Preliminary method for profiling volatile organic compounds in breath that correlate with pulmonary function and other clinical traits of subjects diagnosed with cystic fibrosis: a pilot study.

Cystic fibrosis (CF) is characterized by chronic respiratory infections which progressively decrease lung function over time. Affected individuals experience episodes of intensified respiratory symptoms called pulmonary exacerbations (PEx), which in turn accelerate pulmonary function decline and decrease survival rate. An overarching challenge is that there is no standard classification for PEx, which results in treatments that are heterogeneous. Improving PEx classification and management is a significant research priority for people with CF. Previous studies have shown volatile organic compounds (VOCs) in exhaled breath can be used as biomarkers because they are products of metabolic pathways dysregulated by different diseases. To provide insights on PEx classification and other CF clinical factors, exhaled breath samples were collected from 18 subjects with CF, with some experiencing PEx and others serving as a baseline. Exhaled breath was collected in Tedlar bags during tidal breathing and cryotransferred to headspace vials for VOC analysis by solid phase microextraction coupled to gas chromatography-mass spectrometry. Statistical significance testing between quantitative and categorical clinical variables displayed percent-predicted forced expiratory volume in one second (FEV1pp) was decreased in subjects experiencing PEx. VOCs correlating with other clinical variables (body mass index, age, use of highly effective modulator treatment (HEMT), and the need for inhaled tobramycin) were also explored. Two volatile aldehydes (octanal and nonanal) were upregulated in patients not taking the HEMT. VOCs correlating to potential confounding variables were removed and then analyzed by regression for significant correlations with FEV1pp measurements. Interestingly, the VOC with the highest correlation with FEV1pp (3,7-dimethyldecane) also gave the lowestp-value when comparing subjects at baseline and during PEx. Other VOCs that were differentially expressed due to PEx that were identified in this study include durene, 2,4,4-trimethyl-1,3-pentanediol 1-isobutyrate and 5-methyltridecane. Receiver operator characteristic curves were developed and showed 3,7-dimethyldecane had higher ability to classify PEx (area under the curve (AUC) = 0.91) relative to FEV1pp values at collection (AUC = 0.83). However, normalized ΔFEV1pp values had the highest capability to distinguish PEx (AUC = 0.93). These results show that VOCs in exhaled breath may be a rich source of biomarkers for various clinical traits of CF, including PEx, that should be explored in larger sample cohorts and validation studies.

FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy.

The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG's glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.

ERBIN deficiency links STAT3 and TGF-ß pathway defects with atopy in humans.

Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-ß activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-ß signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3mut ) or a loss-of-function mutation in ERBB2IP (ERBB2IPmut ) have evidence of deregulated TGF-ß signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3-ERBIN-SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-ß. In turn, cell-intrinsic deregulation of TGF-ß signaling is associated with increased functional IL-4Rα expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4Rα/GATA3 axis in vitro. These findings link increased TGF-ß pathway activation in ERBB2IPmut and STAT3mut patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.

Boolean network identification from perturbation time series data combining dynamics abstraction and logic programming.

Boolean networks (and more general logic models) are useful frameworks to study signal transduction across multiple pathways. Logic models can be learned from a prior knowledge network structure and multiplex phosphoproteomics data. However, most efficient and scalable training methods focus on the comparison of two time-points and assume that the system has reached an early steady state. In this paper, we generalize such a learning procedure to take into account the time series traces of phosphoproteomics data in order to discriminate Boolean networks according to their transient dynamics. To that end, we identify a necessary condition that must be satisfied by the dynamics of a Boolean network to be consistent with a discretized time series trace. Based on this condition, we use Answer Set Programming to compute an over-approximation of the set of Boolean networks which fit best with experimental data and provide the corresponding encodings. Combined with model-checking approaches, we end up with a global learning algorithm. Our approach is able to learn logic models with a true positive rate higher than 78% in two case studies of mammalian signaling networks; for a larger case study, our method provides optimal answers after 7min of computation. We quantified the gain in our method predictions precision compared to learning approaches based on static data. Finally, as an application, our method proposes erroneous time-points in the time series data with respect to the optimal learned logic models.

Generalised peliosis hepatis mimicking metastases after long-term use of oral contraceptives.

