Multifractal dimensions for all moments for certain critical random-matrix ensembles in the strong multifractality regime.
We construct perturbation series for the qth moment of eigenfunctions of various critical random-matrix ensembles in the strong multifractality regime close to localization. Contrary to previous investigations, our results are valid in the region q<1/2. Our findings allow one to verify, at first leading orders in the strong multifractality limit, the symmetry relation for anomalous fractal dimensions Δ(q)=Δ(1-q), recently conjectured for critical models where an analog of the metal-insulator transition takes place. It is known that this relation is verified at leading order in the weak multifractality regime. Our results thus indicate that this symmetry holds in both limits of small and large coupling constant. For general values of the coupling constant we present careful numerical verifications of this symmetry relation for different critical random-matrix ensembles. We also present an example of a system closely related to one of these critical ensembles, but where the symmetry relation, at least numerically, is not fulfilled.


Speech Emotion Recognition Using Convolution Neural Networks and Multi-Head Convolutional Transformer.
Speech emotion recognition (SER) is a challenging task in human-computer interaction (HCI) systems. One of the key challenges in speech emotion recognition is to extract the emotional features effectively from a speech utterance. Despite the promising results of recent studies, they generally do not leverage advanced fusion algorithms for the generation of effective representations of emotional features in speech utterances. To address this problem, we describe the fusion of spatial and temporal feature representations of speech emotion by parallelizing convolutional neural networks (CNNs) and a Transformer encoder for SER. We stack two parallel CNNs for spatial feature representation in parallel to a Transformer encoder for temporal feature representation, thereby simultaneously expanding the filter depth and reducing the feature map with an expressive hierarchical feature representation at a lower computational cost. We use the RAVDESS dataset to recognize eight different speech emotions. We augment and intensify the variations in the dataset to minimize model overfitting. Additive White Gaussian Noise (AWGN) is used to augment the RAVDESS dataset. With the spatial and sequential feature representations of CNNs and the Transformer, the SER model achieves 82.31% accuracy for eight emotions on a hold-out dataset. In addition, the SER system is evaluated with the IEMOCAP dataset and achieves 79.42% recognition accuracy for five emotions. Experimental results on the RAVDESS and IEMOCAP datasets show the success of the presented SER system and demonstrate an absolute performance improvement over the state-of-the-art (SOTA) models.


Significant prevalence of peripheral artery disease in patients with disturbed wound healing following elective foot and ankle surgery: Results from the ABI-PRIORY (ABI as a PRedictor of Impaired wound healing after ORthopedic surgerY) trial.
Disturbed wound healing (DWH) following elective foot and ankle surgery is associated with a number of known risk factors. The purpose of this study was to determine if peripheral artery disease (PAD) is a potential risk factor that contributes to an increase in postoperative DWH. In a case-control study, we analyzed all patients undergoing elective foot and ankle surgery between January 1, 2014 and December 31, 2017 at two institutions and identified 51 patients with postoperative DWH. After matching with 51 control patients without DWH, all 102 patients were evaluated for PAD. The prevalence of PAD was significantly higher in the DWH group compared to the control group (41.2% vs 19.6%, p < 0.01). This difference was even more distinctive for patients with any abnormal ankle-brachial index (ABI) (51.0% vs 19.6%, p < 0.001). After adjustment for diabetes, hypertension, hypercholesterolemia, and smoking, any abnormal ABI or a history of PAD remained an independent risk factor for DWH (odds ratio 3.28; 95% CI 1.24-8.71). In this dual-center study, postoperative DWH was associated with significantly higher rates of PAD. These findings suggest that preoperative evaluation for PAD could be a helpful tool to identify patients at high risk for postoperative wound complications undergoing foot and ankle surgery. This trial is registered with drks.de, number DRKS00012580.


Expression of vascular endothelial growth factor (VEGF) and VEGF-receptor messenger ribonucleic acids in the peri-implantation rabbit uterus.
The endometrial vasculature undergoes expansion during preimplantation stages and, even more prominently, after implantation. In addition to angiogenesis, vascular hyperpermeability accompanies the attachment and invasion of blastocysts into the uterine lining. Vascular endothelial growth factor (VEGF) is an angiogenic factor expressed in mammalian uteri that also has potent activity in inducing vascular permeability. Rabbit uteri were examined using Northern and in situ hybridization to assess the temporal and spatial expression of VEGF and its receptor (Flk-1, Flt-1) mRNAs during the pre- and peri-implantation periods (Days 0-8). Steady-state levels of VEGF mRNA were highest in endometrium at estrous and peri-implantation stages (Days 6-8). In situ hybridization revealed a shift from uniform expression of VEGF transcripts throughout the uterus at estrus and Day 4, to an endometrial epithelial localization just before and during implantation. At implantation sites, a pronounced signal was present in the trophoblastic knobs, the syncytial aggregates that attach to and invade the endometrium. VEGF protein was detected by immunoblot analysis in peri-implantation-stage uteri but was below the limit of detection in estrous endometrium. VEGF receptor mRNAs were expressed in the uterus at all stages examined, with high levels of Flk-1 and Flt-1 at estrus and again just before implantation, 6-3/4 days pregnant. The high level just before implantation correlates with in situ hybridization results showing a prominent, but transient, signal for Flk-1 mRNA in the endometrial epithelium. During implantation, Flk-1 mRNA was associated with blood vessels of the endometrial stroma. We conclude that VEGF is a candidate factor for the induction of vascular hyperpermeability at implantation in the rabbit and in the angiogenic process that follows.


Central processing of natural odor mixtures in insects.
In nature, virtually all olfactory stimuli are mixtures of many single odorants. Behavioral experiments repeatedly have demonstrated that an animal's olfactory system is capable of discriminating behaviorally relevant from irrelevant odor mixtures. However, the sensory mechanisms that underlie such discriminative capability remain elusive. The limited anatomical and physiological evidence collected from both insect and vertebrate models that pertains to this topic is scattered in the literature dating back to early 1980s. Thus, a synthesis of this information that includes more recent findings is needed in order to provide a basis for probing the fundamental question from a new angle. In this review, we discuss several proposed models for mixture processing, along with experimental data gathered from both the initial stage of olfactory processing (i.e., antennal lobe in insects or olfactory bulb in vertebrates) and higher areas of the brain, with an emphasis on how the lateral circuits in the antennal lobe or olfactory bulb may contribute to mixture processing. Based on empirical data as well as theoretical modeling, we conclude that odor mixtures may be represented both at the single-neuron level and at the population level. The difference between these two types of processing may reside in the degree of plasticity, with the former being hard-wired and the latter being more subjected to network modulation.


Speedy: a novel cell cycle regulator of the G2/M transition.
Stage VI Xenopus oocytes are suspended at the G2/M transition of meiosis I, and represent an excellent system for the identification and examination of cell cycle regulatory proteins. Essential cell cycle regulators such as MAPK, cyclins and mos have the ability to induce oocyte maturation, causing the resumption of the cell cycle from its arrested state. We have identified the product of a novel Xenopus gene, Speedy or Spy1, which is able to induce rapid maturation of Xenopus oocytes, resulting in the induction of germinal vesicle breakdown (GVBD) and activation of M-phasepromoting factor (MPF). Spy1 activates the MAPK pathway in oocytes, and its ability to induce maturation is dependent upon this pathway. Spy1-induced maturation occurs much more rapidly than maturation induced by other cell cycle regulators including progesterone, mos or Ras, and does not require any of these proteins or hormones, indicating that Spy1-induced maturation proceeds through a novel regulatory pathway. In addition, we have shown that Spy1 physically interacts with cdk2, and prematurely activates cdk2 kinase activity. Spy1 therefore represents a novel cell cycle regulatory protein, inducing maturation through the activation of MAPK and MPF, and also leading to the premature activation of cdk2.


Thyroid autoimmunity: really an important cause of sporadic congenital hypothyroidism?
The transplacental transfer of maternal antithyroid antibodies has recently been hypothesised as an aetiological factor in CH. In order to test this hypothesis, mothers and newborns identified by neonatal screening as suffering from hypothyroidism were tested for TgAb, MAb and TSHBAb. Significant titres of MAb and TgAb antibodies were found in 5% of the newborns and their mothers. TSHBAb was found in 1 out of 18 newborns and 1 out of 14 mothers. A causal link was found between the transplacental transfer of IgG inhibiting thyroid growth and function induced by TSH from a mother with Hashimoto's thyroiditis a newborn with CH and in her CH newborn. However the present series did not reveal the high percentage of cases with CH and thyroid antibodies reported by others and particularly not among the neonates born to mothers without any kind of maternal thyroid pathology. It therefore seems that the role of autoimmunity in the pathogenesis of CH and TH is yet to be clarified.


[Adrenal glucocorticoid function and its regulation in human prenatal ontogeny and in the 1st week of life].
A comparison of cortisol and ACTH level determination in 82 human fetal sera obtained in the 11th-34th week of the intrauterine development and 50 sera from infants 1-7 days of age has revealed several stages of pituitary-adrenal system (PAS) maturation. PAS is immature in the first trimester of embryogenesis when cortisol concentration in the human fetal blood is low. The functional relations between pituitary and adrenal glands begin to establish in the middle of prenatal developmental period. A prominent response to delivery stress indicates that by delivery PAS reaches a certain stage of maturation. The feedback between ACTH and cortisol secretions in the blood of infants 1-7 days of age demonstrates that the refractory period of PAS is absent in the neonates during the first week of their life.


