Miracle-dz/UniFAR-FTUs huggingface dataset:
Neuronavigation in der Zentralregion: Bedeutung für einzelne Operationsphasen bei verschiedenen Prozesslokalisationen

The neurosurgical treatment of space occupying processes in the central area bears a relatively high risk of either postoperative neurological deficits ("radical approach") or of residual tumor ("conservative approach"). Therefore, special techniques of intraoperative topographic orientation (image-guided surgery) play an important role here. The possible impact of neuronavigation on different neurosurgical steps (craniotomy, corticotomy, localization of the process, definition of borders of resection) was studied in relation to the site of pathology (extraaxial, intraaxial/superficial, intraaxial/deep) in 46 patients harbouring space occupying lesions of the central area. In intraaxial pathologies, additional electrophysiological monitoring was done. It could be shown, that in cases of deep seated processes, neuronavigation had the greatest impact on craniotomy, corticotomy and localization of the process, whereas the borders of resection were defined predominantly on the basis of differences in colour or consistency. In extraaxial pathologies, neuronavigation was of significance only for craniotomy; in intraaxial processes visible at the surface, it had an impact on craniotomy and--in a few cases--on definition of resection borders. In neurosurgery of intraaxial pathologies of the central area (particularly those not visible at the surface), the use of neuronavigation (or another method of intraoperative localization) in combination with neurophysiologic monitoring is strongly recommended.
β2 integrins inhibit TLR responses by regulating NF‐κB pathway and p38 MAPK activation

Outside‐in signals from β2 integrins require immunoreceptor tyrosine‐based activation motif adapters in myeloid cells that are known to dampen TLR responses. However, the relationship between β2 integrins and TLR regulation is unclear. Here we show that deficiency in β2 integrins (Itgb2−/−) causes hyperresponsiveness to TLR stimulation, demonstrating that β2 integrins inhibit signals downstream of TLR ligation. Itgb2−/− macrophages and dendritic cells produced more IL‐12 and IL‐6 than WT cells when stimulated with TLR agonists and Itgb2−/− mice produced more inflammatory cytokines than WT mice when injected with LPS. TLR hypersensitivity was not the result of insufficient ABIN‐3, A20, Hes‐1, or IRAK‐M expression, nor to changes in IL‐10 production or sensitivity, though Itgb2−/− macrophages had reduced p38 MAPK phosphorylation after LPS treatment. Furthermore, a Cbl‐b‐MyD88 regulatory axis is not required for TLR inhibition in macrophages. Instead, Itgb2−/‐ macrophages presented with enhanced IκBα degradation, leading to changes in NF‐κB recruitment to target promoters and elevated cytokine, chemokine, and anti‐apoptotic gene transcription. Thus, β2 integrins limit TLR signaling by inhibiting NF‐κB pathway activation and promoting p38 MAPK activation, thereby fine‐tuning TLR‐induced inflammatory responses.
Determining Change in Self-Perceived Knowledge and Skills About Disease/ Medication Therapy Management Programs in P3 Students

The study objectives were to determine a change in the self-perceived knowledge and skills of the third-professional year Doctor of Pharmacy students after taking a course on developing, implementing, and evaluating a disease/medication therapy management program. The study used a cross-sectional before-and-after design in which the data were collected once at the beginning of the course and then upon course completion. A self-administered questionnaire that had 4 sections and 36 questions, focusing on self-perceived knowledge and skills was administered. The data were analyzed using SPSS version 14.0. Descriptive statistics, paired sample t tests, and repeated measures analysis of variance were conducted. A total of 95 students completed the pretest, and 69 students completed the posttest. There was an overall increase in average self-perceived knowledge and skills about disease/medication therapy management programs after the students completed the course. Therefore, classes focusing on disease/medication therapy management can significantly increase the knowledge and skills about these programs for the Doctor of Pharmacy students who will soon enter professional careers and be expected to perform these services.
A natural tapasin isoform lacking exon 3 modifies peptide loading complex function