Peliosis hepatis (PH) is a rare vascular condition of the liver characterised by the presence of cystic blood-filled cavities distributed randomly throughout the liver parenchyma. PH should be considered in the differential diagnosis of women with a long history of use of oral contraceptives with suspected hypervascular lesions diagnosed by imaging, but with an unknown primary tumour. Because of the extensive use of oral contraceptives in the general female population worldwide, PH should be added to the differential diagnosis of suspected hypervascular liver lesions.

Cierre primario de fasciotomías con técnica con elásticos: experiencia nacional multicéntrica / Fasciotomy closure technique with vessel loops

Aim: Present and describe the progressive fasciotomy closure technique with vessel loops. Methods: Progressive and multicentric study in the period between June of 2007 and June of 2011. Results: In 2007 we initiated the complementary treatment for fasciotomy closure related to compartment syndrome or acute ischemia cases. Progressive closure with vessel loops, the shoelace technique. In 2010's preliminary report, we published a total of 56 fasciotomies closed by this technique, with an average closure time of 9.5 +/- 3.31 days. Current report is the result of a 4 years prospective study intending to prove that is possible to associate this technique to the initial management of fasciotomies closure. This final report shows a total of 122 fasciotomies cases closed in 7.9 +/- 3.31 days, without skin grafts. Conclusion: The technique is easy to learn, reproducible and not expensive. Results show that this technique is useful in reduce the time for fasciotomy closure.

Objetivos: Presentar y describir la técnica de cierre progresivo de fasciotomías con elásticos. Métodos: Estudio prospectivo multicéntrico realizado en Santiago de Chile entre junio de 2007 y junio de 2011. Resultados: En el año 2007 se inició un protocolo de manejo del cierre de las fasciotomías realizadas a pacientes portadores de síndrome compartimental o isquemia aguda de extremidades. Utilizando una técnica de entrelazado con elásticos vasculares se realizó el cierre de las fasciotomías. En el 2010 se publicó un reporte preliminar, presentando una serie de 56 fasciotomías cerradas con esta técnica, con un promedio de cierre de 9,5 +/- 3,31 días. La serie actual es el resultado de un estudio prospectivo de 4 años de duración que ha buscado demostrar que resulta posible asociar esta técnica con elásticos al manejo inicial del cierre de las fasciotomías. Nuestro reporte final muestra un total de 122 fasciotomías cerradas en un promedio de 7,9 +/- 3,31 días sin requerir de injertos de piel. Conclusiones: Presentamos una técnica quirúrgica fácil de reproducir, de bajo costo y con buenos resultados. El uso de elásticos vasculares muestra beneficios en el tiempo de cierre de las fasciotomías.

S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma.

BACKGROUND: Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages. On the basis of evidence of dysregulation of the epidermal growth factor receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers. METHODS: Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function. Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily, respectively. RESULTS: Thirty-four eligible patients were recruited. The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months. There were two unconfirmed partial responses (6%, 95% CI: 1-20%), with a median progression-free survival of 2 months (95% CI: 2-3), and median overall survival of 6 months (95% CI: 3-8 months). Grade 3 and 4 adverse events included hypertension, AST/ALT increase, bilirubin increase, diarrhoea, hypokalaemia, hypophosphatemia and rash. CONCLUSIONS: Despite compelling preclinical rationale, the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers. Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease.

Gestational flu exposure induces changes in neurochemicals, affiliative hormones and brainstem inflammation, in addition to autism-like behaviors in mice.

The prevalence of neurodevelopmental disorders such as autism is increasing, however the etiology of these disorders is unclear and thought to involve a combination of genetic, environmental and immune factors. A recent epidemiological study found that gestational viral exposure during the first trimester increases risk of autism in offspring by twofold. In mice gestational viral exposures alter behavior of offspring, but the biological mechanisms which underpin these behavioral changes are unclear. We hypothesized that gestational viral exposure induces changes in affiliative hormones, brainstem autonomic nuclei and neurotransmitters which are associated with behavioral alterations in offspring. To address this hypothesis, we exposed pregnant mice to influenza A virus (H3N2) on gestational day 9 and determined behavioral, hormonal and brainstem changes in male and female offspring. We found that gestational flu exposure induced dose-dependent alterations in social and aggressive behaviors (p≤0.05) in male and female offspring and increases in locomotor behaviors particularly in male offspring (p≤0.05). We found that flu exposure was also associated with reductions in oxytocin and serotonin (p≤0.05) levels in male and female offspring and sex-specific changes in dopamine metabolism. In addition we found changes in catecholaminergic and microglia density in brainstem tissues of male flu exposed offspring only (p≤0.05). This study demonstrates that gestational viral exposure induces behavioral changes in mice, which are associated with alterations in affiliative hormones. In addition we found sex-specific changes in locomotor behavior, which may be associated with sex-specific alterations in dopamine metabolism and brainstem inflammation. Further investigations into maternal immune responses are necessary to unravel the molecular mechanisms which underpin abnormal hormonal, immune and behavioral responses in offspring after gestational viral exposure.

