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Summary: Rett syndrome (RTT) is a neurodevelopmental disorder that is characterized by developmental regression, loss of communicative ability, stereotyped hand wringing, cognitive impairment, and central apneas, among many other symptoms. RTT is caused by loss-of-function mutations in a methyl-reader known as methyl-CpG-binding protein 2 (MeCP2), a protein that links epigenetic changes on DNA to larger chromatin structure. Historically, target identification for RTT has relied heavily on Mecp2 knockout mice; however, we recently adopted the alternative approach of performing transcriptional profiling in autopsy samples from RTT patients. Through this mechanism, we identified muscarinic acetylcholine receptors (mAChRs) as potential therapeutic targets. Here, we characterized a cohort of 40 temporal cortex samples from individuals with RTT and quantified significantly decreased levels of the M1, M2, M3, and M5 mAChRs subtypes relative to neurotypical controls. Of these four subtypes, M1 expression demonstrated a linear relationship with MeCP2 expression, such that M1 levels were only diminished in contexts where MeCP2 was also significantly decreased. Further, we show that M1 potentiation with the positive allosteric modulator (PAM) VU0453595 (VU595) rescued social preference, spatial memory, and associative memory deficits, as well as decreased apneas in Mecp2+/- mice. VU595's efficacy on apneas in Mecp2+/- mice was mediated by the facilitation of the transition from inspiration to expiration. Molecular analysis correlated rescue with normalized global gene expression patterns in the brainstem and hippocampus, as well as increased Gsk3β inhibition and NMDA receptor trafficking. Together, these data suggest that M1 PAMs could represent a new class of RTT therapeutics. [ABSTRACT FROM AUTHOR]

Lactobacillus casei N87 and L. casei N2014, cultivated in anaerobic and respiratory conditions, were used as adjuncts for the production of Cheddar-type cheeses. Cheese inoculated only with a defined lactococcal starter was used as control. After 14, 30, 60, 120 and 180 days of ripening, microbial counts, gross composition, proteolysis, production of volatile organic compounds, radical scavenging activity and lipid and protein oxidation were evaluated. The addition of anaerobic or respirative cultures of L. casei N87 and N2014 did not affect cheese composition and primary proteolysis. Respirative cells increased the production of free amino acids, peptides, diacetyl and acetoin and reduced the content of free radicals as well as lipid and protein oxidation. The lower redox potential in Cheddar-type cheeses produced with respirative cells also contributed to the reduction of oxidation processes. Respirative strains of L. casei could be successfully used to improve the organoleptic and nutritional properties of dairy products. [ABSTRACT FROM AUTHOR]

In this paper we investigate the instabilities arising in a flow through a compressor passage using BiGlobal stability analysis. The adopted geometry comes from the results of previous experimental and numerical investigations on a linear low-pressure (LP) compressor cascade [6,19,20] . Specifically, we address the role of laminar separation of the boundary layers at Re = 138 , 500 , where such separation effects are enhanced by the strong adverse pressure gradients that the flow experiences, in contrast to the more commonly studied low-pressure (LP) turbines. The vortical structures downstream the separation bubble on the suction surface were recognised to show a well-defined time periodicity, which could be precisely detected. Floquet stability analysis was then used to investigate the response of the flow to infinitesimal perturbations. To overcome the difficulty of performing a Floquet stability analysis when the periodicity is restricted just to a small region of the domain, a phase-averaged base flow was computed, such that only the organised motions are extracted, neglecting all the background unsteadiness. The same technique allowed us to confirm the presence of strong energy transient growth phenomena, which are directly associated with convective instabilities occurring in the region downstream from the separation bubble. [ABSTRACT FROM AUTHOR]

Abstract: The ever increasing life expectancy in the general population has prompted the multiplication of institutional reports focusing on the surgical management of the “elderly” with lung cancer. In fact, there is no consensus on the age cutoff, the risk assessment protocols, and, modalities for continuation of postsurgical care. Moreover, the definition of age in the biomolecular era is destined to alter our current concept of elderly surgical candidates by implementing prognostic group stratification based on genomic profiling. The latter, along with an unprecedented attempt at reducing functional thresholds for surgery, the introduction of a holistic approach to geriatrics, and, the consolidation and further refinement of minimally invasive surgery will represent a cultural revolution for the surgeon dealing with the elderly lung cancer patient. [Copyright &y& Elsevier]

