdx):Utrn-/- mice.

A new species of Furciseta (Diptera, Ctenostylidae) from the Brazilian Amazon.

Furciseta Aczél, 1956 [type species: F. plaumanni (Hennig, 1952)] was described as a monotypic genus from southern Brazil and is known only from the type material. Herein, F hyalipennis n. sp. is described and illustrated based on three males and one female collected in the Brazilian states of Amazonas and Maranhão. An illustrated key to the two known species is presented.

Lamprempis Wheeler & Melander (Diptera, Empididae, Empidinae) from Maranhão, Brazil.

Lamprempis Wheeler & Melander, 1901 is a Neotropical genus with 22 known species. Two species collected in the Brazilian state of Maranhão, L. longipenis sp. nov. and L. triangulata sp. nov., are here described and illustrated. A published Lamprempis key is modified to include the newly described species.

A new species of Atrichopleura Bezzi (Diptera, Empididae, Empidinae) from Ceará, Brazil.

Atrichopleura Bezzi, 1909 occurs in different regions of the Southern Hemisphere (24 Neotropical species, 2 Afrotropical species and 2 Australasian species). A new species collected in the Brazilian state of Ceará, A. acuminata sp. nov. is described and illustrated. This is the first record of the genus from northeastern Brazil. A modified key to the five Brazilian species is presented.

Pain drawings in somatoform-functional pain.

BACKGROUND: Pain drawings are a diagnostic adjunct to history taking, clinical examinations, and biomedical tests in evaluating pain. We hypothesized that somatoform-functional pain, is mirrored in distinctive graphic patterns of pain drawings. Our aim was to identify the most sensitive and specific graphic criteria as a tool to help identifying somatoform-functional pain. METHODS: We compared 62 patients with somatoform-functional pain with a control group of 49 patients with somatic-nociceptive pain type. All patients were asked to mark their pain on a pre-printed body diagram. An investigator, blinded with regard to the patients' diagnoses, analyzed the drawings according to a set of numeric or binary criteria. RESULTS: We identified 13 drawing criteria pointing with significance to a somatoform-functional pain disorder (all p-values ≤ 0.001). The most specific and most sensitive criteria combination for detecting somatoform-functional pain included the total number of marks, the length of the longest mark, and the presence of symmetric patterns. The area under the ROC-curve was 96.3% for this criteria combination. CONCLUSION: Pain drawings are an easy-to-administer supplementary technique which helps to identify somatoform-functional pain in comparison to somatic-nociceptive pain.

Avoidance and inhibition do not predict nonrespondent bias among patients with inflammatory bowel disease.

BACKGROUND: It has been suggested that participant withdrawal from studies can bias estimates. However, this is only possible when withdrawers and nonwithdrawers differ in an important way. We tested the hypothesis that withdrawers are more likely than nonwithdrawers to be avoidant and negatively affected. METHODS: A total of 1160 participants with inflammatory bowel disease were recruited at different sites in Switzerland. Their levels of avoidance coping and negative affectivity were rated by means of 2 short baseline questionnaires. One year later, they were sent a longer follow-up questionnaire. The primary outcome was return versus non-return of the follow-up questionnaire within 3 months. After controlling for potential confounders identified in an extensive literature search, we estimated the odds of returning the follow-up questionnaire for 1 standard deviation of avoidance coping and negative affectivity. RESULTS: The odds ratio for 1 standard deviation was 1.03 (95% confidence interval: 0.89-1.18) for avoidance coping and 1.02 (0.89-1.17) for negative affectivity. CONCLUSIONS: The odds of returning the questionnaires did not depend on avoidance coping or negative affectivity.

Algometry with a clothes peg compared to an electronic pressure algometer: a randomized cross-sectional study in pain patients.