[Breaking Bad News to Cancer Patients: Content, Communication Preferences and Psychological Distress].
Objectives Breaking bad news can be a very distressing situation for both patients and physicians. Physician communication behavior should therefore match patients' communication preferences. The aim of this study was to characterize the content of bad news from the patients' perspective. Patients' preferences for communication of bad news as well as the fit to communication behavior displayed by physicians were also investigated. Finally, consequences of a mismatch between patients' preferences and physician communication were investigated in relation to psychological distress in patients. Methods The sample consisted of N=270 cancer patients (mean age=56.8 years, 48% female) with various cancer entities and different stages of disease (n=115 patients with early stage of cancer, n=155 patients with advanced cancer). The content of bad news was assessed with a specifically developed list of questions. The Measure of Patients' Preferences Scale (MPP) was used to assess patients' preferences for communication of bad news. Patients further completed the NCCN Distress Thermometer (cancer specific distress), the Hospital Anxiety and Depression Scale (HADS- anxiety and depression) and the Demoralization Scale (DS-Scale) to gain information about psychological distress. Results Patients with early stage breast cancer received bad news M=1.6 times (SD=1.1, range: 1-5), patients with advanced cancers M=2.1 times (SD=1.6, range: 1-12). For 77% of early stage cancer patients and 70% of advanced cancer patients, the subjectively worst consultation was receiving the diagnosis and discussing treatment options. Patients' most important communication preferences were physicians' clinical competence and patient-centered communication, clear and direct communication and asking about patients information preferences. Patients in advanced stages report significantly more (29%) unmet communication needs than patients' in early stages (20%; p<0.01). Breaking bad news without considering patients' preferences was associated with higher psychological distress in patients. Conclusion Physicians should communicate in a patient-centered way to reduce mismatch with patients' preferences and thereby potentially reduce patients' psychological distress.


Endoneurial edema in sural nerve may indicate recent onset inflammatory neuropathy.
Sural nerve biopsy is an important means of establishing the diagnosis of inflammatory neuropathies. We investigated the diagnostic value of endoneurial edema. Diagnostic sural nerve biopsies from 42 patients with inflammatory and 28 patients with noninflammatory neuropathies were re-evaluated for the presence of endoneurial edema. Edema was assessed on hematoxylin-eosin stained paraffin and frozen sections and on azure II-methylene blue stained semithin sections. We determined the area of endoneurial edema on digitized images in relation to the entire endoneurial area of each fascicle. Edema was more extensive in neuropathies with short disease duration (≤12 months) as compared to long duration (>12 months; P < 0.01). Edema in inflammatory neuropathies of ≤12 months duration covered a larger area than in noninflammatory neuropathies (P < 0.01), and the extent of edema correlated negatively with disease duration (P < 0.05). Endoneurial edema may be a useful additional disease marker in inflammatory neuropathies of recent onset.


Ischemic versus nonischemic dilated cardiomyopathy: the implications of heart failure etiology on left ventricular assist device outcomes.
The effect of heart failure etiology on outcomes after left ventricular assist device (LVAD) implantation has not been fully investigated. The aim of this study was to compare postoperative survival, incidence of LVAD-related complications, left and right heart catheterizations, and echocardiographic findings in patients with ischemic cardiomyopathy (ICM) and nonischemic dilated cardiomyopathy (NIDCM) who underwent continuous-flow LVAD implantation. A total of 100 patients underwent implantation of a HeartMate II (Thoratec Corp., Pleasanton, CA) or HeartWare (HeartWare Inc., Framingham, MA) LVAD at our institution. Patients were stratified into two groups based on the etiology of heart failure, ICM and NIDCM. We identified 34 (34.0%) patients with ICM and 66 (66.0%) with NIDCM. Patients with ICM were significantly older (59.5 vs. 49.3; p < 0.001) and had higher rates of hypertension (91.2% vs. 84.8%; p = 0.021), chronic renal insufficiency (38.2% vs. 25.8%; p < 0.001), peripheral vascular disease (11.8% vs. 10.6%; p = 0.015), and previous cardiac surgery (58.8% vs. 13.6%; p < 0.001). Survival was similar for both groups with 30 day, 6 month, and 1 year survivals of 94.1%, 85.3%, and 82.4%, respectively, for ICM patients versus 95.5%, 92.4%, and 89.4%, respectively, for NIDCM patients (p = 0.743). Etiology of heart failure was not an independent predictor of survival in multivariate logistic regression analysis (p = 0.505). Post-LVAD complications and improvements in postoperative hemodynamic measurements were also similar for both groups. The etiology of heart failure did not appear to affect postoperative outcomes significantly.


Prophylactic use of an infrarenal abdominal aorta balloon catheter in pregnancies complicated by placenta accreta.
This study evaluated the surgical and neonatal outcomes of 71 patients diagnosed with placenta accreta before caesarean section with or without placement of a prophylactic abdominal aorta balloon catheter. This study took place at our hospital from January 2013 to May 2015. Thirty patients had a prophylactic balloon catheter inserted (balloon group), and 41 patients did not receive the intervention (control group). The mean estimated blood loss and decrease in haemoglobin after surgery was significantly lower in the balloon group than in the control group. No significant difference was found in duration of operation, transfusion, or percentage requirement of caesarean hysterectomy. The incidence of catheterisation-related complications was 3.3%. One patient had pain in her right leg, caused by an ultrasound-confirmed haematoma in the front wall of the right common femoral artery. No significant difference was found in the rate of surgery-related complications and neonatal outcomes between the groups. Prophylactic placement of an infrarenal abdominal aorta balloon catheter in patients with placenta accreta can effectively reduce intraoperative haemorrhage, without causing any obvious adverse maternal or neonatal outcomes. Impact statement Prophylactic placement of endovascular balloon catheters for controlling intraoperative haemorrhage in women with placenta accreta has been a topic of debate for nearly 2 decades. The most common type of occlusion is internal iliac artery balloon occlusion, only a few studies have focused on intraoperative aortic balloon occlusion This retrospective case-control study included relatively large number of cases and the result shown this technique can effectively reduce intraoperative haemorrhage in patients with placenta accreta, without causing any obvious adverse maternal or neonatal outcomes. It provides another safe and effective method for intraoperative haemorrhage control and even uterine preservation.


Evaluation of musical skills in children with a diagnosis of an auditory processing disorder.
Impaired musical skills are reported in parental questionnaires to be present in children with an auditory processing disorder (APD). To formally assess musical skills in children with a diagnosis of APD. We used a validated musical test battery with extensive normative pediatric data, the Gordon's Musical Aptitude Profile and the tests of metre and melody in particular, in order to assess the musical skills of 8 children with a previously given diagnosis of APD (APD group) and 8 normal controls (control group) aged 7-15 years old. The two groups were well matched for age, sex, handedness, socio-economic factors and musical training. The APD group had significantly lower metre percentile scores than normal children (mean difference 28.9, p=0.003). Melody scores tended to be lower in the APD group than in the controls, but this did not reach significance, possibly due to low power of the study. This is the first study that systematically assesses musical skills in children with a formal diagnosis of APD in the absence of other developmental disorders. The APD group did significantly worse than the control group in judging metre. Musical skills assessment in children with APD may help constrain our understanding of this heterogeneous condition and possibly inform the management plan for these children.


FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes.
Obesity and related metabolic disorders constitute one of the most pressing heath concerns worldwide. Increased adiposity is linked to autophagy upregulation in adipose tissues. However, it is unknown how autophagy is upregulated and contributes to aberrant adiposity. Here we show a FoxO1-autophagy-FSP27 axis that regulates adipogenesis and lipid droplet (LD) growth in adipocytes. Adipocyte differentiation was associated with upregulation of autophagy and fat specific protein 27 (FSP27), a key regulator of adipocyte maturation and expansion by promoting LD formation and growth. However, FoxO1 specific inhibitor AS1842856 potently suppressed autophagy, FSP27 expression, and adipocyte differentiation. In terminally differentiated adipocytes, AS1842856 significantly reduced FSP27 level and LD size, which was recapitulated by autophagy inhibitors (bafilomycin-A1 and leupeptin, BL). Similarly, AS1842856 and BL dampened autophagy activity and FSP27 expression in explant cultures of white adipose tissue. To our knowledge, this is the first study addressing FoxO1 in the regulation of adipose autophagy, shedding light on the mechanism of increased autophagy and adiposity in obese individuals. Given that adipogenesis and adipocyte expansion contribute to aberrant adiposity, targeting the FoxO1-autophagy-FSP27 axis may lead to new anti-obesity options.


Endocrine pathophysiology of luteal phase deficiency as assessed by GnRH/TRH stimulation tests performed in the early follicular and midluteal phases of the menstrual cycle.
To investigate endocrine pathophysiology of luteal phase deficiency (LPD), GnRH/TRH stimulation tests were performed in the early follicular (EFP) and midluteal phases (MLP) of the menstrual cycle in 52 infertile women with a history of short luteal phase, in whom pituitary responsiveness to GnRH/TRH and steroidogenic competency of the corpus luteum were analyzed. Twelve women with either elevated basal-LH or exaggerated PRL response to GnRH/TRH in EFP were eliminated, and the remaining 40 women were studied. Basal-FSH in EFP inversely correlated with steroidogenic parameters in MLP, indicating that compromised folliculogenesis causes LPD. In a fraction of LPD women, decreased basal-LH in MLP was associated with decreased basal-progesterone (p), in spite of normal steroidogenic potential of the corpus luteum, suggesting that aberrant LH secretion is another progenitor of LPD. The other group of LPD women showed shortening of high phase period and/or extravagant discrepancy in endometrial dating without apparent abnormal endocrine parameters, suggesting that unknown factors are involved in establishment of LPD. From the diagnostic point of view, they were discriminated into three groups, normal, incomplete LPD and complete LPD groups, with a modified classification of LPD; 1) shortening of high phase period < 11 days, 2) delay in histological to chronological dating of the endometrium > 2 days, and 3) decreased max-P in MLP < 10 ng/ml. Normal (n = 14) and complete LPD (n = 7) groups consisted of women having all the criteria of classification within and out of the cut-off values, respectively. The remainders were enrolled into incomplete LPD group (n = 19). Complete LPD group mainly consisted of women having compromised folliculogenesis as a cause of LPD. In contrast, incomplete LPD group appeared a mixture of heterogeneous populations as to the genesis of LPD. GnRH/TSH stimulation test, especially when performed in MLP, would unveil endocrine pathophysiology of LPD and provide an accurate standard for diagnosis of LPD.