Several issues regarding the surgical management of N2 disease remain unresolved. First, the anatomical attribution of a mediastinal nodal station, especially in certain areas (i.e., azygos recess), is a source of continuous debate. Second, the presence of occult N2, single or multilevel N2, bulky N2, the skip phenomenon and the observation of a different prognostic outlook for specific mediastinal nodal stations are all elements of discussion that cannot clarify whether stage IIIA-N2 non-small cell lung cancer is indeed a locally, albeit advanced, manifestation of the disease or the prodrome of an actual systemic dissemination. In this subset of patients lies the challenge for multidisciplinary treatment modalities, where the surgical role needs to be further defined in the context of an integrated collaborative effort with the medical oncologist and the radiotherapist. [ABSTRACT FROM AUTHOR]

Introduction: Since the early 1990s, many studies have shown lower mortality for abdominal aortic aneurysm (AAA) repair at high-volume centers compared with low-volume centers. The introduction of endovascular AAA repair (EVAR) also has changed the practice of AAA repair. The goal of this study was to determine if regionalization of AAA repair occurred in the United States. Etiologic factors were examined in addition to any reduction in operative mortality rates. Methods: Patient discharges of nonruptured AAA repair were identified from the Nationwide Inpatient Sample between 1998 and 2004. Hospitals were stratified by yearly AAA surgical volume of low (≤17 cases), medium (18 to 50), and high (>50). Results: A total of 46,901 patients underwent AAA repair (72.7% open vs 27.3% endovascular). The percentage of AAA repairs performed at both low-volume (36.2% to 24.3%) and medium-volume (51.0% to 44.8%) centers fell; whereas, the percentage performed at high-volume centers nearly tripled (12.9% vs 30.9%). In 1998 there were 10 high-volume centers; by 2004 this had increased to 26. The number of low-volume centers decreased, from 412 to 328. EVAR was more rapidly adopted by high-volume centers compared with low-volume centers. By 2004, 64.3% of AAA repairs at high-volume centers were done with endovascular techniques compared with 31.8% in low-volume centers. A concurrent reduction occurred in patient mortality, from 4.4% in 1998 to 2.5% in 2004 (P < .0001). Conclusion: Between 1998 and 2004, a trend towards the regionalization of AAA repair to high-volume centers occurred. Nearly one-third of all AAA repairs were performed at high-volume centers. There was a concurrent increase in the frequency of endovascular AAA repair, especially at high-volume centers. During this period of regionalization of AAA repair to high-volume centers, patient mortality after AAA repair decreased by 23%. Thus, the observed regionalization of AAA repair and the reduction in short-term patient mortality for this operation may be explained by increased utilization of endovascular technologies at high-volume centers. [Copyright &y& Elsevier]

We assessed the impact on patient outcomes of comorbidities and type of aneurysm repair, open vs. endovascular aortic repair (EVAR). Functional health status was measured prospectively using the Short Form 36 (SF-36) Health Survey. Length of stay (LOS) and need for postdischarge resources (nursing and rehabilitation) were compared between groups. We reviewed the records of 218 patients (126 open, 92 EVAR) who underwent intervention between 1998 and 2003. The SF-36 was completed preoperatively and at intervals ranging from 2 weeks to 1 year after intervention. To identify factors impacting outcome, univariate and multivariate analyses were performed. Overall mortality was 1.9%: 3.2% for open repair and 0% for EVAR ( p = 0.13). Physical and mental health were higher during the 3 months following EVAR compared with open repair: physical function (PF) (65.2 ± 4.1 vs. 54.0 ± 4.1), vitality (VT) (55.5 ± 2.5 vs. 44.9 ± 3.4), and emotional role (ER) (74.9 ± 5.0 vs. 51.4 ± 6.7) (analysis of variance p < 0.05). Women following EVAR had decreased physical summary scores (PSS) (34.8 ± 2.5 vs. 40.4 ± 1.1, p < 0.05) compared with men postprocedure despite no difference preoperatively. Congestive heart failure (CHF) was an independent factor that negatively impacted PF, body pain (BP), and PSS. EVAR was associated with improved VT and ER. Differences among open repair and EVAR diminished over time. LOS (in days) was greater for open vs. EVAR (9.2 ± 0.78 vs. 2.0 ± 0.17) and in women following both open (11.8 ± 1.5 vs. 8.0 ± 0.9) and EVAR (3.2 ± 0.9 vs. 1.8 ± 0.1) procedures ( p < 0.05). Factors that adversely affected LOS were open repair, age, renal insufficiency, pulmonary disease, CHF, and female gender. Following EVAR, patients were less likely to require home care or transfer to a rehabilitation facility than after open repair (14.1 vs. 36.0%, p < 0.05). Women were significantly more likely to require postdischarge care after open repair (48.7 vs. 30.1%) and EVAR (41.7 vs. 10.0%) ( p < 0.05). Logistic regression identified female gender, open repair, advanced age, and pulmonary disease as independent predictors of need for postdischarge care. Those patients undergoing abdominal aortic aneurysm (AAA) repair by open technique (compared to EVAR) had significantly impaired functional health with regard to PF, VT, and ER in the first 3 months after surgery. CHF and hypertension also significantly impaired individual functional health scores. Of significance was that female gender was associated with increased LOS and increased utilization of postdischarge nursing and rehabilitation resources following both open and endovascular surgery for AAA. [ABSTRACT FROM AUTHOR]