To assure efficient MHC class I (MHC‐I) peptide loading, the peptide loading complex (PLC) recruits the peptide‐receptive form of MHC‐I, and in this process, tapasin (tpn) connects MHC‐I with the peptide transporter TAP and forms a stable disulfide bond with ERp57. Here, we describe an alternatively spliced tpn transcript lacking exon 3, observed in cells infected with human cytomegalovirus. Recognition of exon 3 was regulated via G‐runs, suggesting that members of the hnRNP (heterogeneous nuclear ribonucleoprotein)‐family regulate expression of the ΔExon3 variant of tpn. Exon 3 includes Cys‐95, which is responsible for the disulfide bond formation with ERp57 and, consequently, interaction of the ΔExon3 variant with ERp57 was strongly impaired. Although the ΔExon3 variant specifically stabilized TAP expression but not MHC‐I in tpn‐deficient cells, in tpn‐proficient cells, the ΔExon3 tpn reduced cell surface expression of the tpn‐dependent HLA‐B*44:02 allele; the stability of the tpn‐independent HLA‐B*44:05 was not affected. Most importantly, detailed analysis of the PLC revealed a simultaneous binding of the ΔExon3 variant and tpn to TAP, suggesting modification of PLC functions. Indeed, an altered MHC‐I ligandome was observed in HeLa cells overexpressing the ΔExon3 variant, highlighting the potential of the alternatively spliced tpn variant to impact CD8+ T‐cell responses.
Supraventricular tachyarrhythmias and their management in the perioperative period

This review will provide an overview of supraventricular tachycardias (SVTs), their classification, diagnostic features, and management in the perioperative period of adult non-cardiac surgery. The term ‘SVT’ refers to paroxysmal tachyarrythmias that require atrial or atrioventricular (AV) nodal tissue, or both, for their initiation and maintenance. The incidence of persistent SVT is 2% before operation and 6% in the postoperative period. In non-cardiac surgery, perioperative arrhythmias are more likely to be supraventricular than ventricular in origin. Atrial arrhythmias occur most frequently 2–3 days post-surgery similar to perioperative acute coronary syndromes and are likely related to sympathetic stimulation associated with an inflammatory response. Other precipitants of SVT often associated with high sympathetic tone are summarized in Table 1. Such arrhythmias are important for the anaesthetist; in particular, atrial fibrillation (AF) is associated with haemodynamic derangement, postoperative stroke, perioperative myocardial infarction, ventricular arrhythmia, heart failure, and longer hospital stay.
Recent cocaine and crack use among new drug treatment clients in Scotland

UK and US literature indicate that cocaine and crack users experience multiple problems and poor treatment outcomes (Gossop et al., 2002, 2003). Using data collected as part of a Scottish national evaluation of drug treatment effectiveness, this paper: (i) provides information on the nature and extent of recent cocaine and crack use among 585 new drug treatment clients; and (ii) investigates whether those who had recently used cocaine and/or crack comprised distinct treatment subpopulations. Data were analysed using chi-square tests of association (or Fisher's exact tests), ANOVA and stepwise multivariate logistic regression. Although more respondents than anticipated reported cocaine and/or crack use, consumption was generally infrequent and not considered problematic. Recent cocaine and/or crack users were more likely than other respondents to have taken non-prescribed benzodiazepines in the last 90 days; be seeking residential treatment; have recently committed acquisitive crime; have been robbed, attacked or assaulted in the last six months; have a spouse or partner; and have a longer history of problematic drug use. In contrast, few differences between those who had recently used ‘cocaine only’, ‘crack only’, and ‘both cocaine and crack’ were found. It is concluded that drug agency staff in Scotland must be alert to, and have the resources and training to deal with, the complex needs of the increasing numbers of cocaine and crack users approaching their services.
Induced and thymus‐derived Foxp3+ regulatory T cells share a common niche

Foxp3+ regulatory T (Treg) cells, which play a central role for the maintenance of immune homeostasis and self‐tolerance, are known to be both generated in the thymus (thymus‐derived, tTreg cells) and in the periphery, where they are converted from conventional CD4+ T cells (induced Treg (iTreg) cells). Recent data suggest a division of labor between these two Treg‐cell subsets since their combined action was shown to be essential for protection in inflammatory disease models. Here, using the transfer colitis model, we examined whether tTreg cells and iTreg cells fill different niches within the CD4+ T‐cell compartment. When naive T cells were co‐transferred with either pure tTreg cells or with a mixture of tTreg cells and iTreg cells, induction of Foxp3+ Treg cells from naive T cells was not hampered by preoccupation of the Treg‐cell niche. Using neuropilin‐1 (Nrp1) as a surface marker to separate tTreg cells and iTreg cells, we demonstrate that tTreg cells and iTreg cells alone can completely fill the Treg‐cell niche and display comparable TCR repertoires. However, when transferred together Nrp1+ tTreg cells outcompeted Nrp1− iTreg cells and dominated the Treg‐cell compartment. Taken together, our data suggest that tTreg cells and iTreg cells share a common peripheral niche.
Efficacy and safety of micafungin for the treatment of patients with proven or probable invasive aspergillosis