BACKGROUND: Hypersensitivity of the central nervous system is widely present in pain patients and recognized as one of the determinants of chronic pain and disability. Electronic pressure algometry is often used to explore aspects of central hypersensitivity. We hypothesized that a simple pain provocation test with a clothes peg provides information on pain sensitivity that compares meaningfully to that obtained by a well-established electronic pressure algometer. "Clinically meaningful" was defined as a medium (r = 0.3-0.5) or high (r > 0.5) correlation coefficient according to Cohen's conventions. METHODS: We tested 157 in-patients with different pain types. A calibrated clothes peg was applied for 10 seconds and patients rated the pain intensity on a 0 to 10 numerical rating scale. Pressure pain detection threshold (PPdt) and pressure pain tolerance threshold (PPtt) were measured with a standard electronic algometer. Both methods were performed on both middle fingers and ear lobes. In a subgroup of 47 patients repeatability (test-retest reliability) was calculated. RESULTS: Clothes peg values correlated with PPdt values for finger testing with r = -0.54 and for earlobe testing with r = -0.55 (all p-values < 0.001). Clothes peg values also correlated with PPtt values for finger testing with r = -0.55 (p < 0.001). Test-retest reliability (repeatability) showed equally stable results for clothes peg algometry and the electronic algometer (all r-values > 0.89, all p-values < 0.001). CONCLUSIONS: Information on pain sensitivity provided by a calibrated clothes peg and an established algometer correlate at a clinically meaningful level.

Selective loss of sarcolemmal nitric oxide synthase in Becker muscular dystrophy.

Becker muscular dystrophy is an X-linked disease due to mutations of the dystrophin gene. We now show that neuronal-type nitric oxide synthase (nNOS), an identified enzyme in the dystrophin complex, is uniquely absent from skeletal muscle plasma membrane in many human Becker patients and in mouse models of dystrophinopathy. An NH2-terminal domain of nNOS directly interacts with alpha 1-syntrophin but not with other proteins in the dystrophin complex analyzed. However, nNOS does not associate with alpha 1-syntrophin on the sarcolemma in transgenic mdx mice expressing truncated dystrophin proteins. This suggests a ternary interaction of nNOS, alpha 1-syntrophin, and the central domain of dystrophin in vivo, a conclusion supported by developmental studies in muscle. These data indicate that proper assembly of the dystrophin complex is dependent upon the structure of the central rodlike domain and have implications for the design of dystrophin-containing vectors for gene therapy.

[The effect of stress-relieving interventions on inflammatory bowel disease: quality assessment of 10 therapeutic studies]. / Der Effekt stressreduzierender Interventionen auf chronisch entzündliche Darmerkrankungen: Qualitätskontrolle von zehn therapeutischen Studien.

OBJECTIVES: Patient comments and empirical studies suggest an influence of stress on inflammatory bowel diseases (IBD). We performed a quality assessment of previous studies on the effect of stress reduction on IBD in order to formulate recommendations for future studies and to evaluate their potential for improvement. METHODS: Studies were searched for in the PubMed online library and in the bibliographies of the located sources. Based on an analysis of the study design and the methodology of individual studies, we made specific recommendations following recognized methodological principles and used them to evaluate the analyzed studies. RESULTS: The 10 studies identified differed in terms of exclusion criteria, distribution of characteristics, stress reduction, and effect measurements. The recommendations formulated had not been followed exhaustively in these studies. CONCLUSIONS: Computation of sample size to detect relevant effects, orientation toward previous studies, documentation of potential confounders, and confidence intervals are criteria that are easy to consider and well-known, and that, if applied to future studies, might enhance the quality of IBD research.

Age and Gender as Factors of Pressure Sensitivity of Pain-Free Persons: Are They Meaningful?

PURPOSE: Prior findings suggest that women and elderly persons are more sensitive to pressure than men and younger persons; however, the magnitudes of these differences are substantially inconsistent. We answered the question whether the higher sensitivity of women and elderly persons is quantitatively meaningful. Specifically, we investigated if it is large enough to hamper the diagnosis, classification and follow-up of pain conditions by clinicians. MATERIALS AND METHODS: From each age stratum (18-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, and >80 years), 40 pain-free women and 40 pain-free men were recruited. They rated the intensity of pressure of ten Newtons over ten seconds on an analogue zero to ten rating scale. The pressure was applied on their middle fingers and ear lobes with a threshold algometer. Centile curves visualized the sex- and age-dependent fluctuation of pressure sensitivity. RESULTS: Over the entire age range from 20 to 80 years, the median curves fluctuated within the interval of less than two points. The distance between the median curves of men and women was also less than two points. On the average, the median difference was half a point on the finger (p = 0.249) and the ear lobe (p = 0.083). CONCLUSION: Less than two points is below the minimal clinically important difference for a zero to ten analogue pain rating scale; differences smaller than one point are even below the resolution of the scale. Sex differences and age fluctuations of pressure sensitivity are negligible.