Is Gemcitabine and Cisplatin Induction Chemotherapy Superior in Locoregionally Advanced Nasopharyngeal Carcinoma?
To investigate the outcome of locoregionally advanced nasopharyngeal carcinoma (NPC) treated with induction chemotherapy followed by chemoradiotherapy. Between June 2005 and October 2007, 604 patients with locoregionally advanced NPC were analyzed, of whom 399 and 205 were treated with conventional radiotherapy and intensity-modulated radiotherapy (IMRT) respectively. Meanwhile, 153 patients received concurrent chemotherapy, and 520 were given induction chemotherapy. With a median follow-up time of 65 months, the 3-, and 5-year overall survival (OS), locoregional free survival (LRFS), and distant-metastasis free survival (DMFS) rates were 82.5% vs. 72.6%, 90.6% vs. 87.1%, and 82.5% vs. 81.2%, respectively. Induction chemotherapy was not an independent prognostic factor for OS (P=0.193) or LRFS, but there was a positive tendency for DMFS (P=0.088). GP regimen (gemcitabine + cisplatin) was an independent prognostic factor for OS (P = 0.038) and it had a trend toward improved DMFS (P = 0.109). TP regimen (taxol + cisplatin) was only a significant prognostic factor for DMFS (P =0.038). Adding induction chemotherapy had no survival benefit, but GP regimen benefited overall survival and had a trend toward improved DMFS. GP regimen may be superior to TP/FP regimen (fluorouracil + cisplatin) in treating locoregionally advanced NPC.


Common fragile sites.
Aphidicolin-induced common fragile sites are site-specific gaps or breaks seen on metaphase chromosomes after partial inhibition of DNA synthesis. These fragile sites were first recognized during the early studies of the fragile X syndrome and are induced by the same conditions of folate or thymidylate stress used to induce the fragile X site. Common fragile sites are normally stable in cultured human cells. However, following induction with replication inhibitors, they display a number of characteristics of unstable and highly recombinogenic DNA. From the many studies that have cloned and characterized fragile sites, it is now known that these sites extend over large regions, are associated with genes, exhibit late or delayed replication, and contain regions of high flexibility but are otherwise unremarkable in sequence. Studies showing that fragile sites and their associated genes are frequently deleted or rearranged in cancer cells have clearly demonstrated their importance in genome instability in tumorigenesis. Yet until recently, very little was known about the molecular mechanisms involved in their stability. Recent findings showing that the key checkpoint genes ATR and BRCA1 are critical for genome stability at fragile sites have shed new light on these mechanisms and on the biological significance of common fragile sites.


Antigen-Specific TCR-T Cells for Acute Myeloid Leukemia: State of the Art and Challenges.
The cytogenetic abnormalities and molecular mutations involved in acute myeloid leukemia (AML) lead to unique treatment challenges. Although adoptive T-cell therapies (ACT) such as chimeric antigen receptor (CAR) T-cell therapy have shown promising results in the treatment of leukemias, especially B-cell malignancies, the optimal target surface antigen has yet to be discovered for AML. Alternatively, T-cell receptor (TCR)-redirected T cells can target intracellular antigens presented by HLA molecules, allowing the exploration of a broader territory of new therapeutic targets. Immunotherapy using adoptive transfer of WT1 antigen-specific TCR-T cells, for example, has had positive clinical successes in patients with AML. Nevertheless, AML can escape from immune system elimination by producing immunosuppressive factors or releasing several cytokines. This review presents recent advances of antigen-specific TCR-T cells in treating AML and discusses their challenges and future directions in clinical applications.


Consumer segmentation based on three dimensions of sustainable food consumption: a simultaneous analysis of meat, organic food, and sweet snack purchases based on household panel data in Germany.
The literature on sustainable food consumption laments two major gaps: First, the majority of previous studies analyzed consumer behavior based on survey data on consumers' self-reported behaviors and attitudes. Second, most existing studies focused on one dimension of sustainable food choices. This paper identifies and analyzes consumer segments based on the actual purchases of 8,400 households recorded in the GfK household panel data from Germany. We used three indicators of sustainable food consumption behavior: (1) the purchase of organic products as a proxy for the environmental impact of diets, (2) the purchase of meat as a proxy for the climate impact of diets, and (3) the purchase of sweet snacks as a proxy for the healthiness of a diet. The analysis yielded two larger segments with high expenditure shares for one type of unsustainable food (meat/sweet snacks, respectively), two small segments with above average (medium/high) expenditure shares for organic food, and a large 'mainstream' segment. The five consumer segments were further analyzed regarding the observed attitude-behavior gap, and the actual prices paid in different product categories. Clear gaps between stated and actual behavior were revealed with interesting differences between the five segments and the three sustainability characteristics. The analysis is a vital starting point for designing a holistic policy instrument mix to close the gaps and to reach a sustainable transformation of the food system.


The structure of the interstitial tissue of the active and resting avian testis.
The interstitial tissue of the testis was studied in gonadally active and gonadally inactive domestic fowl (Gallus gallus domesticus), guinea-fowl (Numida meleagris), duck (Anas platyrhynchos) and Japanese quail (Coturnix coturnix japonica). Gonadal inactivity in the fowl was induced by a single subcutaneous injection of 50 mg oestradiol benzoate. The structure of this tissue was similar in all the birds studied. Lymphatic vessels were mostly thin and meandered between the peritubular tissue peripherally and the centrally located blood vessels, Leydig cells and macrophages. The basal lamina rested on a closely associated homogeneous microfibrillar layer free of collagen fibres. The myofibroblast layer was several cells thick, and quite compact. The basal lamina of gonadally resting birds was highly irregular, relatively electron-dense, contained electron-lucent globules, and sent numerous finger-like processes or plicae into the seminiferous epithelium, particularly into the Sertoli cells. The Leydig cells were few but typical in structure. In gonadally inactive birds they accumulated lipid droplets, dense heterogeneous bodies, probably lysosomes, and appeared to degenerate. The avian testicular interstitium is similar to that of the human and cat in possessing a multi-layered myofibroblast component, and to that of the rodent in possessing a small number of Leydig cells, as well as in the location of the lymphatic vessels. Thus the bird combines characteristics of the interstitium found variably in mammals.


Changes in conjunctival clusterin expression in severe ocular surface disease.
Clusterin is a unique gene transcript in the human ocular surface epithelia and is synthesized by and localized in mucosal epithelia in general. It is not present, however, in keratinized epithelia, such as epidermis. In severe ocular surface disease, pathologic keratinization (squamous metaplasia) of the ordinarily nonkeratinized corneal and conjunctival mucosal epithelia results in severe visual loss. In the current study, the expression of clusterin was examined in conjunctivalized corneas with severe ocular surface disease. We examined conjunctiva covering cornea in eight eyes with ocular surface disease (Stevens-Johnson syndrome and ocular cicatricial pemphigoid) in which pathologic keratinization was present. Normal conjunctiva from four age-matched individuals served as the control. Semiquantitative RT-PCR was used to investigate expression of the clusterin gene. Immunohistochemistry was used to study the distribution of clusterin protein. The level of clusterin mRNA was significantly lower than normal in the diseased ocular surfaces. Clusterin protein was also markedly decreased in keratinized conjunctiva compared with that in normal eyes. Clusterin expression is markedly reduced in the pathologic, keratinized ocular surface epithelium, suggesting its importance in maintaining the ocular surface epithelium as a nonkeratinizing epithelium.


Use of the pulmonary artery catheter is not associated with worse outcome in the ICU.
In critically ill patients, the impact of pulmonary artery catheter (PAC) use on outcome is debatable. We investigated the epidemiology of PAC use in European ICUs and its relation to outcome. International cohort, observational study. One hundred ninety-eight European ICUs participating in the Sepsis Occurrence in Acutely Ill Patients Study. All 3,147 adult patients admitted to one of the participating ICUs between May 1, 2002, and May 15, 2002. None. Patients were classified according to whether or not they had a PAC at any time during their ICU stay, and were followed up until death, hospital discharge, or for 60 days. Propensity score case matching was performed, and matched pairs were examined for baseline characteristics and outcome. Of 3,147 patients, 481 patients (15.3%) had a PAC. Patients with a PAC were older, had a higher incidence of heart failure, a lower incidence of cancer, and were more commonly surgical admissions. Fluid balance was comparable between the two groups. ICU and hospital mortality rates were higher in patients with a PAC (28.1% vs 16.8% and 32.5% vs 22.5%, respectively; p < 0.001). However, PAC use was not an independent risk factor for 60-day mortality in multivariate analysis, and in 453 propensity-matched pairs ICU and hospital mortality rates were comparable between groups (26.7% vs 26.3% and 31.4% vs 32.8%, p = not significant). Survival to 60 days was similar between the two matched groups (log rank = 0.02; p = 0.894). This observational study suggests that PAC use is not associated with increased mortality in this heterogeneous population.


Non-invasive in vivo imaging of cardiac stem/progenitor cell biodistribution and retention after intracoronary and intramyocardial delivery in a swine model of chronic ischemia reperfusion injury.
The safety and efficacy of cardiac stem/progenitor cells (CSC) have been demonstrated in previous preclinical and clinical assays for heart failure. However, their optimal delivery route to the ischemic heart has not yet been assessed. This study was designed to determine by a non-invasive imaging technique (PET/CT) the biodistribution and acute retention of allogeneic pig CSC implanted by two different delivery routes, intracoronary (IC) and intramyocardial (IM), in a swine preclinical model of chronic ischemia-reperfusion. Ischemia-reperfusion was induced in six Goettingen hybrid minipigs by 90 min coronary artery occlusion followed by reperfusion. Thirty days later, animals were allocated to receive IC (n = 3) or NOGA®-guided IM injection (n = 3) of 50 million of 18F-FDG/GFP-labeled allogeneic pig CSC. Acute retention was quantified by PET/CT 4 h after injection and cell engraftment assessed by immunohistochemical quantification of GFP+ cells three days post-injection. Biodistribution of 18F-FDG-labeled CSC was clearly visualized by PET/CT imaging and quantified. No statistical differences in acute cell retention (percentage of injected dose, %ID) were found in the heart when cells were administered by NOGA®-guided IM (13.4 ± 3.4%ID) or IC injections (17.4 ± 4.1%ID). Interestingly, engrafted CSC were histologically detected only after IM injection. PET/CT imaging of 18F-FDG-labeled CSC allows quantifying biodistribution and acute retention of implanted cells in a clinically relevant pig model of chronic myocardial infarction. Similar levels of acute retention are achieved when cells are IM or IC administered. However, acute cell retention does not correlate with cell engraftment, which is improved by IM injection.