Introduction: Few studies have assessed the efficacy and safety of micafungin in patients with proven or probable invasive aspergillosis (IA). This was the aim of the current study, which was conducted in 22 hospitals in China, where micafungin was approved for treatment of IA in 2006. Methods: This was a non-comparative, phase IV open-label study (NCT02646774). Eligible patient were adults with proven or probable IA. Efficacy endpoints included rates of overall treatment success (primary endpoint) and clinical improvement, fungal clearance, mortality, and the site of Aspergillus infection (all secondary endpoints). Safety endpoints included incidences of treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and adverse drug reactions (ADRs). These endpoints were reported descriptively with associated 95% confidence intervals (CI); no hypotheses were tested. Results: The study was discontinued early due to low patient recruitment, which did not allow for the planned sample size to be reached. In total, 68 patients were enrolled: 42 into the full analysis set (for efficacy) and 61 into the safety analysis set. All patients were Han Chinese; the majority were male (n = 26; 61.9%) and ⩽60 years of age (n = 35; 83.3%). Rates of overall treatment success, clinical improvement, fungal clearance, and mortality were 45.2% (n = 19/42; 95% CI: 29.85–61.33); 59.5% (n = 25/42; 95% CI: 43.28–74.37), 80.0% (n = 4/5; 95% CI: 28.36–99.49), and 7.1% (n = 3/42; 95% CI: 1.50–19.48), respectively. All patients were diagnosed with pulmonary Aspergillus infection. Overall, 155 TEAEs and 8 SAEs were reported by 37 (60.7%) and 7 (11.5%) patients. The most common TEAEs were decreased platelet count and fatigue (both n = 5; 8.2%) and the most common SAEs were intracranial hemorrhage and lung infection (n = 3; 4.9% and n = 2; 3.3%). Eight ADRs (n = 6; 9.8%) were reported but all were completely remitted or remitting during follow-up. Conclusions: Results suggest that micafungin is efficacious and well-tolerated in patients with proven or probable IA in China. However, these findings should be interpreted with care, due to the small number of patients included in this study. Further comparative trials should be used to confirm the efficacy and safety of micafungin in patients with proven or probable IA.
Hypotensive effects in hypertenses after judo class

The hypotensive effects after exercise was investigated in several physical activities. However up to now in literature, it was not verifi ed in Judo training in hypertensive subjects. This way, the aim of the present study was to verify the hypotensive effects after Judo class, during 60 minutes. Twelve hypertensive Judos players, none of them medicated, during alternated three days were evaluated. In the fi rst visit to the lab, they did anthropometrics evaluation and the maximal cardiopulmonary test. In the second day, a Judo class was taken to reproduce the real training. In the last day, the training session was taking during 60 minutes and the measurement of the blood pressure was taken during 60 minutes in 10 minutes cycle. The data of blood pressure were analyzed by ANOVA of repeated measures (p<0.05). Non signifi cant differences were found in blood pressure in rest. However the blood pressure assumes a tendency to decrease. So, the Judo class tends to decrease the blood pressure, but not with signifi cance.
NKG2C zygosity influences CD94/NKG2C receptor function and the NK‐cell compartment redistribution in response to human cytomegalovirus

Human cytomegalovirus (HCMV) infection promotes a persistent expansion of a functionally competent NK‐cell subset expressing the activating CD94/NKG2C receptor. Factors underlying the wide variability of this effect observed in HCMV‐seropositive healthy individuals and exacerbated in immunocompromized patients are uncertain. A deletion of the NKG2C gene has been reported, and an apparent relation of NKG2C genotype with circulating NKG2C+ NK‐cell numbers was observed in HCMV+ children. We have assessed the influence of NKG2C gene dose on the NK‐cell repertoire in a cohort of young healthy adults (N = 130, median age 19 years). Our results revealed a relation of NKG2C copy number with surface receptor levels and with NKG2C+ NK‐cell numbers in HCMV+ subjects, independently of HLA‐E dimorphism. Functional studies showed quantitative differences in signaling (i.e. iCa2+ influx), degranulation, and IL‐15‐dependent proliferation, in response to NKG2C engagement, between NK cells from NKG2C+/+ and hemizygous subjects. These observations provide a mechanistic interpretation on the way the NKG2C genotype influences steady‐state NKG2C+ NK‐cell numbers, further supporting an active involvement of the receptor in the HCMV‐induced reconfiguration of the NK‐cell compartment. The putative implications of NKG2C zygosity over viral control and other clinical variables deserve attention.
Age-related characteristics of outpatients with anxiety disorders: the Leiden routine outcome monitoring study