Animal models for muscular dystrophy show different patterns of sarcolemmal disruption.

Genetic defects in a number of components of the dystrophin-glycoprotein complex (DGC) lead to distinct forms of muscular dystrophy. However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue. One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage. Using tracer molecules, we compared sarcolemmal integrity in animal models for muscular dystrophy and in muscular dystrophy patient samples. Evans blue, a low molecular weight diazo dye, does not cross into skeletal muscle fibers in normal mice. In contrast, mdx mice, a dystrophin-deficient animal model for Duchenne muscular dystrophy, showed significant Evans blue accumulation in skeletal muscle fibers. We also studied Evans blue dispersion in transgenic mice bearing different dystrophin mutations, and we demonstrated that cytoskeletal and sarcolemmal attachment of dystrophin might be a necessary requirement to prevent serious fiber damage. The extent of dye incorporation in transgenic mice correlated with the phenotypic severity of similar dystrophin mutations in humans. We furthermore assessed Evans blue incorporation in skeletal muscle of the dystrophia muscularis (dy/dy) mouse and its milder allelic variant, the dy2J/dy2J mouse, animal models for congenital muscular dystrophy. Surprisingly, these mice, which have defects in the laminin alpha2-chain, an extracellular ligand of the DGC, showed little Evans blue accumulation in their skeletal muscles. Taken together, these results suggest that the pathogenic mechanisms in congenital muscular dystrophy are different from those in Duchenne muscular dystrophy, although the primary defects originate in two components associated with the same protein complex.

Transgenic mdx mice expressing dystrophin with a deletion in the actin-binding domain display a "mild Becker" phenotype.

The functional significance of the actin-binding domain of dystrophin, the protein lacking in patients with Duchenne muscular dystrophy, has remained elusive. Patients with deletions of this domain (domain I) typically express low levels of the truncated protein. Whether the moderate to severe phenotypes associated with such deletions result from loss of an essential function, or from reduced levels of a functional protein, is unclear. To address this question, we have generated transgenic mice that express wild-type levels of a dystrophin deleted for the majority of the actin-binding domain. The transgene derived protein lacks amino acids 45-273, removing 2 of 3 in vitro identified actin interacting sites and part of hinge 1. Examination of the effect of this deletion in mice lacking wild-type dystrophin (mdx) suggests that a functional domain I is not essential for prevention of a dystrophic phenotype. However, in contrast to deletions in the central rod domain and to full-length dystrophin, both of which are functional at only 20% of wild-type levels, proteins with a deletion in domain I must be expressed at high levels to prevent a severe dystrophy. These results are also in contrast to the severe dystrophy resulting from truncation of the COOH-terminal domain that links dystrophin to the extracellular matrix. The mild phenotype observed in mice with domain I-deletions indicates that an intact actin-binding domain is not essential, although it does contribute to an important function of dystrophin. These studies also suggest the link between dystrophin and the subsarcolemmal cytoskeleton involves more than a simple attachment of domain I to actin filaments.

Forced expression of dystrophin deletion constructs reveals structure-function correlations.

Dystrophin plays an important role in skeletal muscle by linking the cytoskeleton and the extracellular matrix. The amino terminus of dystrophin binds to actin and possibly other components of the subsarcolemmal cytoskeleton, while the carboxy terminus associates with a group of integral and peripheral membrane proteins and glycoproteins that are collectively known as the dystrophin-associated protein (DAP) complex. We have generated transgenic/mdx mice expressing "full-length" dystrophin constructs, but with consecutive deletions within the COOH-terminal domains. These mice have enabled analysis of the interaction between dystrophin and members of the DAP complex and the effects that perturbing these associations have on the dystrophic process. Deletions within the cysteine-rich region disrupt the interaction between dystrophin and the DAP complex, leading to a severe dystrophic pathology. These deletions remove the beta-dystroglycan-binding site, which leads to a parallel loss of both beta-dystroglycan and the sarcoglycan complex from the sarcolemma. In contrast, deletion of the alternatively spliced domain and the extreme COOH terminus has no apparent effect on the function of dystrophin when expressed at normal levels. The proteins resulting from these latter two deletions supported formation of a completely normal DAP complex, and their expression was associated with normal muscle morphology in mdx mice. These data indicate that the cysteine-rich domain is critical for functional activity, presumably by mediating a direct interaction with beta-dystroglycan. However, the remainder of the COOH terminus is not required for assembly of the DAP complex.

