Effects of one-year tofacitinib therapy on bone metabolism in rheumatoid arthritis.

Janus kinase (JAK) inhibitors are used to treat rheumatoid arthritis (RA). We assessed the effects of tofacitinib on bone density and bone markers in association with clinical and laboratory parameters in RA. Tofacitinib stabilized bone density and resulted in a positive balance of bone turnover. INTRODUCTION: Janus kinase (JAK) inhibitors emerged as new therapeutic options in rheumatoid arthritis (RA). We have little information on how it affects areal and volumetric bone mineral density (BMD) and bone turnover markers. The aim of this study was to assess the effects of 1-year tofacitinib therapy on bone metabolism in RA. METHODS: Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP) levels, as well as serum levels of sclerostin, osteocalcin (OC), P1NP, DKK-1, OPG, RANKL, and 25-hydroxy-vitamin D3. Areal and volumetric BMD were assessed by DXA and peripheral quantitative CT (QCT), respectively. RESULTS: Twenty-six patients (13 on each arm) completed the study. Tofacitinib was clinically effective by suppressing DAS28, CRP, and HAQ. This was accompanied by the attenuation of further bone loss. Tofacitinib therapy significantly increased OC, OPG, and vitamin D3, while decreased CTX levels (p < 0.05). Age and multiple bone markers (OC, CTX, P1NP, RANKL) inversely correlated with L2-4 and femoral neck BMD by DXA. CRP, DAS28, and RANKL inversely determined volumetric BMD by QCT. Age, CRP, anti-CCP, and DKK-1 influenced the effects of tofacitinib therapy on BMD changes. CONCLUSIONS: One-year tofacitinib treatment stabilized BMD in RA patients and resulted in a positive balance of bone turnover as indicated by bone biomarkers. Further studies are needed to evaluate the potential beneficial effects of JAK inhibitors on inflammatory bone loss.

Synthesis, radiolabeling, and pre-clinical evaluation of [44Sc]Sc-AAZTA conjugate PSMA inhibitor, a new tracer for high-efficiency imaging of prostate cancer.

PURPOSE: The aim of this work was to demonstrate the suitability of AAZTA conjugated to PSMA inhibitor (B28110) labeled with scandium-44 as a new PET tracer for diagnostic imaging of prostate cancer. BACKGROUND: Nowadays, scandium-44 has received significant attention as a potential radionuclide with favorable characteristics for PET applications. A polyaminopolycarboxylate heptadentate ligand based on a 1,4-diazepine scaffold (AAZTA) has been thoroughly studied as chelator for Gd3+ ions for MRI applications. The excellent results of the equilibrium, kinetic, and labeling studies led to a preliminary assessment of the in vitro and in vivo behavior of [44Sc][Sc-(AAZTA)]- and two derivatives, i.e., [44Sc][Sc (CNAAZTA-BSA)] and [44Sc][Sc (CNAAZTA-cRGDfK)]. RESULTS: B28110 was synthesized by hybrid approach, combining solid-phase peptide synthesis (SPPS) and solution chemistry to obtain high purity (97%) product with an overall yield of 9%. Subsequently, the radioactive labeling was performed with scandium-44 produced from natural calcium target in cyclotron, in good radiochemical yields (RCY) under mild condition (pH 4, 298 K). Stability study in human plasma showed good RCP% of [44Sc]Sc-B28110 up to 24 h (94.32%). In vivo PET/MRI imaging on LNCaP tumor-bearing mice showed high tracer accumulation in the tumor regions as early as 20 min post-injection. Ex vivo biodistribution studies confirmed that the accumulation of 44Sc-PSMA-617 was two-fold lower than that of the radiolabeled B28110 probes. CONCLUSIONS: This work demonstrated the suitability of B28110 for the complexation with scandium-44 at room temperature and the high performance of the resulting new tracer based on AAZTA chelator for the diagnosis of prostate cancer using PET.

Abdominal Compartment Syndrome After Liver Transplant in Drug-Induced Acute Liver Failure: A Case Report.