Prevalence of high-risk human papilloma virus among women with hepatitis C virus before liver transplantation.

BACKGROUND: We sought to assess the prevalence and risk factors for high-risk human papillomavirus (HPV) infection among female liver transplant (LT) candidates. Traditional health screening before LT listing has included Pap smear and is typically carried out by the patient's local provider. The prevalence of high-risk HPV in this population has not been studied. METHODS: With Institutional Review Board approval, 62 LT candidates received a liquid-based Pap smear with high-risk HPV testing as part of their pre-transplant evaluation by a single provider. Clinical variables included age, ethnicity, insurance status, prior Pap smear, and HPV results, HPV risk factors including age of first intercourse, number of lifetime partners, last sexual activity, smoking, birth control pill use, history of sexually transmitted infections, human immunodeficiency virus status, immunosuppressive medication, medical diagnoses, prescribed medications, and history of hepatitis A, B, C, or D. RESULTS: The 62 women had a median age of 56 years, and 39% had high-risk behavior known to be associated with HPV. Ten of 62 patients (16.1%) had high-risk HPV at baseline screening, 5 of whom had atypical cytology. All of the patients who were positive for high-risk HPV had an etiology of hepatitis C virus (HCV) as the underlying cause of liver disease, with the majority (90%) having no history of high-risk behavior for HPV. In contrast, all patients with high-risk behavior who were HCV negative were HPV negative. Fisher's exact test demonstrated a statistically significant relationship between HPV and HCV; odds ratio = 24.4, 95% confidence interval, 1.4, 438.7, P-value = 0.0013. None of the other potential risk factors were associated with HPV in this cohort. CONCLUSIONS: In this study, we provide evidence of a strong association between HCV and HPV in LT candidates, which has not been previously reported. HPV positivity was observed in non-sexually active women, suggesting a reactivation of dormant HPV. An association between hepatitis C and high-risk HPV could involve impairment of T-cell function by hepatitis C. These data support close surveillance in women's health screening for LT candidates. Further studies to characterize immune responses in these patients will be in order.

[Patient participation in medical decision making within an integrated health care system in Germany: results of a controlled cohort study]. / Patientenbeteiligung bei medizinischen Entscheidungen in der Integrierten Versorgung Gesundes Kinzigtal: Ergebnisse einer kontrollierten Kohortenstudie.

An integrated health care project called "Gesundes Kinzigtal" was conducted in a rural area in Germany. As part of the project, physicians were trained and other measures were taken to enhance patient involvement in medical decision making. As part of the external evaluation, various effects regarding patient involvement in medical decision making, patient involvement and information preference, decision confidence, patient satisfaction with ambulatory care and patient quality of life were examined. The data were gathered by means of a questionnaire on an annual basis between 2007 and 2009. Effects were compared between patients who were participating in the integrated care project and two control groups. Analyses are based on the data of 1,205 patients. Over time all outcomes decreased slightly, except for information preference and physical quality of life. No statistically significant intervention effects on patient involvement in medical decision making or any other outcome variable could be found. The intensity of the training was presumably too low to establish an enduring change in the physician-patient interaction.

Structural phase transition in LiFeSi2O6 from ab initio calculations.

The changes in crystal structure of LiFeSi(2)O(6) induced by the phase transition between the high-temperature C2/c and low-temperature P2(1)/c phase are studied using the density functional theory. For both monoclinic phases, the phonon dispersion curves and phonon density of states are calculated. The infrared absorption coefficients are obtained and analyzed in both structural phases of LiFeSi(2)O(6). The soft mode inducing the phase transition is revealed at the Z point of the Brillouin zone of the high-symmetry C2/c phase. The pressure dependence of the soft mode is studied and the mechanism of the structural phase transition in LiFeSi(2)O(6) is discussed.

