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Objective: Most physicians generously dispense drugs and sometimes physical maneuvers to lower body temperature in febrile patients. However, animal studies suggest that fever is essential for optimal host defense. The molecular basis of these observations is not yet understood. Resolution of inflammation requires that activated neutrophils undergo apoptosis. Activation and apoptosis of neutrophils is pivotal to a variety of inflammatory renal diseases. We tested the hypothesis that neutrophil apoptosis is temperature dependent. Methods: Neutrophils were isolated from healthy donors; apoptosis was assayed by annexin V and propidium iodide staining followed by flow cytometry. p38 MAPK, ERK, Akt, and IkBa were assayed by Western blotting. NF-κB activation was assessed by IKK activity assays, electromobility shift assays, and Taq-man. Results: Short-term heat exposure to 42°C for 60 min did not affect constitutive apoptosis. LPS, GM-CSF, IL-8, and dexamethasone delayed apoptosis. Short-term heat exposure blocked the apoptosis-delaying effect of LPS, but not of all other substances. The inhibitory effect by temperature occurred in a dose-dependent fashion, starting already at 40°C. By flow cytometry, heat exposure did not result in LPS receptor shedding. We next investigated antiapoptotic signaling pathways and found that NF-κB, but not ERK, p38 MAPK, or PI3-K/Akt, controlled LPS-delayed neutrophil apoptosis. Moreover, LPS-induced activation of IKK activity, IkBa degradation, and NF-κB DNA binding were all abrogated by short-term heat exposure. Quantitative RT-PCR of IkBa mRNA showed that heat exposure resulted in decreased NF-κB-dependent gene transcription. Conclusions: Our data suggest that fever-like temperature prevents activation of NF-κB in neutrophils. This effect may help to dispose of neutrophils activated by LPS and to inhibit a variety of NF-κB-dependent genes during bacterial infections. The data support the idea that fever is a physiological rather than a pathological event. [ABSTRACT FROM AUTHOR]

Background: Risk factors for ipsilateral breast cancer tumor recurrence (IBTR) are well established and include grading, nodal status, and receptor status. Little is known about the influence of the local distance between the primary tumor and recurrences on changes in tumor characteristics and prognosis., Methods: In a retrospective setting, we analyzed primary breast cancers and their recurrences. Localizations of primary and recurrent breast cancer were recorded to calculate the relative distance in pixels. Analysis was performed regarding tumor characteristics, relative distance between both, and their impact on breast cancer prognosis., Results: In a cohort of 142 patients with ipsilateral recurrence, no statistically significant difference could be shown in the change in tumor characteristics depending on distance. Progesterone receptor (PR) and estrogene receptor (ER) status changed in 22.7% and 14.9% of cases, respectively. human epidermal growth factor receptor 2 (ERBB2, HER2) status changed in 18.3% of cases. Survival was in accordance with the literature, with luminal-A-like tumors as best and triple negative breast cancers (TNBC) as worst prognosis. With a threshold of 162 pixels, the survival was significantly better in the group with shorter distance., Conclusion: Change in tumor characteristics from primary breast cancer to recurrence occurs more often in PR than ER. In contrast to other work, in this dataset, recurrences with a larger distance to the primary tumor had a worse prognosis in univariate analysis. A Cox model might indicate the possibility that this influence is independent of other risk factors.