We evaluated the transfer of patients with the diagnosis of a ruptured AAA (rAAA) from community centers to a tertiary care center. Our purpose was to identify factors associated with mortality and outcomes following the open repair of rAAA and to evaluate the differences between transferred and nontransferred patients. All patients who underwent repair of rAAA at our institution between 1995 and 2002 were retrospectively reviewed. Univariate and multivariate analysis was performed to identify patient specific factors on presentation and intraoperatively. Fifty-two patients underwent repair of rAAA, 20 patients were transferred to our institution. The overall mortality rate was 67%. The mortality rates for nontransferred and transferred groups were 69% and 65%, respectively. The incidence of mortality within 24 hr of surgery was significantly higher in the patients who were not transferred, 10 vs. 41% (p<0.05). Patient-specific factors assessed for impact on survival by logistic regression included decreased body temperature on arrival to our institution (p= 0.02) and free rupture (p= 0.05). Of intraoperative factors tested, low systolic blood pressure was significantly associated with mortality (p= 0.05). No difference in total length of stay was noted. Transfer patients’ length of stay in the intensive care unit was significantly greater than that of nontransferred patients (18.8 ± vs. 7.3 ± days,p<0.05). The difference in ICU cost was $36,000 among groups. We found the acceptance of transfer patients from community centers with rAAA did not adversely affect patient survival. Transferred patients had an over twofold increases in ICU days used. The identification of hypothermia was the single independent factor associated with poor survival and may be a marker for transfer selection. Given reduced reimbursements and increased utilization, tertiary care centers will need to consider the economic ramifications of accepting transfer patients with rAAA. [ABSTRACT FROM AUTHOR]

Abstract Stress can precipitate or worsen symptoms of many psychiatric illnesses. Dysregulation of the prefrontal cortex (PFC) glutamate system may underlie these disruptions and restoring PFC glutamate signaling has emerged as a promising avenue for the treatment of stress disorders. Recently, we demonstrated that activation of metabotropic glutamate receptor subtype 3 (mGlu 3) induces a postsynaptic form of long-term depression (LTD) that is dependent on the activity of another subtype, mGlu 5. Stress exposure disrupted this plasticity, but the underlying signaling mechanisms and involvement in higher-order cognition have not yet been investigated. Acute stress was applied by 20-min restraint and early reversal learning was evaluated in an operant-based food-seeking task. We employed whole-cell patch-clamp recordings of layer 5 prelimbic (PL)-PFC pyramidal cells to examine mGlu 3 -LTD and several mechanistically distinct mGlu 5 -dependent functions. Acute stress impaired both mGlu 3 -LTD and early reversal learning. Interestingly, potentiating mGlu 5 signaling with the mGlu 5 positive allosteric modulator (PAM) VU0409551 rescued stress-induced deficits in both mGlu 3 -LTD and reversal learning. Other aspects of PL-PFC mGlu 5 function were not disrupted following stress; however, signaling downstream of mGlu 5 -Homer interactions, phosphoinositide-3-kinase (PI3K), Akt, and glycogen synthase kinase 3β was implicated in these phenomena. These findings demonstrate that acute stress disrupts early reversal learning and PL-PFC-dependent synaptic plasticity and that potentiating mGlu 5 function can restore these impairments. These findings provide a framework through which modulating coordinated mGlu 3 /mGlu 5 signaling may confer benefits for the treatment of stress-related psychiatric disorders. Highlights • PL-PFC mGlu 3 /mGlu 5 -LTD requires PI3K-Akt signaling, and not Ca2+ mobilization. • Acute stress disrupts mGlu 3 /mGlu 5 -LTD without a gross impairment to mGlu 5 function. • Potentiating mGlu 5 rescues LTD deficit following acute restraint stress. • Potentiating mGlu 5 ameliorates reversal learning deficit following acute stress. [ABSTRACT FROM AUTHOR]