Hemolysis in vitro by sorbose, sorbitol and xylitol.
L-sorbose, xylitol and sorbitol solutions (56 mM) were not hemolytic when incubated with erythrocytes of 30 healthy volunteers, 14 thalassemic heterozygotes and in 30 horses, 30 cows and 30 Osborne-Mendel rats. Lysis of dog erythrocytes was most pronounced when incubated with L-sorbose but was also significant in xylitol and sorbitol solutions.


Colony-stimulating factor 1 in the human response to neonatal listeriosis.
Immunity to Listeria monocytogenes, an important pathogen in human neonatal sepsis, is mediated by mononuclear phagocytes, which are regulated by the hematopoietic growth factor colony-stimulating factor 1. Neonates with listeriosis had higher circulating colony-stimulating factor 1 levels and subsequent monocyte counts than those of both noninfected newborns and newborns infected with nonlisterial organisms.


Synthesis and characterization of a multifunctional gold-doxorubicin nanoparticle system for pH triggered intracellular anticancer drug release.
A nanoparticle drug carrier system has been developed to alter the cellular uptake and chemotherapeutic performance of an available chemotherapeutic drug. The system comprises of a multifunctional gold nanoparticle based drug delivery system (Au-PEG-PAMAM-DOX) as a novel platform for intracellular delivery of doxorubicin (DOX). Spherical gold nanoparticles were synthesized by a gold chloride reduction, stabilized with thiolated polyethylene glycol (PEG) and then covalently coupled with a polyamidoamine (PAMAM) G4 dendrimer. Further, conjugation of an anti-cancer drug doxorubicin to the dendrimer via amide bond resulted in Au-PEG-PAMAM-DOX drug delivery system. Acellular drug release studies proved that DOX released from Au-PEG-PAMAM-DOX at physiological pH was negligible but it was significantly increased at a weak acidic milieu. The intracellular drug release was monitored with confocal laser scanning microscopy analysis. In vitro viability studies showed an increase in the associated doxorubicin cytotoxicity not attributed to carrier components indicating the efficiency of the doxorubicin was improved, upon conjugation to the nano system. As such it is postulated that the developed pH triggered multifunctional doxorubicin-gold nanoparticle system, could lead to a promising platform for intracellular delivery of variety of anticancer drugs.


[Prevalence of diabetes-related autoantibodies in celiac disease].
of this study is to investigate the prevalence of diabetes-related autoantibodies in a group of children with celiac disease and to compare it with a control group. We recruited 31 celiac children at diagnosis (on gluten containing diet) and 31 age and sex matched healthy children. Anti-islet cell antibodies (ICA) were detected by indirect immunofluorescence on monkey pancreas. Anti-glutamate decarboxylase (anti-GAD) and anti-tyrosine phosphatase (anti-IA2) antibodies were assessed by a radio-immuno- precipitation method. Three out of 31 celiac patients (9.7%) had one or more diabetes-related autoantibodies. ICA, anti-GAD and anti-IA2 were found in respectively 3.2%; 3.2% and 9.7% of patients. Only one control (3.2%) had anti-GAD. There was no statistically significant difference between the 2 groups. The risk to develop diabetes seems to be the same in celiac patients and in healthy subjects thus screening of diabetes-related autoantibodies is not justified in celiac patients.


The use of nerve conduction studies in determining the short-term outcome of Bell's palsy.
Bell's palsy is a common neurological problem causing considerable loss of self-esteem among patients. A prospective observational study was conducted to determine the short-term outcome of Bell's palsy at 1 month and 2 months after the onset and the relationship between these outcomes with facial nerve degeneration. We also determined if gender, age, diabetes, systolic and diastolic blood pressure influence the severity of facial nerve degeneration and the clinical outcome at 2 months after the onset. After clinically grading the newly diagnosed unilateral Bell's palsy patients using the House-Brackmann facial nerve grading system, nerve conduction studies of the facial nerve were done to determine the severity of facial nerve degeneration. The recovery of the facial paralysis was clinically graded again at the end of 1 month and 2 months from the onset. A total of 37 patients were recruited. There was a strong positive correlation between facial nerve degeneration and the clinical outcome of Bell's palsy at 1 month (r = 0.794; p < 0.0005) and 2 months (r = 0.732; p < 0.0005) after the onset. There was no significant correlation between either the facial nerve degeneration or the clinical outcome at 2 months with the patients' age (p = 0.288 and p = 0.799 respectively), systolic blood pressure (p = 0.425 and p = 0.933 respectively) or diastolic blood pressure (p = 0.243 and p = 0.579 respectively). Neither the severity of facial nerve degeneration nor the clinical outcome at 2 months were significantly different between male and female patients (p = 0.460 and p = 0.725 respectively) or diabetic and non-diabetic patients (p = 0.655 and p = 0.655 respectively).


Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6.
Autism spectrum disorders (ASDs) have been associated with brain inflammation as indicated by microglia activation, as well as brain expression and increased plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF). Here we report that serum levels of IL-6 and TNF were elevated (61.95 ± 94.76 pg ml(-1) and 313.8 ± 444.3 pg ml(-1), respectively) in the same cohort of patients with elevated serum levels of corticotropin-releasing hormone (CRH) and neurotensin (NT), while IL-9, IL-31 and IL-33 were not different from controls. The elevated CRH and NT levels did not change after treatment with a luteolin-containing dietary formulation. However, the mean serum IL-6 and TNF levels decreased significantly (P=0.036 and P=0.015, respectively) at the end of the treatment period (26 weeks) as compared with levels at the beginning; these decreases were strongly associated with children whose behavior improved the most after luteolin formulation treatment. Our results indicate that there are distinct subgroups of children within the ASDs that may be identifiable through serum levels of IL-6 and TNF and that these cytokines may constitute distinct prognostic markers for at least the beneficial effect of luteolin formulation.


Interrater variation of vascular classifications used in enhanced laryngeal contact endoscopy.
Combined use of contact endoscopy (CE) and Narrow Band Imaging (NBI, Olympus®) is suggested for the visualization of specific vascular changes indicative of glottic neoplasia. We investigated the interrater reliability and agreement in 3 recognized classification systems of vascular changes applied to images from CE + NBI in patients suspected for glottic neoplasia. Six experienced head and neck surgeons familiar with NBI rated 120 images obtained by CE + NBI by 3 classification systems of vascular changes as suggested by Ni et al. (N-C), Puxeddu et al. (P-C), and the European Laryngological Society (ELS-C). Three raters were experienced in CE, and three raters had only limited experience with CE. Crude agreement and Fleiss' kappa with 95% confidence interval were estimated for all 6 raters, and for the 2 levels of expertise for each original classification system and for dichotomized versions of the N-C and the P-C based on suggested neoplastic potential. The interrater crude agreement and the corresponding kappa values for the ELS-C were good and significantly higher than those for the N-C and P-C for all raters, irrespective of the level of experience with CE (p < 0.0001). There were no significant differences between the N-C and the P-C (p = 0.16). Kappa was considerably improved for both the N-C and the P-C to a level not different from the ELS-C (p = 0.21-0.71) when their 5 original categories were pooled into dichotomized classifications. Difficulties in reliably classifying vascular changes in CE + NBI are evident. Two-tier classification systems are the most reliable.


Did psychotropic drug consumption increase during the 2008 financial crisis? A cross-sectional population-based study in Spain.
Although psychotropic drugs are used to treat mental health disorders, little evidence analyses the effects the 2008 economic downturn had on psychotropic drug consumption in the case of Spain. We analyse these effects, considering both gender and employment situation. We used the microdata from the face-to-face cross-sectional population-based Spanish National Health Survey for two periods: 2006-2007 (n=28 954) and 2011-2012 (n=20 509). Our samples included adults (>15 years old). The response variables are consumption (or not) of antidepressants or sedatives and the explanatory variables are the year of the survey, gender and employment status. Covariates are mental health problems, mental health index General Health Questionnaire (GHQ-12) and self-reported health outcome variables such as self-rated health, chronic diseases, smoking behaviour, sleeping hours, body mass index, physical activity in the workplace, medical visits during the past year, age, region of residence (autonomous communities), educational level, marital status and social class of the reference person. Finally, we include interactions between time period, gender and employment status. We specify random effects logistic regressions and use Bayesian methods for the inference. The economic crisis did not significantly change the probability of taking antidepressant drugs (OR=0.56, 95% CI 0.18 to 2.56) nor sedatives (OR=1.21, 95% CI 0.26 to 5.49). In general, the probability of consuming antidepressants among men and women decreases, but there are differences depending on employment status. The probability of consuming sedatives also depends on the employment status. While the year of the financial crisis is not associated with the consumption of antidepressants nor sedatives, it has widened the gap in consumption differences between men and women. Although antidepressant use dropped, the difference in consumption levels between men and women grew significantly among the retired, and in the case of sedatives, risk of women taking sedatives increased in all groups except students.