Abstract Objective: It has been hypothesised that clinically important age-related differences between adults with anxiety disorders exist; this study aims to elucidate these differences. Methods: We analysed data from 1950 outpatients diagnosed with DSM-IV-TR anxiety disorders treated at a Dutch hospital or affiliated mental healthcare centres. Three age-groups (young- (18–25; n = 435), mid- (26–40; n = 788) and older adult (41–65; n = 727)) were compared with regard to social demographic characteristics, diagnostic characteristics, anxiety symptom profile, general psychiatric symptom profile and generic health status, in addition, linear analyses were carried out with age as a continuous variable. Results: Average age was 36.48 years (SD 11.71), 62.8% were female. Significant associations with age emerged for gender, employment, education level, living situation, observed depression, agoraphobia (AP), social phobia, aches and pains, inner tension, sleep, interpersonal sensitivity, observed hostility, physical functioning, role limitations due to physical problems, vitality and bodily pain in categorical and continuous analyses. Self reported hostility was only significant in group-wise comparisons; role limitations due to emotional problems were only significant in linear analyses (all at p < .001). Conclusions: This study identified clinically relevant differences between younger and older adult outpatients with anxiety disorders. Clinicians should take these findings into account, as they may support treatment.
B‐cell‐intrinsic STAT6 signaling controls germinal center formation

Infection with helminths and exposure to antigens induce a strong type 2 immune response resulting in the secretion of the cytokines IL‐4 and IL‐13 by CD4+ T cells and several innate cell types. IL‐4 and IL‐13 promote class switch recombination to IgG1 and IgE while their role for germinal center (GC) formation is poorly understood. We found a dramatic reduction in the numbers of GC B cells when investigating different type 2 immune responses in IL‐4/IL‐13‐deficient mice. IL‐4/IL‐13 from T cells located outside B‐cell follicles was sufficient for GC formation. We further revealed that IL‐4/IL‐13 acts directly on B cells for the formation of a robust GC response. The frequency of apoptotic GC B cells was not altered in the absence of IL‐4/IL‐13 and proliferation was even enhanced. However, deficiency of signal transducer and activator of transcription 6 signaling in B cells resulted in failure to downregulate the chemotactic receptor Gpr183 (Ebi2) and downregulation of this receptor has been shown to be essential for proper GC B‐cell differentiation. Thus, T‐cell‐derived extrafollicular IL‐4/IL‐13 and signal transducer and activator of transcription 6‐regulated genes in B cells play a critical role for orchestration of the GC response in type 2 immunity.
Autophagy plays a protective role as an anti‐oxidant system in human T cells and represents a novel strategy for induction of T‐cell apoptosis

Autophagy is an intracellular degradation system that plays an important role in T‐cell survival. However, the precise mechanism linking autophagy and cell death in primary human T cells is unclear because methods for monitoring autophagy in small numbers of primary human cells remain controversial. We established a novel method for assessing autophagy in activated human T cells using a retroviral GFP–LC3 expression system. We found that autophagy was induced after TCR stimulation and that autophagy‐defective naïve CD4+ T cells were susceptible to apoptosis through the intrinsic apoptotic pathway. Enhanced apoptosis of autophagy‐defective T cells resulted from accumulation of ROS due to impaired mitophagy. We also demonstrated that effector memory CD4+ T cells had lower autophagic activity than naïve CD4+ T cells, which contributed to their enhanced apoptosis due to increased ROS. Moreover, blocking autophagy increased intracellular mitochondrial volume and ROS levels in activated T cells. These results suggest a protective role of autophagy as an anti‐oxidant system in activated human T cells. The combination of an autophagy blocker and a mitochondrial electron transport chain inhibitor has a synergistic effect on T‐cell death, which could be a novel strategy for induction of T‐cell apoptosis.
Laparoscopic resection of hepatic colorectal metastases.