Objectives: In patients with testicular Germ Cell Tumors (GCT) noncaseating granulomatous diseases such as Sarcoid Like Lesions (SLL) or Sarcoidosis can mimic metastasis due to hilar or mediastinal lymphadenopathy. Due to the clinical and prognostic impact, exclusion of malignant diseases is mandatory., Material and Methods: Retrospectively, data from 636 GCT patients, who were seen in the course of tumor surveillance/follow-up were collected. Focus was put on the detection of tumor relapse vs. noncaseating granulomatous reactions. For the differential diagnosis of thoracic lymphadenopathy or pulmonary infiltrates either bronchoscopy (e.g., endobronchial ultrasound-guided transbronchial needle aspiration, endobronchial ultrasound-guided transbronchial needle aspiration) or thoracic surgery was performed. Both GCT patients with either tumor relapse or coexisting SLL were compared to GCT patients without SLL and tumor relapse., Results: Twenty-nine patients suffered from suspected tumor relapse. Whereas thoracic relapses were suspected in 15 patients on chest computed tomography, thoracic relapse was confirmed in 5 cases by open surgery. In 2 cases open surgery yielded reactive lymphadenitis, and in 8 cases SLL was diagnosed either via EBUS-TBNA (n = 7) or thoracoscopic wedge resection plus lymphadenectomy (n = 1). With focus on overall survival, no relevant difference was found between all tested subgroups (P = 0.265; logrank test)., Conclusions: In GCT patients, the coexistence of noncaseating granulomatous disease is common. Minimal invasive bronchoscopic techniques can serve for the cytopathologic exclusion of malignant thoracic manifestations. In our monocenter patient group the coexistence of SLL did not have any prognostic impact on overall survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Basal cell carcinomas are the most common periocular malignant tumor. In advanced periocular basal cell carcinoma, vismodegib is a new treatment option which might potentially avoid surgical eye removal., Case Report: We treated a 76-year-old patient unwilling to consent to surgery with vismodegib for advanced periocular basal cell carcinoma on the left forehead that had already undergone several previous treatments. After initial partial remission, the tumor regrew under ongoing therapy, so that radical surgical excision including orbital exenteration was performed. Unfortunately, the patient died thereafter due to septic multi-organ failure., Conclusion: Basal cell carcinoma and its new treatment options are gaining importance for ophthalmology due to rising incidence and prevalence rates. Vismodegib is a new encouraging option. However, for advanced tumors, it must be resolved whether complete histological remission may be achieved to avoid surgical intervention, or whether the area of resection can be significantly reduced. Current multicenter studies investigate these aspects further (ClinicalTrails.gov identifier: NCT03035188).

Purpose: To determine sensitivity, specificity and inter-observer variability of different whole-body MRI (WB-MRI) sequences in patients with multiple myeloma (MM)., Methods and Materials: WB-MRI using a 1.5T MRI scanner was performed in 23 consecutive patients (13 males, 10 females; mean age 63+/-12 years) with histologically proven MM. All patients were clinically classified according to infiltration (low-grade, n=7; intermediate-grade, n=7; high-grade, n=9) and to the staging system of Durie and Salmon PLUS (stage I, n=12; stage II, n=4; stage III, n=7). The control group consisted of 36 individuals without malignancy (25 males, 11 females; mean age 57+/-13 years). Two observers independently evaluated the following WB-MRI sequences: T1w-TSE (T1), T2w-TIRM (T2), and the combination of both sequences, including a contrast-enhanced T1w-TSE with fat-saturation (T1+/-CE/T2). They had to determine growth patterns (focal and/or diffuse) and the MRI sequence that provided the highest confidence level in depicting the MM lesions. Results were calculated on a per-patient basis., Results: Visual detection of MM was as follows: T1, 65% (sensitivity)/85% (specificity); T2, 76%/81%; T1+/-CE/T2, 67%/88%. Inter-observer variability was as follows: T1, 0.3; T2, 0.55; T1+/-CE/T2, 0.55. Sensitivity improved depending on infiltration grade (T1: 1=60%; 2=36%; 3=83%; T2: 1=70%; 2=71%; 3=89%; T1+/-CE/T2: 1=50%; 2=50%; 3=89%) and clinical stage (T1: 1=58%; 2=63%; 3=79%; T2: 1=58%; 2=88%; 3=100%; T1+/-CE/T2: 1=50%; 2=63%; 3=100%). T2w-TIRM sequences achieved the best reliability in depicting the MM lesions (65% in the mean of both readers)., Conclusions: T2w-TIRM sequences achieved the highest level of sensitivity and best reliability, and thus might be valuable for initial assessment of MM. For an exact staging and grading the examination protocol should encompass unenhanced and enhanced T1w-MRI sequences, in addition to T2w-TIRM.