Affective state influences retrieval-induced forgetting for integrated knowledge.
Selectively testing parts of learned materials can impair later memory for nontested materials. Research has shown that such retrieval-induced forgetting occurs for low-integrated materials but may be prevented for high-integrated materials. However, previous research has neglected one factor that is ubiquitous in real-life testing: affective state. We investigated whether affect influences the resistance of integrated materials to retrieval-induced forgetting by inducing neutral, positive, or negative affect immediately before selectively testing previously learned textbook passages containing interrelated facts and concepts. As negative affect is known to promote a detail-oriented local processing style, we hypothesized that experiencing negative affect during testing may decrease the protective effects of integration and lead to reoccurrence of forgetting. By contrast, as positive affect is known to promote a relation-oriented global processing style, we hypothesized that experiencing positive affect may support effects of integration and prevent forgetting. Our findings are consistent with these predictions. No subsequent forgetting occurred when testing memories for integrated text materials in affectively neutral and positive states, whereas forgetting occurred when testing in negative states. A correlation analysis showed that forgetting decreased with higher positive affect, with participants experiencing high positive affect even showing facilitation instead of forgetting. These findings indicate that affect can moderate the memory consequences of test taking and suggest that educators should use testing as a tool to improve memory with care.


Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up.
Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non-small-cell lung cancer (NSCLC). Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs-landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)-were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up.Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes.Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data.Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting.Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup.


[End of life in France].
Two major changes in end-of-life management have occured in recent decades: first, because of the increase in life expectancy and the resulting aging of the population, most deaths now involve old or very old people; second, more than two-thirds of deaths occur in a hospital or an institution. Our fellow citizens are afraid of suffering and death. They wish for a peaceful death, as rapid as possible and, in recent surveys, say they favour euthanasia. Yet euthanasia is illegal in France and in most other Western countries (with the exception of the Benelux nations). Palliative care ensures dignity in death, without anxiety of suffering, and is expanding rapidly in France. Léonetti's law of 22 April 2005 ensures the protection of the weakest, who should never be considered unworthy of life, yet is poorly known to the public and even to physicians. It now needs to be applied in practice.


Changes in Employment Uncertainty and the Fertility Intention-Realization Link: An Analysis Based on the Swiss Household Panel.
How do changes in employment uncertainty matter for fertility? Empirical studies on the impact of employment uncertainty on reproductive decision-making offer a variety of conclusions, ranging from gender and socio-economic differences in the effect of employment uncertainty on fertility intentions and behaviour, to the effect of employment on changes in fertility intentions. This article analyses the association between a change in subjective employment uncertainty and fertility intentions and behaviour by distinguishing male and female partners' employment uncertainty, and examines the variation in these associations by education. Using a sample of men and women living in a couple from the Swiss Household Panel (SHP 2002-2011), we examine through multinomial analysis how changes in employment uncertainty and selected socio-demographic factors are related to individual childbearing decisions. Our results show strong gendered effects of changes in employment uncertainty on the revision of reproductive decisions among the highly educated population.


Surface display of bacterial tyrosinase on spores of Bacillus subtilis using CotE as an anchor protein.
Tyrosinases, copper-containing monooxygenases, are widely used enzymes for industrial, medical, and environmental applications. We report the first functional surface display of Bacillus megaterium tyrosinase on Bacillus subtilis spores using CotE as an anchor protein. Flow Cytometry was used to verify surface expression of tyrosinase on the purified spores. Moreover, tyrosinase activity of the displayed enzyme on B. subtilis spores was monitored in the presence of L-tyrosine (substrate) and CuSO4 (inducer). The stability of the spore-displayed tyrosinase was then evaluated after 15 days maintenance of the spores at room temperature, and no significant decrease in the enzyme activity was observed. In addition, the tyrosinase-expressing spores could be repeatedly used with 62% retained enzymatic activity after six times washing with Tris-HCl buffer. This genetically immobilized tyrosinase on the spores would make a new advance in industrial, medical, and environmental applications.


Effects of repetitive facilitative exercise with neuromuscular electrical stimulation, vibratory stimulation and repetitive transcranial magnetic stimulation of the hemiplegic hand in chronic stroke patients.
Repetitive facilitative exercise (RFE) is a developed approach to the rehabilitation of hemiplegia. RFE can be integrated with neuromuscular electrical stimulation (NMES), direct application of vibratory stimulation (DAVS) and repetitive transcranial magnetic stimulation (rTMS). The aims of the present study were to retrospectively compare the effects of RFE and NMES, DAVS with those of RFE and rTMS, and to determine the maximal effect of the combination of RFE with NMES, DAVS, rTMS and pharmacological treatments in stroke patients. Thirty-three stroke patients were enrolled and divided into three groups: 15 who received RFE with rTMS (4 min) (TMS4 alone), 9 who received RFE with NMES, DAVS (NMES, DAVS alone) and 9 who received RFE with NMES, DAVS and rTMS (10 min) (rTMS10 + NMES, DAVS). The subjects performed the Fugl-Meyer Assessment (FMA) and Action Research Arm Test (ARAT) before and after the 2-week session. The 18 patients in the NMES, DAVS alone and rTMS10 + NMES, DAVS group underwent the intervention for 4 weeks. There were no significant differences in the increases in the FMA, ARAT scores in the three groups. The FMA or ARAT scores in the NMES, DAVS alone and the rTMS10 + NMES, DAVS group were increased significantly. The FMA and ARAT scores were significantly improved after 4 weeks in the NMES, DAVS alone group. RFE with NMES, DAVS may be more effective than RFE with rTMS for the recovery of upper-limb function. Patients who received RFE with NMES, DAVS and pharmacological treatments showed significant functional recovery.


Measuring vibration and shock in power wheelchairs for clinical application.
Research evidence demonstrates the negative effects of Whole-Body Vibration (WBV) and correlation between exposure to WBV and detriment to health. ISO Standard 2631-1 (1997) is the accepted standard for human exposure to WBV in vehicle vibration, and provides vibration guidelines for health and comfort. These standards have not been applied to power wheelchairs (PWC), and no clinical tool exists that measures vibration levels during live power wheelchair driving. This study measures WBV and shock levels during PWC driving, considering the impact of terrains, base configurations, and seat cushions. A sensor tag accelerometer was used to measure vibration and shock in three different PWC configurations driven over seven different terrains. Data was collected for two runs per wheelchair, per terrain type, per cushion type. Differences were significant (p < .001) for overall mean and median peak vibration compared across the seven terrains, and for overall mean vibration for basic and enhanced cushions. Differences were also noted in mean and peak vibration in the three different base configurations (p = .0052). Results were compared with ISO 2631-1 guidelines. Mechanical shock on certain terrains created peak vibration levels with likely health risk. Results from this study can inform PWC prescription process.


A 69-year-old woman with periodic fever, facial swelling, and neck pain.
We presented a case of a 69-year-old woman who experienced monthly episodes of facial swelling and nonpruritic, erythematous rash on her face, accompanied by high fever, nausea, headache, and neck pain over 1 year. Her symptoms started with myalgia, arthralgia, fever and neck stiffness, and headache, and then angioedema occurred, which was painful to touch. She underwent multiple iatrogenic diagnostic and therapeutic procedures that did not lead to the correct diagnosis. Subsequently, relevant immunology laboratory tests were conducted after a careful history and physical examination, which led to the diagnosis. This case illustrated the need for a detailed history and thorough immunologic assessment, and the requirement to maintain a broad differential diagnosis.


Improvement of Lipoplexes With a Sialic Acid Mimetic to Target the C1858T PTPN22 Variant for Immunotherapy in Endocrine Autoimmunity.
The C1858T variant of the protein tyrosine phosphatase N22 (PTPN22) gene is associated with pathophysiological phenotypes in several autoimmune conditions, namely, Type 1 diabetes and autoimmune thyroiditis. The R620W variant protein, encoded by C1858T, leads to a gain of function mutation with paradoxical reduced T cell activation. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes, LiposiRNA) that selectively inhibit variant allele expression. In this manuscript, we functionalize lipoplexes carrying siRNA for variant C1858T with a high affinity ligand of Siglec-10 (Sig10L) coupled to lipids resulting in lipoplexes (LiposiRNA-Sig10L) that enhance delivery to Siglec-10 expressing immunocytes. LiposiRNA-Sig10L lipoplexes more efficiently downregulated variant C1858T PTPN22 mRNA in PBMC of heterozygous patients than LiposiRNA without Sig10L. Following TCR engagement, LiposiRNA-Sig10L more significantly restored IL-2 secretion, known to be paradoxically reduced than in wild type patients, than unfunctionalized LiposiRNA in PBMC of heterozygous T1D patients.


Protease activity of Clostridium difficile strains.
The production of proteolytic enzymes by 10 Clostridium difficile isolates of varying toxigenicity and clinical origin was studied to determine if all isolates secreted proteases. Different protease substrates were studied: gelatin, collagen, phenylazobenzyloxycarbonyl-leucyl-glycyl-L-prolyl-D-arginine (Pz-peptide), casein, azocasein, and azocoll. All isolates degraded gelatin, collagen, and azocoll. The supernatants of all isolates contained an enzyme capable of attacking gelatin incorporated in a polyacrylamide gel (zymograms) and forming two closely spaced lytic bands with an estimated molecular mass of 35-40 kDa. Polyclonal antibodies, produced against the C. difficile gelatinase, revealed in Western blots a 35-kDa protein in the culture supernatants of all C. difficile isolates. In the same manner, Clostridium perfringens collagenase polyclonal antibodies detected a 120-kDa protein in the culture supernatants of all isolates; this suggests that at least two proteases may exist in C. difficile. The protease activities of the 10 strains examined did not seem strikingly different quantitatively but were in general weak and their role in pathogenicity is suspect.