The incidence of drug-induced acute liver failure (ALF) has been increasing in recent years. Despite the complex intensive treatment, liver transplant should be performed in progressive cases. A systemic inflammatory response syndrome and the burden of surgical intervention promote abdominal compartment syndrome (ACS); observed preoperatively, they are significant negative prognostic factors. THE CASE: We demonstrate a young woman with liver transplant after ALF and a consecutive ACS. We presumed drug toxicity in the background of the rapidly progressive ALF, based on the preoperative hematologic examination and the histology of the removed liver. An ACS has occurred in the postoperative period that must have been resolved with mesh, and later, anatomic segment 2-3 resection had to be performed to further decrease the pressure. The patient left the hospital after 62 days with good graft function. DISCUSSION: A complex intensive care is mandatory in the case of orthotopic liver transplant for ALF. Outcomes are good after orthotopic liver transplant. An ACS might occur after surgery. In these rare cases a delayed abdominal closure or even a liver resection can be the only solution and sometimes an urgent need to resolve the life-threatening problem.

Neutrophil-to-lymphocyte ratio: a biomarker for predicting systemic involvement in adult IgA vasculitis patients.

BACKGROUND: IgA vasculitis (IgAV) is a small-vessel leucocytoclastic cutaneous vasculitis, often associated with kidney and gastrointestinal (GI) manifestations. Although predictive factors for systemic involvement have been extensively studied in children, there is paucity in the literature regarding adult patients. Neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker, used to assess systemic inflammation in various diseases. OBJECTIVE: We sought to evaluate whether NLR can be used for predicting renal and GI involvement in adult IgA vasculitis patients. METHODS: This was a retrospective review of adult patients who were diagnosed with IgAV at our institution between 2004 and 2016. RESULTS: A total of 40 patients met our inclusion criteria. Half of the enrolled patients had clinical symptoms suggestive of systemic involvement, of which 6 (15%) had only renal, 3 (7.5%) had only GI and 11 (27.5%) had both renal and GI involvement. Pretreatment NLR was significantly associated with renal and/or GI manifestations of the disease (P < 0.001). The optimal cut-off value of NLR, for predicting systemic involvement was 3.34, with a specificity of 95% and a sensitivity of 85%. In addition, pretreatment NLR was also found to be significantly correlated with the severity of the systemic manifestations of IgAV (P = 0.022). CONCLUSION: This study suggests that NLR is a potential indicator for prognosticating systemic involvement in adult IgAV.

Toxicological effects of aflatoxin B1 on the earthworm Eisenia fetida as determined in a contact paper test.

In this study, aflatoxin B1 (AFB1) toxicity toward the earthworm Eisenia fetida (Savigny 1826) was evaluated in contact paper test systems containing distilled water and ethanol or 20 to 400 µg/ml of AFB1 over 72 h of exposure. The results indicated that AFB1 could induce significant damage to earthworms (coiling, curling, excessive mucus secretion, clitellum swelling) at greater than 75 µg/ml. Moreover, AFB1 had harmful effects on E. fetida (degenerative changes such as bulging of the clitella regions) at levels higher than 150 µg/ml. The calculated LD50 was 168.5 µg/ml. These findings confirm that E. fetida and standardized methods based on this organism (OECD 207 1984) are applicable and useful in mycotoxin related toxicity studies.

Multidimensional Analysis of 16 Glucose Isomers by Ion Mobility Spectrometry.

Diastereomeric adducts comprising an enantiomerically pure monosaccharide analyte, a peptide, and/or an amino acid and a divalent metal ion (for 16 different monosaccharide isomers) are generated by electrospray ionization and analyzed by combined ion mobility spectrometry-mass spectrometry (IMS-MS) techniques. Mobility distributions of [l-Ser + M + H](+) (where l-Ser is l-serine and M is a given monosaccharide), [l-Phe-Gly + M + H](+) (where l-Phe-Gly is l-phenylalanine-glycine), and [Mn(II) + (l-Phe-Gly - H) + M](+) complex ions are used to determine collision cross sections (ccs in Å(2)), and groups of cross sections for different clusters are proposed as means of identifying the sugar isomers. Within one type of complex, variations in ccs do not always allow delineation between the 16 glucose isomers, but interestingly, when ccs of three different ions are combined as a spatial vector, enantiomers are partially resolved. As a result of this analysis, l-glucose, d-glucose, l-allose, d-allose, d-gulose, d-galactose, and l-mannose are delineated, and for all eight enantiomeric pairs, d and l entities display different coordinates. In addition, different combinations of amino acids, peptide, and metal ions are surveyed, and the potential for yielding unique coordinates for the generated diastereomeric complexes is assessed.