[Patients as customers? The term "customer" in the perception of medical students at the end of their university training]. / Der Patient als Kunde? Zur Perzeption eines marktwirtschaftlich geprägten Begriffs bei Medizinstudierenden am Ende ihres Studiums.

In the preceding decades a new perspective on the role of patients in the health-care system has gained ground, considering patients not merely as "suffering persons" but additionally as "customers". Physicians, however, tend to disagree with this approach because of the economic connotation of the term customer. Until now, there is only poor evidence of whether students of medicine - who are going to work as physicians in the future - agree or disagree with that approach and whether they are ready to accept patients as customers. In the following study students of medicine were interviewed on their perspectives towards that approach, in particular on their attitudes towards the idea of "the patient as customer", the appropriateness of the term consumer in different clinical settings and sectors of health care, the implementation of consumer orientation in clinical routine, and their favoured model of physician-patient relationship.As the study could not build upon data of prior similar studies, a quantitative and qualitative cross-sectional study with a descriptive-explorative design was conducted. Using a semi-standardised questionnaire, 313 medical students (response rate: 95%) were interviewed in Spring 2010. At the time of the survey, the students were enrolled at the faculty of medicine at Freiburg University, Germany, and were in their last semester which immediately preceded their exam.The future physicians do not consider patients primarily as customers. More than 80% of the respondents "absolutely" or "largely" supported the idea that patients are considerably more than customers. The analysis of the qualitative data of the study shows different results. Here, more statements were made that patients could equally be seen as customers (449 students supported this idea, 298 did not). Statements contradicting the customer approach referred mostly to the asymmetry of the physician-patient relationship and the special role of the patient. The highest level of acceptance of the customer approach was found in classical service settings such as pharmacies, the lowest level in emergency medical aid. According to medical students, a consumer orientation has been realised in different health service areas in correspondingly different degrees: On top of the list are plastic surgery clinics, followed by private health insurances and homeopathic clinics. A minority of medical students predict the implementation of consumer orientation in the emergency medical aid. Future physicians consider their relationship to patients largely as a relationship between a healing person and a person seeking help rather than a relationship between a service provider and a customer.Considering recent developments in the organisation of medical services and health services in general, it becomes increasingly important to know what kind of 'service behaviour' patients expect from their doctors and other health providers. Obviously, it is not self-evident for medical students to perceive their future patients as customers and to act as customer-oriented 'service providers'. In view of this, the faculties of medicine at universities - which provide professional training to students of medicine - should be aware of the challenge to 'socialise' their students so that they can keep up with patients' expectations.

Necrosis cutánea por tratamiento anticoagulante oral: caso clínico / Cutaneous necrosis caused by acenocumarol: case report

Cutaneous necrosis is a rare but serious complication, among patients treated with warfarin or acenocumarol derivatives. We report a 71 years old female with a history of deep venous thrombosis, receiving acenocumarol for three months. The treatment was discontinued, but had to be restarted, due to a new episode of thrombosis. Three days after restarting acenocumarol, the patient consulted for ecchymosis and pain of the right foot. At physical examination, there was distal cyanosis and absence of distal pulses. The patient was subjected to an embolectomy with the suspicion of an acute arterial occlusion, but no emboli were found. Due to the possibility of a cutaneous necrosis caused by Acenocumarol, the medication is discontinued. The cutaneous lesions progressed and eight days after the failed embolectomy, a gangrene of the right foot was diagnosed. The patient did not accept amputation dying fourteen days after the first intervention.

A propósito un caso registrado, se resume la historia clínica y se revisa la literatura, dada la escasa frecuencia de esta complicación derivada del tratamiento por anticoagulantes orales. La necrosis cutánea es un evento adverso raro, pero serio, de la anticoagulación con derivados de acenocumarol o warfarina. Se comunicó por primera vez en 1943. La incidencia de la necrosis cutánea inducida por anticoagulantes orales es de 0,01 al 0,1 por ciento de los pacientes tratados. El número de casos publicados en el mundo es de aproximadamente 300, y menos de 100 en lengua inglesa en las últimas tres décadas. Este trabajo reporta el caso de una paciente que presenta necrosis cutánea en hombro izquierdo y pierna derecha.