Identification of stress responsive genes by studying specific relationships between mRNA and protein abundance.
Protein expression is regulated by the production and degradation of mRNAs and proteins but the specifics of their relationship are controversial. Although technological advances have enabled genome-wide and time-series surveys of mRNA and protein abundance, recent studies have shown paradoxical results, with most statistical analyses being limited to linear correlation, or analysis of variance applied separately to mRNA and protein datasets. Here, using recently analyzed genome-wide time-series data, we have developed a statistical analysis framework for identifying which types of genes or biological gene groups have significant correlation between mRNA and protein abundance after accounting for potential time delays. Our framework stratifies all genes in terms of the extent of time delay, conducts gene clustering in each stratum, and performs a non-parametric statistical test of the correlation between mRNA and protein abundance in a gene cluster. Consequently, we revealed stronger correlations than previously reported between mRNA and protein abundance in two metabolic pathways. Moreover, we identified a pair of stress responsive genes (ADC17 and KIN1) that showed a highly similar time series of mRNA and protein abundance. Furthermore, we confirmed robustness of the analysis framework by applying it to another genome-wide time-series data and identifying a cytoskeleton-related gene cluster (keratin 18, keratin 17, and mitotic spindle positioning) that shows similar correlation. The significant correlation and highly similar changes of mRNA and protein abundance suggests a concerted role of these genes in cellular stress response, which we consider provides an answer to the question of the specific relationships between mRNA and protein in a cell. In addition, our framework for studying the relationship between mRNAs and proteins in a cell will provide a basis for studying specific relationships between mRNA and protein abundance after accounting for potential time delays.


[Clinical aspects and therapy in primary ovarian cancer].
The charts and the histological slides of 122 cases of ovarian cancer, treated at the 2nd Gynaecological Department, University of Vienna, in the years 1968 to 1977 were reexamined. The statistic evaluation were done by Pearson's correlations coefficient, the Breslow and Mantel test or the trend test after Tarone. Priority was given to the prognostic value of all the data gathered. Problems of presurgical diagnosis and symptoms were outlined. The 5 years survival rate was in stage I 73%, in stage II 25% and in stage III 5%. The survival curves of stage Ia and Ib did not show any differences wether the adnexa had been removed or total exstirpation had been performed. The presence of ascites however impaired the prognosis significantly. In almost all cases of stage II total exstirpation had been performed. In stage III no significantly different effects could be observed between "incomplete" surgery as probatoria, exstirpation of the inflicted adnexa and total exstirpation of the internal genitals. Therefore an additional total omentectomy seems to be obligatory for further improvement of survival curves. A significant improvement of the survival rates has been achieved by telecobalt irradiation.


F-Box and Leucine-Rich Repeat Protein 7 Is a Prognostic Biomarker and Is Correlated with the Immunosuppressive Microenvironment in Colorectal Cancer.
Background: Colorectal cancer (CRC) is a common malignancy of the digestive system, but its specific mechanisms of occurrence and development remain incompletely understood. F-Box and leucine-rich repeat protein 7 (FBXL7) is a subunit of the Skp-cullin-F-box ubiquitin ligase, involved in cell cycle regulation, endothelial cell damage, and inflammatory immunological responses. However, the role of FBXL7 in CRC remains unknown. In this study, we investigated the clinical significance and potential mechanism of FBXL7 expression in CRC progression. Methods: We utilized data from The Cancer Genome Atlas (TCGA) and the University of California Santa Cruz Xena (UCSC Xena) database for bioinformatic analyses. Clinical CRC samples were used to confirm FBXL7 expression. Gene set enrichment analysis (GSEA) and various databases, such as TCGA, UCSC Xena, cBioPortal, University of ALabama at Birmingham CANcer data analysis portal, MethSurv, Tumor Immune Estimation Resource (TIMER), TIMER2.0, Tumor-Immune System Interaction Database, and Tumor Immune Dysfunction and Exclusion Database (TIDB), were used to investigate the role of FBXL7 in CRC. Statistical analysis was performed using R (v.3.6.3) or GraphPad Prism 8.0. Results: Our findings revealed the predictive significance of FBXL7 in CRC patients. FBXL7 expression was associated with tumor stage, lymph node stage, pathological stage, perineural invasion, and lymphatic invasion. GSEA analysis identified associations between FBXL7 and extracellular matrix organization, as well as immune-related pathways. Immunological analysis revealed a correlation between high FBXL7 expression and the development of an immunosuppressive microenvironment. Conclusion: Identifying FBXL7 as a novel biomarker for CRC could shed light on the promotion of CRC development by the immune environment.


Intradiscal electrothermal annuloplasty therapy: a case series study leading to new considerations.
To evaluate outcomes of intradiscal electrothermal annuloplasty (IDEA) therapy in the treatment of chronic discogenic low back pain in consecutive IDEA patients treated at a rural pain management clinic. An observational case series study design was applied to consecutive IDEA patients qualifying under the inclusion and exclusion criteria. Patient assessment of pain and disability were performed at baseline and 6 weeks, 3, 6, 12, and 24 months post-IDEA. Selected patients underwent IDEA for an average of 15 minutes at a temperature of 90 degrees C. Analyses of outcomes included Visual Analog Scale (VAS) assessments of levels of pain, and Roland Morris Disability Questionnaire (RMDQ) assessments of functional capacity at pretreatment, and 6 weeks, 3, 6, 12, and 18 months post-treatment time points. At 6 months post-IDEA treatment, patients (n=51) demonstrated statistically significant improvement (P < 0.001) as measured by a mean change of over 20 points from the pretreatment score on the RMDQ. At 1 year, post data remained significant in the 33 patients who had achieved this time point. VAS pain data were also statistically significant at 6 months (P = 0.023). Analysis of patient profiles revealed that statistically significant improvement of pain and functional capacity was strongly associated with female gender and age (range of 18-45 years), and that statistically significant improvement was not sustained in males beyond the 3-6 month point. These data support the outcomes reported in the few existing observational studies to date. Of 86 patients receiving IDEA therapy, 73 provided RMDQ data at baseline and at 3 months or later and were included in the analyses. Some patients were lost to follow-up at later time points. These data show favorable outcomes after IDEA therapy, and suggest that women may experience more improvement than men, particularly with regard to perceived disability improvements. Data suggest that greater improvement in IDEA outcomes may be achieved by profiling the characteristics of patients who achieve the optimal long-term outcomes following treatment and should be considered during evaluation of patient eligibility for IDEA.


Functional Outcomes of Decompressive Craniectomy in Patients with Malignant Middle Cerebral Artery Infarction and Their Association with Preoperative Thalamus Deformation: An Analysis of 12 Patients.
Objective Decompressive craniectomy (DC) in patients with malignant middle cerebral artery (MCA) infarction is known to decrease the mortality rate. However, the functional outcomes (communication and oral intake) of this procedure remain unclear. Most patients with malignant MCA infarction exhibit a loss of consciousness, which may be principally governed by the thalamus. We herein investigated the functional outcomes of DC at 90 days after the onset of malignant MCA infarction and their association with preoperative thalamus deformation, which can occur due to pressure and edema. Methods Twelve of 2,692 patients with acute cerebral infarction were diagnosed with malignant MCA infarction and underwent DC. We evaluated preoperative thalamus damage using brain computed tomography and its association with communication and oral intake abilities and the modified Rankin Scale (mRS) and Barthel index scores at 90 days after stroke onset. Results The mRS score at 90 days was 0-4 in five patients. Seven patients could communicate immediately after surgery, while five could do so by 90 days. Five patients were able to resume the oral intake of food at 90 days. All patients with preoperative thalamus deformation showed a poor recovery, while those with absent or slight preoperative thalamus deformation showed a good recovery. Conclusion Patients with preoperative thalamus deformation caused by pressure and edema show a poor oral intake and communication abilities after DC, suggesting that preoperative thalamus deformation is a predictor of poor functional outcomes after DC in patients with malignant MCA infarction.


Exploring the limits to turning performance with size and shape variation in dogs.
Manoeuvrability, the ability to make rapid changes in direction, is central to animal locomotion. Turning performance may depend on the ability to successfully complete key challenges including: withstanding additional lateral forces, maintaining sufficient friction, lateral leaning during a turn and rotating the body to align with the new heading. We filmed high-speed turning in domestic dogs (Canis lupus familiaris) to quantify turning performance and explore how performance varies with body size and shape. Maximal speed decreased with higher angular velocity, greater centripetal acceleration and smaller turning radii, supporting a force limit for wider turns and a friction limit for sharp turns. Variation in turning ability with size was complex: medium sized dogs produced greater centripetal forces, had relatively higher friction coefficients, and generally aligned the body better with the heading compared with smaller and larger bodied dogs. Body shape also had a complex pattern, with longer forelimbs but shorter hindlimbs being associated with better turning ability. Further, although more crouched forelimbs were associated with an increased ability to realign the body in the direction of movement, more upright hindlimbs were related to greater centripetal and tangential accelerations. Thus, we demonstrate that these biomechanical challenges to turning can vary not only with changes in speed or turning radius, but also with changes in morphology. These results will have significant implications for understanding the link between form and function in locomotory studies, but also in predicting the outcome of predator-prey encounters.


MC-Fit: using Monte-Carlo methods to get accurate confidence limits on enzyme parameters.
A program is described for estimating enzymatic parameters from experimental data using Apple Macintosh computers. MC-Fit uses iterative least-square fitting and Monte-Carlo sampling to get accurate estimates of the confidence limits. This approach is more robust than the conventional covariance matrix estimation, especially in cases where experimental data is partially lacking or when the standard error on individual measurements is large. This happens quite often when analysing the properties of variant enzymes obtained by mutagenesis, as these can have severely impaired activities and reduced affinities for their substrates.


Localization of prealbumin in human eye.
Although the aqueous humor contained several serum proteins and the concentration of each protein was very low in normal eyes, the aqueous/serum ratio of prealbumin was reported to be higher than the ratios of other human aqueous proteins in a previous paper. This study investigated the possibility of the intraocular synthesis of prealbumin, by examining postmortem human eyes using the peroxidase-antiperoxidase method. The immunohistochemical survey revealed the presence of prealbumin in the nonpigmented layer of the ciliary epithelium and in the ganglion cell layer of the retina. Some cells situated on the inner side of the internal nuclear layer of the retina also showed staining. We believe that this is the first study to demonstrate the possibility of synthesis of prealbumin in the human eye by immunohistochemistry.