Dynamic Reorganization of Vortex Matter into Partially Disordered Lattices.

We report structural evidence of dynamic reorganization in vortex matter in clean NbSe(2) by joint small-angle neutron scattering and ac susceptibility measurements. The application of oscillatory forces in a transitional region near the order-disorder transition results in robust bulk vortex lattice configurations with an intermediate degree of disorder. These dynamically originated configurations correlate with intermediate pinning responses previously observed, resolving a long-standing debate regarding the origin of such responses.

Radiosurgery for cerebral cavernomas.

The role of stereotactic radiosurgery (SRS) in the management of cerebral cavernomas (CCMs) remains controversial. However, during the last decade the increasing knowledge on natural history and numerous publications from SRS centers using modern treatment protocols has been changing the initial resistance of the neurosurgical community. Unfortunately, the quality of publications on CCM SRS remains heterogeneous. Controversies arise from the lack of control groups, the different definition of hemorrhage, heterogeneous patient populations, and poor definition of treatment protocols. The key for proper interpretation of results is the understanding of the natural history of CCMs, which is varied both according to anatomical location and the presence or absence of previous hemorrhage. Hemispheric lesions appear to be more benign with lower annual bleed rate and risk of persisting disability, whereas those found in the thalamus, basal ganglia and brainstem typically have higher rebleed risk resulting in higher cumulative morbidity following subsequent hemorrhages. However, we are still unable at presentation to predict the future behavior of an individual lesion. In the present paper we critically review and analyze the modern SRS literature on CCMs. The expanding number of available data with current treatment protocols strongly supports the initial intuition that SRS is an effective treatment alternative for deep-seated CCMs with multiple hemorrhages reducing pretreatment annual rebleed rates from 32% pre-treatment to 1.5% within 2 years after treatment (N.=197). Moreover, it appears to stabilize lesions with no more than one bleed, and it is also effective for CCMs causing therapy resistant epilepsy especially if applied within 3 years after presentation. In modern SRS series the rate of persisting adverse radiation effects is low, resulting only in mild morbidity even in deep-seated lesions (4.16%, N.=376), and morbidity caused by post-treatment hemorrhages is also low (5.3%, N.=132). Admittedly, there is no high quality evidence to define the relative roles of microsurgery, SRS and wait-and-see policy in the management of detected CCMs at present. However, based on increasing positive experience, we recommend early SRS soon after presentation in neurologically intact or minimally disabled patients harboring deep-seated CCMs, because waiting for the cumulative morbidity of the natural history to justify an otherwise low-risk intervention does not serve the patient well.

Absorption, fluorescence and second harmonic generation in Cr³âº-doped BiB3O6 glasses.

Synthesis, spectral properties and photoinduced nonlinear optical effects of chromium-doped BiB3O6 glass are studied in the present paper. Absorption, excitation and time resolved luminescence spectra are presented and luminescence decay behavior is discussed. Detailed analysis of the obtained spectra (assignment of the most prominent spectral features in terms of the corresponding Cr(3+) energy levels, crystal field strength Dq, Racah parameters B and C) was performed. A weak photostimulated second harmonic generation signal was found to increase drastically due to poling by proton implantation in the investigated sample.

Childhood bone tuberculosis from Roman Pécs, Hungary.

A child from a Roman necropolis in Pécs, Hungary (4th century CE) was initially diagnosed with severe spinal osteomyelitis. The post-cranial skeleton displayed bone alterations in the lower thoracic and upper lumbar segments, including vertebral body destruction, collapse and sharp kyphosis, and additional multiple rib lesions, suggesting a most likely diagnosis of pulmonary and spinal tuberculosis. This study discusses a number of selected diagnoses in the context of our pathological findings, complementing the macroscopic examination with radiological and biomolecular analyses.

Amperometric cell for subcutaneous detection of hydrogen sulfide in anesthetized experimental animals.