Aneurisma único de arteria femoral común: caso clínico / Isolated common femoral artery aneurysm: case report

We report a 71 years old male with high blood pressure. During the postoperative follow up after a prostatectomy for a benign prostate hyperplasia, a pulsatile mass was palpated in the left inguinal region. A chest, abdomen and lower limb AngioTC, disclosed a unique sacular aneurysm in the left common femoral artery. The patient was subjected to a surgical excision of the aneurysm, with a favorable postoperative evolution.

Se comunica el caso de un paciente de 71 años, de sexo masculino, hipertenso, a quien en el postoperatorio de prostatectomia por hiperplasia benigna de la próstata, le fue palpada una masa pulsátil inguinal izquierda. La AngioTAC mostró una dilatación sacular única de la arteria femoral común, la que fue resecada con éxito.

The influence of passive stretch and NF-κB inhibitors on the morphology of dystrophic muscle fibers.

The triangularis sterni (TS) is an expiratory muscle that is passively stretched during inspiration. The magnitude of passive stretch depends upon the location of individual fibers within the TS muscle, with fibers located more caudally being stretched ∼ 5% to 10% more than fibers in the cephalad region. In the mdx mouse model for muscular dystrophy, the TS exhibits severe pathological alterations that are ameliorated by treatment with inhibitors of the NF-κB pathway. The purpose of this study was to assess the influence of passive stretch in vivo on fiber morphology in nondystrophic and mdx TS muscles, and the morphological benefits of treating mdx mice with two distinct NF-κB inhibitors, pyrrolidine dithiocarbamate (PDTC), and ursodeoxycholic acid (UDCA). Transmission electron microscopy revealed Z-line streaming, hypercontraction, and disassociation of the plasma membrane from the basal lamina in mdx fibers. In both nondystrophic and mdx TS muscles, fiber density was larger in more caudal regions. In comparison with nondystrophic TS, fibers in the mdx TS exhibited substantial reductions in diameter throughout all regions. In vivo treatment with either PDTC or UDCA tended to increase fiber diameter in the middle and decrease fiber diameter in the caudal TS, while reducing centronucleation in the middle region. These results suggest that passive stretch induces hypercontraction and plasma membrane abnormalities in dystrophic muscle, and that differences in the magnitude of passive stretch may influence fiber morphology and the actions of NF-κB inhibitors on dystrophic morphology.

Saliva substitutes in combination with highly concentrated fluorides and brushing: in vitro effects on enamel subsurface lesions.

Hyposalivation is often associated with high caries activity, in particular in patients undergoing irradiation in the head/neck area. Besides the use of saliva substitutes to relieve the oral symptoms, daily application of fluoride gels or toothpaste (5,000 µg F⁻/g) is recommended for caries prevention. The aim of this study was to evaluate potentially remineralising effects of these fluoride agents in combination with saliva substitutes on enamel subsurface lesions. Demineralised bovine specimens were either stored in mineral water [control; saturation with respect to octacalcium phosphate (S(OCP)): 0.8], a demineralising saliva substitute (Glandosane; S(OCP): 0.3) or in a modified (with respect to S(OCP)) saliva substitute [Saliva natura (SN); S(OCP): 1.9] for 5 weeks (37°C). The following treatments were applied twice daily (11-13/group): no treatment (0), ProSchmelz fluoride gel (PS; 10 min application), Duraphat toothpaste (DP; 10 s; brushing with toothpaste/storage solution slurry), combination of DP+PS. Mineral parameters before/after storage were evaluated from microradiographs. Storage in Glandosane led to significant demineralisation (p < 0.05; paired t test), whereas additional use of fluoride agents neutralised the demineralising effect (p > 0.05). Storage in water alone resulted in no changes in mineral parameters (p > 0.05), whereas in combination with fluorides remineralisation could be shown (p < 0.05). For SN alone, remineralisation was observed (p < 0.05), but no additional beneficial effects of fluorides were detected. Under the conditions chosen, the fluoride agents reduce the demineralising effects of Glandosane and promote the remineralisation of specimens stored in water. Remineralising effects of SN could not be enhanced by the fluorides.