The role of psychological stress in inflammatory bowel disease: quality assessment of methods of 18 prospective studies and suggestions for future research.

BACKGROUND: Enquiries among patients on the one hand and experimental and observational studies on the other suggest an influence of stress on inflammatory bowel diseases (IBD). However, since this influence remains hypothetical, further research is essential. We aimed to devise recommendations for future investigations in IBD by means of scrutinizing previously applied methodology. METHODS: We critically reviewed prospective clinical studies on the effect of psychological stress on IBD. Eligible studies were searched by means of the PubMed electronic library and through checking the bibliographies of located sources. RESULTS: We identified 20 publications resulting from 18 different studies. Sample sizes ranged between 10 and 155 participants. Study designs in terms of patient assessment, control variables, and applied psychometric instruments varied substantially across studies. Methodological strengths and weaknesses were irregularly dispersed. Thirteen studies reported significant relationships between stress and adverse outcomes. CONCLUSIONS: Study designs, including accuracy of outcome assessment and repeated sampling of outcomes (i.e. symptoms, clinical, and endoscopic), depended upon conditions like sample size, participants' compliance, and available resources. Meeting additional criteria of sound methodology, like taking into account covariates of the disease and its course, is strongly recommended to possibly improve study designs in future IBD research.

Current Treatment of Comorbid Insomnia and Obstructive Sleep Apnea With CBTI and PAP-Therapy: A Systematic Review.

Insomnia and obstructive sleep apnea (OSA) are often both present in patients with sleep-disordered-breathing (SDB). The coexistence of the two disorders shows an increase in cumulative morbidity and an overall greater illness severity. There is still considerable controversy regarding management decisions in this group of patients. This systematic review focused on more recent evidence regarding treatment of patients presenting with both clinical entities of comorbid insomnia and OSA (COMISA) in terms of their management, especially using combinations of positive airway pressure [PAP, namely aPAP, cPAP, adaptive servo-ventilation (ASV)] and CBTi as well as each one of these two modalities alone. As a conclusion it is necessary to specifically target distinct combinations of both insomnia (initial, middle, late) and OSA (mild, moderate, severe) phenotypes. The present review gives reason to assume that both CBTi and PAP-therapy are necessary. However, it appears that distinct treatment patterns may suit different COMISA phenotypes.

Cost-Saving Early Diagnosis of Functional Pain in Nonmalignant Pain: A Noninferiority Study of Diagnostic Accuracy.

Objectives. We compared two index screening tests for early diagnosis of functional pain: pressure pain measurement by electronic diagnostic equipment, which is accurate but too specialized for primary health care, versus peg testing, which is cost-saving and more easily manageable but of unknown sensitivity and specificity. Early distinction of functional (altered pain perception; nervous sensitization) from neuropathic or nociceptive pain improves pain management. Methods. Clinicians blinded for the index screening tests assessed the reference standard of this noninferiority diagnostic accuracy study, namely, comprehensive medical history taking with all previous findings and treatment outcomes. All consenting patients referred to a university hospital for nonmalignant musculoskeletal pain participated. The main analysis compared the receiver operating characteristic (ROC) curves of both index screening tests. Results. The area under the ROC curve for peg testing was not inferior to that of electronic equipment: it was at least 95% as large for finger measures (two-sided p = 0.038) and at least equally as large for ear measures (two-sided p = 0.003). Conclusions. Routine diagnostic testing by peg, which is accessible for general practitioners, is at least as accurate as specialized equipment. This may shorten time-to-treatment in general practices, thereby improving the prognosis and quality of life.