Considerations appropriate to a clinical trial of definitive radiation therapy in adenocarcinoma of the pancreas.
The Author describes criteria for selection of patients who might be eligible for entry into a clinical trial of definitive Radiation Therapy for adenocarcinoma of the pancreas. Most emphasis is placed on careful surgical staging, target volume and location, and the use of bypass procedures when appropriate.


18F-Fluoride positron emission tomography and positron emission tomography/computed tomography.
(18)F-Fluoride is a positron-emitting bone-seeking agent, the uptake of which reflects blood flow and remodeling of bone. Assessment of (18)F-fluoride kinetics using quantitative positron emission tomography (PET) methods allows the regional characterization of lesions of metabolic bone diseases and the monitoring of their response to therapy. It also enables the assessment of bone viability and discrimination of uneventful and impaired healing processes of fractures, bone grafts and osteonecrosis. Taking advantage of the favorable pharmacokinetic properties of the tracer combined with the high performance of PET technology, static (18)F-fluoride PET is a highly sensitive imaging modality for detection of benign and malignant osseous abnormalities. Although (18)F-fluoride uptake mechanism corresponds to osteoblastic activity, it is also sensitive for detection of lytic and early marrow-based metastases, by identifying their accompanying reactive osteoblastic changes, even when minimal. The instant fusion of increased (18)F-fluoride uptake with morphological data of computed tomography (CT) using hybrid PET/CT systems improves the specificity of (18)F-fluoride PET in cancer patients by accurately differentiating between benign and malignant sites of uptake. The results of a few recent publications suggest that (18)F-fluoride PET/CT is a valuable modality in the diagnosis of pathological osseous conditions in patients also referred for nononcologic indications. (18)F-fluoride PET and PET/CT are, however, not widely used in clinical practice. The limited availability of (18)F-fluoride and of PET and PET/CT systems is a major factor. At present, there are not enough data on the cost-effectiveness of (18)F-fluoride PET/CT. However, it has been stated by some experts that (18)F-fluoride PET/CT is expected to replace (99m)Tc-MDP bone scintigraphy in the future.


Density functional theory-based prediction of some aqueous-phase chemistry of superheavy element 111. Roentgenium(I) is the "softest" metal ion.
A previous approach (Hancock, R. D.; Bartolotti, L. J. Inorg. Chem. 2005, 44, 7175) using DFT calculations to predict log K1 (formation constant) values for complexes of NH3 in aqueous solution was used to examine the solution chemistry of Rg(I) (element 111), which is a congener of Cu(I), Ag(I), and Au(I) in Group 1B. Rg(I) has as its most stable presently known isotope a t(1/2) of 3.6 s, so that its solution chemistry is not easily accessible. LFER (Linear free energy relationships) were established between DeltaE(g) calculated by DFT for the formation of monoamine complexes from the aquo ions in the gas phase, and DeltaG(aq) for the formation of the corresponding complexes in aqueous solution. For M2+, M3+, and M4+ ions, the gas-phase reaction was [M(H2O)6]n+(g) + NH3(g) = [M(H2O)5NH3]n+(g) + H2O(g) (1), while for M+ ions, the reaction was [M(H2O)2]+(g) + NH3(g) = [M(H2O)NH3]+(g) + H2O(g) (2). A value for DeltaG(aq) and for DeltaE for the formation of M = Cu2+ in reaction 1, not obtained previously, was calculated by DFT and shown to correlate well with the LFER obtained previously for other M2+ ions, supporting the LFER approach used here. The simpler use of DeltaE values instead of DeltaG(aq) values calculated by DFT for formation of monoamine complexes in the gas phase leads to LFER as good as the DeltaG-based correlations. Values of DeltaE were calculated by DFT to construct LFER with M+ = H+, and the Group 1B metal ions Cu+, Ag+, Au+, and Rg+, and with L = NH3, H2S, and PH3 in reaction 3: [M(H2O)2]+(g) + L(g) = [M(H2O)L]+g) + H2O(g) (3). Correlations involving DeltaE calculated by DMol3 for H+, Cu+, Ag+, and Au+ could reliably be used to construct LFER and estimate unknown log K1 values for Rg(I) complexes of NH3, PH3, and H2S calculated using the ADF (Amsterdam Density Functional) code. Log K1 values for Rg(I) complexes are predicted that suggest the Rg(I) ion to be a very strong Lewis acid that is extremely "soft" in the Pearson hard and soft acids and bases sense.


General catalytic deficiency of hepatitis C virus RNA polymerase with an S282T mutation and mutually exclusive resistance towards 2'-modified nucleotide analogues.
The hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B is an important target for antiviral therapies. NS5B is able to initiate viral RNA synthesis de novo and then switch to a fast and processive RNA elongation synthesis mode. The nucleotide analogue 2'-C-methyl CTP (2'-C-Me-CTP) is the active metabolite of NM283, a drug currently in clinical phase II trials. The resistance mutation S282T can be selected in HCV replicon studies. Likewise, 2'-O-Me nucleotides are active both against the purified polymerase and in replicon studies. We have determined the molecular mechanism by which the S282T mutation confers resistance to 2'-modified nucleotide analogues. 2'-C-Me-CTP is no longer incorporated during the initiation step of RNA synthesis and is discriminated 21-fold during RNA elongation by the NS5B S282T mutant. Strikingly, 2'-O-methyl CTP sensitivity does not change during initiation, but the analogue is no longer incorporated during elongation. This mutually exclusive resistance mechanism suggests not only that "2'-conformer" analogues target distinct steps in RNA synthesis but also that these analogues have interesting potential in combination therapies. In addition, the presence of the S282T mutation induces a general cost in terms of polymerase efficiency that may translate to decreased viral fitness: natural nucleotides become 5- to 20-fold less efficiently incorporated into RNA by the NS5B S282T mutant. As in the case for human immunodeficiency virus, our results might provide a mechanistic basis for the rational combination of drugs for low-fitness viruses.


Observational data: Understanding the real MS world.
Randomised clinical trials are the primary source of evidence, guiding the use of disease-modifying drugs in multiple sclerosis. However, the spectrum of questions that can be answered in the trial setting is relatively narrow. 'Real-world' observational data analysis has always been the major source of evidence for epidemiology, aetiology, outcomes and prognostics, but is now also increasingly used to study treatment effectiveness. While analyses of observational cohorts typically offer superior power, generalisability and duration of follow-up relative to prospective randomised trials, they are also subject to multiple biases. It is the role of researchers to mitigate bias and to ensure the results of observational studies are robust and valid. In this review of observational data research, we provide an overview of the inherent biases, the available mitigation strategies, and the state and direction of contemporary treatment outcomes research. The review will help clinicians critically appraise published results of observational studies.


Crew resource management training--clinicians' reactions and attitudes.
Many health care organizations are adopting crew resource management (CRM) training from the aviation industry as a patient safety practice. Although CRM has high face validity, its effects have not been thoroughly evaluated in aviation or health care. Its potential to improve team communication, coordination, and patient safety, however, makes efforts to study CRM necessary and worthwhile. This article evaluates clinicians' attitudes about and reactions to CRM after they participated in an eight-hour, commercially developed training program.


Still necessary to state the obvious: comment on Alessi, Roll, Reilly, and Johanson (2002).
S. M. Alessi, J. M. Roll. M. P. Reilly, and C.-E. Johanson's (2002) conclusions initially seemed to the author to unnecessarily state the obvious: that the determinants of drug effects and self-administration are not reducible to events within the body. On reflection, however, the author realized that this conclusion is not obvious to many individuals in the broader scientific, professional, and political environment that surrounds the behavioral pharmacology scientific community. Educating these individuals about the concepts, methods, data, and applied implications of behavioral pharmacology is of paramount importance, and one way to do this is to continue to state the obvious.


Seroprevalence of Toxoplasma gondii in cats from St. Kitts, West Indies.
The prevalence of antibodies to Toxoplasma gondii was determined in sera from 106 domestic cats from St. Kitts, West Indies. Using a modified agglutination test, antibodies to this parasite were found in 90 (84.9%) of the cats, with titers of 1:20 in 23 cats, 1:40 in 34 cats, 1:80 in 18 cats, 1:160 in 2 cats, 1:320 in 1 cat, and 1:1,280 or higher in 11 cats. This is the first report of the prevalence of T. gondii infections in cats on St. Kitts and suggests widespread contamination of the environment with oocysts.


Abscopal effect in metastatic breast cancer treated with stereotactic body radiotherapy in the absence of immunotherapy.
In this study, we aimed to assess the abscopal effect (AE) after CyberKnife stereotactic body radiotherapy (SBRT) in metastatic breast cancer patients without immunotherapy. We reviewed breast cancer patients who received SBRT with a fraction size of ≥ 6 Gy for metastatic lesions between July 2008 and December 2021. We selected patients who had at least one measurable extracranial lesion in addition to SBRT target lesions and were not treated with immunotherapy. A total of 40 SBRT cases from 34 patients were included in the analysis. The AE was defined as occurring before the overall progression of the disease, regardless of the use of systemic treatment. The median follow-up duration was 16.4 months. Among 40 SBRT cases, the AE was observed in 10 (25.0%) with a median interval of 2.1 months. Of these lesions, 70.0% did not progress for one year. In multivariate logistic regression analysis, no change in systemic treatment after SBRT was significantly associated with an increase in the AE (odds ratio [OR] = 1.428, 95% confidence interval [CI] = 1.108 - 1.841, p = 0.009). A post-SBRT neutrophil-to-lymphocyte ratio (NLR) of < 2 marginally increased the AE (OR = 1.275, 95% CI = 0.998 - 1.629, p = 0.060). However, a high SBRT dose and large planning target volume did not (p = 0.858 and 0.152, respectively) in univariate analysis. One out of four patients experienced the AE after SBRT in the absence of immunotherapy. The AE could occur more frequently when systemic treatment remains unchanged, and patients have a low NLR after SBRT.