BACKGROUND Liver resection for secondary malignancy has become the standard of care in appropriately staged patients, offering 5-year survival rates of >40%. Reports of laparoscopic liver resection have been published with increasing frequency over the last few years. In these small series approximately one-third of all operations have been for malignancy, but survival figures cannot be assessed yet. METHODS A retrospective review of all laparoscopic liver resections performed by four surgeons in Brisbane between 1997 and 2004 was done. Follow-up was by regular patient review and telephone confirmation. RESULTS Of 84 laparoscopic liver resections, 33 (39%) were for malignancy; 28 of these were for metastases (22 colorectal). Thirteen patients had left lateral sectionectomy with minimal morbidity; nine right hepatectomies were attempted and six cases of segmental or subsegmental resection were performed. Survival rates in 12 patients followed for 2 years with colorectal secondaries were 75% with 67% disease-free. DISCUSSION Laparoscopic liver resection is feasible in highly selected cases of malignant disease. Patients need to be appropriately staged and surgeons need a broad experience of open liver surgery and advanced laparoscopic procedures.
Achados clínicopatológicos na tromboembolia pulmonar: estudo de 24 anos de autópsias

BACKGROUND: Pulmonary thromboembolism (PTE) is still an enigmatic disorder in many epidemiological and clinical features, remaining one of the most commonly misdiagnosed disorders. OBJECTIVE: To describe the prevalence and pathological findings of PTE in a series of autopsies, to correlate these findings with underlying diseases, and to verify the frequency of PTE clinically suspected before death. METHOD: The reports on 5261 consecutive autopsies performed from 1979 to 2002 in a Brazilian tertiary referral medical school were reviewed for a retrospective study. From the medical records and autopsy reports of the patients found with macroscopically and/or microscopically documented PTE, were gathered data on demographics, underlying diseases, antemortem suspicion of PTE, and probable PTE site of origin. RESULTS: The autopsy rate was 42.0% and PTE was found in 544 patients. In 225 cases, PTE was the main cause of death (fatal PTE). Infections (p=0.0003) were associated with nonfatal PTE and trauma (p=0.007) with fatal PTE. The rate of antemortem unsuspected PTE was 84.6% and 40.0% of these patients presented fatal PTE. Diseases of the circulatory system (p=0.0001), infections (p<0.0001), diseases of the digestive system (p=0.0001), neoplasia (p=0.024) and trauma (p=0.005) were associated with unsuspected PTE. The most frequent PTE site of origin was the lower limbs (48.9%). Probable PTE sites of origin such as right-sided cardiac chambers (p=0.012) and pelvic veins (p=0.015) were associated with fatal PTE. CONCLUSION: A large number of cases do not have antemortem suspicion of PTE. Special attention should be paid to the possibility of PTE in patients with diseases of the circulatory system, infections, diseases of the digestive system, neoplasia, and trauma.
Squalene emulsion potentiates the adjuvant activity of the TLR4 agonist, GLA, via inflammatory caspases, IL‐18, and IFN‐γ

The synthetic TLR4 agonist glucopyranosyl lipid adjuvant (GLA) is a potent Th1‐response‐inducing adjuvant when formulated in a squalene oil‐in‐water emulsion (SE). While the innate signals triggered by TLR4 engagement are well studied, the contribution of SE remains unclear. To better understand the effect of SE on the adjuvant properties of GLA‐SE, we compared the innate and adaptive immune responses elicited by immunization with different formulations: GLA without oil, SE alone or the combination, GLA‐SE, in mice. Within the innate response to adjuvants, only GLA‐SE displayed features of inflammasome activation, evidenced by early IL‐18 secretion and IFN‐γ production in memory CD8+ T cells and neutrophils. Such early IFN‐γ production was ablated in caspase‐1/11−/− mice and in IL‐18R1−/− mice. Furthermore, caspase‐1/11 and IL‐18 were also required for full Th1 CD4+ T‐cell induction via GLA‐SE. Thus, we demonstrate that IL‐18 and caspase‐1/11 are components of the response to immunization with the TLR4 agonist/squalene oil‐in‐water based adjuvant, GLA‐SE, providing implications for other adjuvants that combine oils with TLR agonists.