Hydrogen sulfide (H2S) is a toxic gas. It has been recognized that H2S evolving in biochemical reactions in living organisms has an important role in different physiologic processes. Nowadays, H2S is known as an endogenous messenger molecule. Natural sulfurous spring water has been proved beneficial in the therapy of diseases of the skin and other organs (Boros et al 2013). In vivo real-time detection of local H2S concentration is an important but challenging task.We developed a two-electrode amperometric cell for selective subcutaneous detection of H2S in anesthetized mice. The cell is a small size implantable gas sensor containing a platinum disc anode and a silver cathode. The selectivity is provided by a membrane permeable only by gases. There is a buffered reversible electrochemical mediator solution in an oxidized form inside the cell. As gaseous H2S penetrates into the cell the mediator is reduced, and +0.4 V versus the reference is employed on the platinum working electrode. The reduced mediator is oxidized on the anode surface. The current provides an analytical signal representing the concentration of H2S.Appropriate shape, size and membrane material were selected, and optimal working parameters--such as mediator concentration, pH and cell voltage--were determined in vitro. The lower limit of detection in the stirred sample solution at pH = 5.5 was as small as 9.4 × 10(-7) M and a dynamic concentration range of 0-6 × 10(-4) M could be achieved.The detecting surfaces of the cell were covered with freshly dissected mouse skin to test dermal H2S permeability. In other experiments, the cell was implanted subcutaneously in an anesthetized mouse and the animal was submerged in a buffer solution containing different concentrations of H2S so that the skin surface over the sensor was covered by the solution. Measurements of subcutaneous H2S concentration were taken. The experiments clearly proved that H2S diffuses through the skin of the live mouse.

Electric-field-induced Skyrmion distortion and giant lattice rotation in the magnetoelectric insulator Cu2OSeO3.

Uniquely in Cu2OSeO3, the Skyrmions, which are topologically protected magnetic spin vortexlike objects, display a magnetoelectric coupling and can be manipulated by externally applied electric (E) fields. Here, we explore the E-field coupling to the magnetoelectric Skyrmion lattice phase, and study the response using neutron scattering. Giant E-field induced rotations of the Skyrmion lattice are achieved that span a range of ∼25°. Supporting calculations show that an E-field-induced Skyrmion distortion lies behind the lattice rotation. Overall, we present a new approach to Skyrmion control that makes no use of spin-transfer torques due to currents of either electrons or magnons.

Description of patients with IgG4-related disease from a Hungarian centre.

OBJECTIVES: Although most reported patients with immunoglobulin G4-related disease (IgG4-RD) are from the Far East, we aimed to identify patients suffering from IgG4-RD in our University Centre in Debrecen, Hungary. METHOD: Serum IgG4 levels were measured at 51 of our 800 patients followed up because of Sjögren's syndrome (SS) if one or more clinical signs during the disease course raised the possibility of IgG4-RD (persisting salivary gland swelling, absence of anti-Ro/SSA and anti-La/SSB antibodies in the serum, and positive salivary gland biopsy, coexistence of autoimmune pancreatitis, autoimmune hepatitis, or primary sclerosing cholangitis, persisting lymphadenopathy). Where available, histological samples of small salivary gland biopsies were revised to detect the particular features of IgG4-RD. Pathologists and surgeons were informed about the disease and asked to refer suspicious cases. RESULTS: Based on our survey, eight patients were identified with IgG4-RD. Pancreatic, salivary gland, aortic, and retroperitoneal manifestations were detected. Of the 51 patients with SS, four appeared to have IgG4-RD, but eventually one was excluded. CONCLUSIONS: Although IgG4-RD is not yet well known to physicians of Western countries, it occurs in Caucasians and probably in other races as well. Moreover, our eight cases diagnosed with IgG4-RD demonstrate a relatively large European patient population collected in a single centre. European clinicians, and especially rheumatologists, should be informed and at least certain laboratories should be prepared to investigate patient samples if the suspicion of IgG4-RD is raised. The main clinical significance of an accurate diagnosis is the extreme corticosteroid sensitivity of IgG4-RD.