Virtually all blood vessels are surrounded by adventitial fat. Adipocytes produce a host of vasoactive substances that may influence vascular contraction. We tested whether or not perivascular adipose tissue modulates contraction of aortic ring preparations. We studied aortic rings surrounded by periadventitial adipose tissue from adult Sprague-Dawley rats. At a maximum concentration of 300 nM angiotensin II, 6.5 microM serotonin, and 5 microM phenylephrine, the contractile response of intact rings was 95%, 80%, and 30% lower than that of vessels without periadventitial fat. The anticontractile effect of periadventitial fat was reduced by inhibition of ATP-dependent K+ channels with glibenclamide (3 microM) and by the tyrosine kinase inhibitor genistein (10 microM). Blocking NOS, cyclo-oxygenase, cytochrome P450, or adenosine receptors did not restore the vascular response in intact vessels. The anticontractile effect of perivascular fat was present in Zucker fa/fa rats, suggesting that leptin receptors were not responsible. Transferring the bath solution from intact vessels, isolated periadventitial tissue, and cultured rat adipocytes to precontracted vessels lacking periadventitial fat resulted in a rapid relaxation. We suggest that perivascular adventitial adipose tissue releases a transferable adventitium-derived relaxing factor that acts by tyrosine kinase-dependent activation of K+ channels in vascular smooth muscle cells.

P450-dependent arachidonic acid (AA) metabolites regulate arterial tone by modulating calcium-activated (BK) potassium channels in vascular smooth muscle cells (VSMC). Because eicosapentaenoic acid (EPA) has been reported to improve vascular function, we tested the hypothesis that P450-dependent epoxygenation of EPA produces alternative vasoactive compounds. We synthesized the 5 regioisomeric epoxyeicosattrienoic acids (EETeTr) and examined them for effects on K(+) currents in rat cerebral artery VSMCs with the patch-clamp technique. 11(R),12(S)-epoxyeicosatrienoic acid (50 nmol/L) was used for comparison and stimulated K(+) currents 6-fold at +60 mV. However, 17(R),18(S)-EETeTr elicited a more than 14-fold increase. 17(S),18(R)-EET and the remaining four regioisomers were inactive. The effect of 17(R),18(S)-EETeTr was blocked by tetraethylammonium but not by 4-aminopyridine. VSMCs expressed P450s 4A1 and 4A3. Recombinant P450 4A1 hydroxylated EPA at C-19 and C-20 and epoxygenated the 17,18-double bond, yielding the R, S- and S, R-enantiomers in a ratio of 64:36. We conclude that 17(R),18(S)-EETeTr represents a novel, potent activator of BK potassium channels. Furthermore, this metabolite can be directly produced in VSMCs. We suggest that 17(R),18(S)-EETeTr may function as an important hyperpolarizing factor, particularly with EPA-rich diets.

Caveolae are plasma membrane invaginations that may play an important role in numerous cellular processes including transport, signaling, and tumor suppression. By targeted disruption of caveolin-1, the main protein component of caveolae, we generated mice that lacked caveolae. The absence of this organelle impaired nitric oxide and calcium signaling in the cardiovascular system, causing aberrations in endothelium-dependent relaxation, contractility, and maintenance of myogenic tone. In addition, the lungs of knockout animals displayed thickening of alveolar septa caused by uncontrolled endothelial cell proliferation and fibrosis, resulting in severe physical limitations in caveolin-1-disrupted mice. Thus, caveolin-1 and caveolae play a fundamental role in organizing multiple signaling pathways in the cell.