Abstract: Background: This study reports the methods used to review the Composite Performance Score (CPS) along with a reference table, which will be used in the upcoming ESTS Quality Certification Program. Methods: Data from 4303 patients who underwent pulmonary resection (July 2007–January 2010) were captured in the ESTS database and used for the present analysis. Only patients submitted from units contributing at least 100 consecutive lung resections were used for developing the score. According to the best available evidence the following measures were selected for each surgical domain: preoperative care (1. % of DLCO measurement in patients submitted to major anatomic resections; 2. % of preoperative invasive mediastinal staging in patients with clinically suspicious N2 disease), operative care (% of systematic lymph node dissection), outcomes (risk-adjusted cardiopulmonary morbidity and mortality rates). Morbidity and mortality risk-models were developed by logistic regression and validated by bootstrap analyses. Individual processes and outcomes scores were rescaled according to their standard deviations and summed to generate the CPS. Units were rated accordingly and a percentile reference table was produced. Results: Risk-adjusted survival and absence of morbidity rates varied from 91.5% to 100%, and from 50.2% to 97.5%, respectively. CPS ranged from −4.038 to 1.24. The 50% percentile of CPS corresponded to 0.404. Conclusions: A revised Composite Performance Score was developed and a reference table presented to be used as a benchmark for the ESTS Quality Certification program. [ABSTRACT FROM AUTHOR]

Adaptive Laboratory Evolution (ALE) is a powerful tool to improve the fitness of industrially relevant microorganisms, because it circumvents some of the problems related to the use of genetically modified strains. In this study, we used an ALE strategy involving serial batch cultivations in aerobic and respiratory conditions to generate spontaneous mutants from the respiration-competent strain Lacticaseibacillus casei N87. Genotypic changes in selected mutants were investigated using whole genome sequencing (WGS). The O 2 -tolerant Lactiplantibacillus plantarum C17 and its mutant C17-m58 (obtained from a previous ALE study) were included in heme uptake experiments and in WGS and variant calling analyses. Several Lcb. casei N87 mutants cultivated under aerobic and respiratory conditions showed improved biomass production, O 2 uptake and oxidative stress tolerance compared to the parental strain. Mutants of Lcb. casei and Lpb. plantarum differed from the parental strains in the ability to use heme and menaquinone. High heme concentrations (> 10 mg/L), however, were toxic for all strains. Single nucleotide modifications (SNPs) were detected in some genes encoding for proteins and transcriptional regulators involved in carbon metabolism, oxidative stress, redox balance, and cell wall properties, but their role in the evolved phenotypes needs further investigations. We conclude that prolonged adaptation to aerobic and respiratory life-style may be used as natural strategy to generate strains with improved O 2 -consuming ability and oxidative stress tolerance, two important features to develop robust cultures and to reduce oxidative processes in foods. • ALE strategy improved growth performances in several mutants of Lacticaseibacillus casei N87. • Mutants of Lcb. casei and Lpb. plantarum differed from the parental strains in the ability to use heme and menaquinone. • SNPs were found in genes involved in carbon metabolism, redox balance, cell wall properties. • Mutants obtained in this study may be useful for several applications. [ABSTRACT FROM AUTHOR]

An orange-coloured protein (ORP) isolated from Desulfovibrio gigas, a sulphate reducer, has been previously shown by extended X-ray absorption fine structure (EXAFS) to contain a novel mixed-metal sulphide cluster of the type [S2MoS2CuS2MoS2] [J. Am. Chem. Soc. 122 (2000) 8321]. We report here the purification and the biochemical/spectroscopic characterisation of this novel protein. ORP is a soluble monomeric protein (11.8 kDa). The cluster is non-covalently bound to the polypeptide chain. The presence of a MoS42- moiety in the structure of the cofactor contributes with a quite characteristic UV–Vis spectra, exhibiting an orange colour, with intense absorption peaks at 480 and 338 nm. Pure ORP reveals an Abs480/Abs338 ratio of 0.535. The gene sequence coding for ORP as well as the amino acid sequence was determined. The putative biological function of ORP is discussed. [Copyright &y& Elsevier]