Area of rests of Malassez in young and adult rat molars: evidences in the formation of large rests.
Recently, we have demonstrated that the reduction in the number of rests of Malassez (RM) according to age may be due to epithelial cell death by apoptosis. It is known that, under experimental or pathological conditions, the epithelial cells of RM can proliferate, resulting in the formation of odontogenic cysts and tumors. In this study, the area of RM profiles and the number of profiles of epithelial cell nuclei/RM were investigated in young and adult rats. Fragments containing upper molars of rats aged 29, 45, and 120 days were fixed, decalcified, and embedded for light microscopy. In the sections stained by hematoxylin and eosin, the numerical density of RM profiles/mm(2) of periodontal ligament, the area of each RM profile and the number of epithelial cell nuclei profile/RM were obtained. Moreover, detection of cytokeratin by immunohistochemistry and ultrastructural analysis of RM were carried out. Smaller RM were found in all groups, but the very large RM were only observed in the 120-day-old rats. The presence of cells in close juxtaposition exhibiting cytokeratin filaments in their cytoplasm, including in the large RM, characterized their epithelial nature. The number of epithelial cells/RM varied proportionally to the area. Moreover, epithelial cells in mitosis were found in small and large RM, indicating that cellular proliferation can be responsible for the enlargement of RM, under physiological conditions. The results suggest that a possible disequilibrium between the proliferative and apoptotic processes can be related to the enlargement of some RM in the 120-day-old rats.


Nurse practitioner curriculum for the 21st century: a model for evaluation and revision.
The popularity and acceptance of the nurse practitioner (NP) role, developed in response to a need for additional health care providers, have led to large numbers of educational programs that prepare nurses for NP practice. These programs, following guidelines developed by the National Organization of Nurse Practitioner Faculties Curriculum Guidelines Task Force prepare NPs who are able to provide care to individuals and families throughout the life span. However, in the present health care environment, the NP curriculum constantly must be monitored and evaluated to reflect change. The authors developed a model for curricula revision that incorporates the elements of health policy, community needs and demands, and curriculum goals. This model promotes ongoing reflection on the educational product and assesses graduates' abilities to serve clients and communities within the constraints and opportunities afforded by the current health care system. This model is proactive and embraces the nurse practitioner curriculum guidelines as its core.


Health practices of educators participating in an Idaho wellness conference: one year follow-up.
The Great Potato Health Conference (GPHC), which convenes annually in Idaho, is one of more than 25 statewide wellness conferences for K-12 school personnel. This follow-up study assessed the health practices of conference participants one year following the GPHC. A 25-item health behavior instrument was administered to 68 school district personnel prior to attending the GPHC and again three months, six months, and one year following the conference. Data were analyzed using a repeated measures one-way factorial analysis of variance to test for differences in the health practices of participants over time. Results indicated statistically significant main effects for both previous conference attendance and time of measurement. No statistically significant interaction effect occurred between previous conference attendance and time of measurement.


p53 expression status is a significant molecular marker in predicting the time to endocrine therapy failure in recurrent breast cancer: a cohort study.
Hormone receptor status has been one of the most important factors in predicting the response to endocrine therapy in breast cancer patients. However, half of those patients with estrogen receptor-positive tumors do not respond to endocrine therapy. There have been no universal factors for predicting resistance to endocrine therapy in this population. Recently, p53 status has been extensively used as a predictive factor for response to systemic therapy, because tumor cells lacking p53 function do not respond to systemic therapy due to a failure in apoptosis. We therefore studied the relationship between the efficacy of endocrine therapy and biological factors, including p53. The expression of p53, Ki67, and human epidermal growth factor receptor (HER)2 was examined by immunostaining in the primary tumors of 53 patients who received endocrine therapy for recurrent or advanced breast cancer. The following clinical factors were also analyzed: site treated, disease-free interval, and response to first-line endocrine therapy. To evaluate the significance of these factors, time to endocrine therapy failure (TTEF), or the total duration of sequential endocrine therapies was adopted as representing the clinical outcome. The median TTEF was 16.1 months (range, 2.5-89.9 months). Multivariate analysis showed significantly reduced TTEF associated with no response to first-line endocrine therapy (P = 0.006 and P = 0.002 in all patients and in recurrent patients, respectively) and associated with positive p53 expression (P = 0.066 and P = 0.004, respectively). p53 expression status was a significant molecular marker as well as the response to first-line endocrine therapy for predicting TTEF in recurrent breast cancer with hormone-sensitive disease.


Attachment-related dimensions in the epigenetic era: A systematic review of the human research.
In recent years, an increasing number of studies documented potential links between parental care and epigenetic mechanisms. The present systematic review focuses on the potential association and interrelationship between attachment-related dimensions and DNA methylation in human studies. We performed a literature review using electronic databases such as PubMed, Scopus, Web of Science, and EBSCOhost. Thirteen papers were included in the review. Findings support significant associations between attachment-related dimensions and epigenetic status in studies which considered different populations, age ranges, attachment measures and peripheral tissues. Although research in this area is still under investigation, available results suggest that DNA methylation associated with attachment-related dimensions might affect the development of stress regulation system and social-emotional capacities, thus contributing to the emerging phenotypic outcomes. However, identifying mediator and moderator effects in the interrelationship between these parameters was problematic owing to heterogeneous methodologies. Finally, we discuss clinical implications, unanswered questions, and future directions for human development in epigenetics research.


The Development of the Brooding Scale.
The purpose of this study was to develop a Brooding Scale (BS) and to confirm its psychometric properties. A preliminary questionnaire was developed based on a literature review and face-to-face interviews with healthy subjects. To evaluate reliability and construct validity, a 15-item BS was administered to 124 healthy subjects. Convergent validity was tested by assessing the relationship between the BS and the Ruminative Response Scale (RRS). Discriminant validity was confirmed in 58 patients with schizophrenia. The internal consistency for the BS was excellent. An exploratory factor analysis yielded two factors: the emotional (six items) and cognitive (five items) domains, which explained 33.83% and 23.69% of the variance, respectively. The BS total score and scores for factors 1 and 2 showed significant positive correlations with the RRS. The total score and sub-factor scores of the BS were significantly higher in patients with schizophrenia than in healthy subjects. The BS can be used as a reliable and valid tool to assess brooding in healthy adults. In addition, it had good discriminant validity for patients with schizophrenia.


Anti-coagulant and anti-thrombotic effects of some protease inhibitors.
Several synthetic tri-peptide enzyme inhibitors of the general sequence Phe-Pro-Arg were studied in vitro and in vivo. Extent and specificity of inhibition of thrombin were different. The inhibitors exert anti-coagulant effects in vitro. The anti-coagulant effect in vivo was used as a measure of bioavailability and duration of action. The tri-peptide inhibitors are rapidly eliminated from the circulation and produce a decrease in blood pressure. Anti-thrombotic effects were demonstrated in a thrombosis model in rabbits.


Enhancement of closed-state inactivation in long QT syndrome sodium channel mutation DeltaKPQ.
DeltaKPQ, a three amino acid [lysine (K), proline (P), glutamine (Q)] deletion mutation of the human cardiac Na channel (hH1), which is one cause of long QT syndrome (LQT3), has impaired inactivation resulting in a late sodium current. To better understand inactivation in DeltaKPQ, we applied a site-3 toxin anthopleurin A, which has been shown to inhibit inactivation from the open state with little or no effect on inactivation from the closed state(s) in wild-type hH1. In contrast to the effect of site-3 toxins on wild-type hH1, inactivation from closed state(s) in toxin-modified DeltaKPQ demonstrated a large negative shift in the Na channel availability curve of nearly -14 mV. Recovery from inactivation showed that toxin-modified DeltaKPQ channels recovered slightly faster than those in control, whereas development of inactivation at potentials negative to -80 mV showed that inactivation developed much more rapidly in toxin-modified DeltaKPQ channels compared with control. An explanation for our results is that closed-state inactivation in toxin-modified DeltaKPQ is enhanced by the mutated inactivation lid being positioned "closer" to its receptor resulting in an increased rate of association between the inactivation lid and its receptor.


[An epidemic of typhoid fever among the German troops in Paris, Christmas 1941].
In 1941, at Christmastime more than 600 German soldiers visited Paris and were infected with the bacillus of Eberth, the agent of typhoid fever. All of the infections occurred at the Brasserie La Brune situated in the center of Paris. It was, in fact, an act of Resistance. The proof of the infection was rapidly given by Lucien Brumpt using a home-made hemodiagnostic method. This quick hemodiagnostic technique is easy to perform, inexpensive and still could be used.


Progressive dyspnea in patient with large mediastinal mass.
Liposarcoma occurs very rarely in the mediastinum. Patients often remain asymptomatic until it grows large enough to cause direct invasion or compression of adjacent organs. We report a case of a 77-year-old male presented with dyspnea of exertion and was found to have a large mediastinal mass which was eventually diagnosed as primary mediastinal well-differentiated liposarcoma. The limited respiratory function at the initial presentation prompted phrenic nerve preserving incomplete resection rather than radical removal of the adjacent mediastinal structures. After surgical removal, the recurrence for well-differentiated mediastinal liposarcomas in the mediastinum is unknown; therefore, close follow-up is crucial.


Understanding adipose tissue development from transgenic animal models.
The World Health Organization has recognized obesity as a health problem of pandemic proportions. Recent work led to major breakthroughs in the understanding of the molecular basis of adipose tissue development with the cloning and characterization of numerous genes involved in fat cell differentiation and metabolism. Transgenesis has proved very useful in establishing the physiological roles of these genes. Here we review transgenic models made to study adipose tissue's metabolic and trophic responses. Genetic modifications unexpectedly associated to alterations of adipose tissue development are also examined because of their potential involvement in obesity and energy balance regulation. After a description of the methodologies commonly used, we review the data obtained on transcription factors, metabolism, signal transduction, secreted products, and models of lipodystrophy. An overview of such integrative studies leads to a better understanding of the physiology of adipose tissue development. Alterations in expression levels of proteins involved at different steps of a regulatory pathway highlight the complementary roles of genes in the regulation of adipose tissue development. However, lack of phenotypes also illustrates the capacity of animals to set up adaptive mechanisms.