Mice with a disrupted beta(1) (BK beta(1))-subunit of the large-conductance Ca(2+)-activated K(+) (BK) channel gene develop systemic hypertension and cardiac hypertrophy, which is likely caused by uncoupling of Ca(2+) sparks to BK channels in arterial smooth muscle cells. However, little is known about the physiological levels of global intracellular Ca(2+) concentration ([Ca(2+)](i)) and its regulation by Ca(2+) sparks and BK channel subunits. We utilized a BK beta(1) knockout C57BL/6 mouse model and studied the effects of inhibitors of ryanodine receptor and BK channels on the global [Ca(2+)](i) and diameter of small cerebral arteries pressurized to 60 mmHg. Ryanodine (10 microM) or iberiotoxin (100 nM) increased [Ca(2+)](i) by approximately 75 nM and constricted +/+ BK beta(1) wild-type arteries (pressurized to 60 mmHg) with myogenic tone by approximately 10 microm. In contrast, ryanodine (10 microM) or iberiotoxin (100 nM) had no significant effect on [Ca(2+)](i) and diameter of -/- BK beta(1)-pressurized (60 mmHg) arteries. These results are consistent with the idea that Ca(2+) sparks in arterial smooth muscle cells limit myogenic tone through activation of BK channels. The activation of BK channels by Ca(2+) sparks reduces the voltage-dependent Ca(2+) influx and [Ca(2+)](i) through tonic hyperpolarization. Deletion of BK beta(1) disrupts this negative feedback mechanism, leading to increased arterial tone through an increase in global [Ca(2+)](i).

This study examined whether the learning advantages of an external focus of attention relative to an internal focus, as demonstrated by Wulf, Höss, and Prinz (1998), would also be found for a sport skill under field-like conditions. Participants (9 women, 13 men; age range: 21-29 years) without experience in golf were required to practice pitch shots. The practice phase consisted of 80 practice trials. One group was instructed to focus on the arm swing (internal focus), whereas another group was instructed to focus on the club swing (external focus). One day after practice, a retention test of 30 trials without instructions was performed. The external-focus condition was more effective for performance during both practice and retention.

The study was aimed at evaluation of diagnostic usefulness, prepared by own method, of a set of latex reagents for identification of enteropathogenic strains of E. coli (EPEC). EPEC strains in feces of 334 children with diarrhoea were searched by application at the same time of two methods: used routinely to this time slide agglutination test with commercial OK sera for enteropathogenic serotypes of E. coli and by a latex test with application of warmed culture of investigated strain in peptone water and polystyrene latex coated with immune globulins for O antigens of EPEC serotypes. By application of both methods EPEC strains were found in 50 (15.04%) children, by a latex test in 94 (28.1%) and by agglutination with OK sera in 67 (20.1%) of tested patients. Conformity of results obtained by both tests amounted to 82%. The latex test was found more useful for identification of EPEC strains because of simplicity of performance, higher sensitiveness and better repeatability of results, when compared with agglutination test with live E. coli and OK sera.

Investigations were carried on a strain isolated from patient hospitalized in Poland. The patient returned from Odessa, a region with cholera epidemic. The strain was suspected to be Vibrio cholerae, but it did not agglutinate in V. cholerae 01 serum. The aim of this study was establishment of taxonomical classification of this strain, in order to demonstrate whether it is a representative of the non-cholera vibrio group (not agglutinating) or another representative of the family Vibrionaceae. The strain was resistant to bile salts in TCBS medium and demonstrated several properties from a borderline of two Vibrio and Aeromonas species. Its properties were similar to the group of recently described pathogenic vibrio, but it did not require higher concentrations of NaCl in the medium and was resistant to the vibriostatic factor 0/129. These properties were considered as decisive in differentiation of Vibrio and Aeromonas. The strain was finally classified as Aeromonas veronii. It is a first case in Poland of isolation of A. veronii from the feces of patient with cholera-like symptoms. As newly described pathogenic species of genus Vibrio and Aeromonas were not isolated in Poland, we present schemes which may serve for beginning of this type of diagnostic investigations.