Polymorphisms in GRM3 , the gene encoding the mGlu 3 metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu 3 receptors regulate synaptic plasticity and cognition. We examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu 3 receptor expression in specific neuronal subpopulations. mGlu 3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu 3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through an mGlu 5 receptor–dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu 3 or mGlu 5 from hippocampal pyramidal cells eliminated effects of mGlu 3 activation, revealing a novel mechanism by which mGlu 3 and mGlu 5 interact to enhance cognitive function. These data demonstrate that activation of mGlu 3 receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function, providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu 3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases. [ABSTRACT FROM AUTHOR]

Background: Cancer may cause financial difficulties, but its impact in countries with public health systems is unknown. We evaluated the association of financial difficulties with clinical outcomes of cancer patients enrolled in academic clinical trials performed within the Italian public health system. Patients and methods: Data were pooled from 16 prospective multicentre trials in lung, breast or ovarian cancer, using the EORTC quality of life (QOL) C30 questionnaire. Question 28 scores financial difficulties related to disease or treatment in four categories from 'not at all' to 'very much'. We defined financial burden (FB) as any financial difficulty reported at baseline questionnaire, and financial toxicity (FT) as score worsening in a subsequent questionnaire. We investigated (i) the association of FB with clinical outcomes (survival, global QOL response [questions 29/30] and severe toxicity), and (ii) the association of FT with survival. Multivariable analyses were performed using logistic regression models or the Cox model adjusting for trial, gender, age, region and period of enrolment, baseline global QOL and, where appropriate, FB and global QOL response. Results are reported as odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI). Results: At baseline 26% of the 3670 study patients reported FB, significantly correlated with worse baseline global QOL. FB was not associated with risks of death (HR 0.94, 95% CI 0.85-1.04, P = 0.23) and severe toxicity (OR 0.90, 95% CI 0.76-1.06, P = 0.19) but was predictive of a higher chance of worse global QOL response (OR 1.35, 95% CI 1.08-1.70, P = 0.009). During treatment, 2735 (74.5%) patients filled in subsequent questionnaires and 616 (22.5%) developed FT that was significantly associated with an increased risk of death (HR 1.20, 95% CI 1.05-1.37, P = 0.007). Several sensitivity analyses confirmed these findings. Conclusion: Even in a public health system, financial difficulties are associated with relevant cancer patients outcomes like QOL and survival. [ABSTRACT FROM AUTHOR]

This manuscript provides recommendations for the diagnosis, treatment and follow-up of early stage non-small cell lung cancer developed during the 2nd ESMO Consensus Conference on Lung Cancer in May 2013To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11–12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease. [ABSTRACT FROM AUTHOR]

Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) have opposing molecular origins in relation to expression and function of the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2). Several clinical and preclinical phenotypes, however, are shared between these disorders. Modulation of MeCP2 levels has recently emerged as a potential treatment option for both of these diseases. However, toxicity concerns remain with these approaches. Here, we focus on pharmacologically modulating the group II metabotropic glutamate receptors (mGlu), mGlu 2 and mGlu 3 , which are two downstream targets of MeCP2 that are bidirectionally affected in expression in RTT patients and mice (Mecp2 Null/+ ) versus an MDS mouse model (MECP2 Tg1/o ). Mecp2 Null/+ and MECP2 Tg1/o animals also exhibit contrasting phenotypes in trace fear acquisition, a form of temporal associative learning and memory, with trace fear deficiency observed in Mecp2 Null/+ mice and abnormally enhanced trace fear acquisition in MECP2 Tg1/o animals. In Mecp2 Null/+ mice, treatment with the mGlu 2/3 agonist LY379268 reverses the deficit in trace fear acquisition, and mGlu 2/3 antagonism with LY341495 normalizes the abnormal trace fear learning and memory phenotype in MECP2 Tg1/o mice. Altogether, these data highlight the role of group II mGlu receptors in RTT and MDS and demonstrate that both mGlu 2 and mGlu 3 may be potential therapeutic targets for these disorders. [Display omitted] • mGlu 2 /mGlu 3 receptors are decreased in Rett syndrome patients and mice, Mecp2 Null/+ • mGlu 2 /mGlu 3 receptors are increased in MECP2 Duplication syndrome mice, MECP2 Tg1/o • mGlu 2/3 activation rescues trace fear acquisition deficits in Mecp2 Null/+ mice • mGlu 2/3 inhibition reverses heightened trace fear acquisition in MECP2 Tg1/o mice [ABSTRACT FROM AUTHOR]