Leptin promotes a proinflammatory lipid profile and induces inflammatory pathways in human SZ95 sebocytes.

BACKGROUND: Leptin, the adipocyte-secreted hormone that regulates weight, is known to link lipid metabolism with inflammation in various cell types. However, its role in human sebocytes has not yet been investigated. OBJECTIVES: The purpose of this study was to investigate the effects of leptin in human sebaceous gland biology. METHODS: Expression of the long form of the leptin receptor (Ob-Rb) was detected by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunochemistry. Lipid analysis was by high-performance thin-layer chromatography, gas chromatography-mass spectrometry and time-of-flight mass spectrometer mass detection. Lipid bodies were visualized by BODIPY staining using fluorescent microscopy and measured by flow cytometry. Interleukin (IL)-6 and IL-8 mRNA levels were assessed by real-time qRT-PCR and their release was evaluated by enzyme-linked immunosorbent assay. Cyclooxygenase (COX)-2 and 5-lipooxygenase (LOX) protein expression and phosphorylation of p65 and signal transducer and activator of transcription (STAT)-3 were determined by Western blot analysis. RESULTS: Expression of Ob-Rb was detected in human sebaceous glands and in cultured human SZ95 sebocytes. The treatment of SZ95 sebocytes with leptin led to enlarged intracellular lipid bodies, increased ratios of unsaturated/saturated fatty acids and decreased vitamin E levels. Further supporting a proinflammatory role, leptin induced COX-2 and 5-LOX expression in SZ95 sebocytes and augmented the production of IL-6 and IL-8 cytokines. On leptin treatment, the STAT-3 and nuclear factor-κB pathways were activated, indicating that these known leptin signalling pathways are active in human sebocytes. CONCLUSIONS: Our findings suggest that leptin signalling may be involved in the proinflammatory regulation of sebaceous lipid metabolism and the induction of inflammatory enzymes and cytokines.

Effects of dietary sodium butyrate on hepatic biotransformation and pharmacokinetics of erythromycin in chickens.

Butyrate, a commonly applied feed additive in poultry nutrition, can modify the expression of certain genes, including those encoding cytochrome P450 (CYP) enzymes. In comparative in vitro and in vivo experiments, the effect of butyrate on hepatic CYP genes was examined in primary cultures of chicken hepatocytes and in liver samples of chickens collected from animals that had been given butyrate as a feed additive. Moreover, the effect of butyrate on the biotransformation of erythromycin, a marker substance for the activity of enzymes of the CYP3A family, was investigated in vitro and in vivo. Butyrate increased the expression of the avian-specific CYP2H1 both in vitro and in vivo. In contrast, the avian CYP3A37 expression was decreased in hepatocytes following butyrate exposure, but not in the in vivo model. CYP1A was suppressed by butyrate in the in vitro experiments, and overexpressed in vivo in butyrate-fed animals. The concomitant incubation of hepatocytes with butyrate and erythromycin led to an increased CYP2H1 expression and a less pronounced inhibition of CYP3A37. In in vivo pharmacokinetic experiments, butyrate-fed animals given a single i.m. injection of erythromycin, a slower absorption phase (longer T(half-abs) and delayed T(max)) but a rapid elimination phase of this marker substrate was observed. Although these measurable differences were detected in the pharmacokinetics of erythromycin, it is unlikely that a concomitant application of sodium butyrate with erythromycin or other CYP substrates will cause clinically significant feed-drug interaction in chickens.

Lymphoid metastasis of rat My2/De leukemia.

By grafting spontaneous leukemia tumor cells, the myeloid My2/De leukemia rat model was established. Death was caused by impaired functions of heavily infiltrated organs. In vitro culturing of tumor cells, blood and bone marrow counts and cytochemic reactions indicated the leukemic the origin resembling human myeoloblastic leukemia. Metastatic spread was followed after i.v. and i.p. injection, and by implantation of leukemia cells under the renal capsule of rats. Primary tumor and metastasis formation was visualized by (18)FDG or (11)C-methionine administration and MiniPET. The accumulation of radiotracers was measured in different organs and expressed as Differential Absorption Ratios (DARs). Subrenal implantation of My2/De cells resulted in their appearance in other abdominal organs and in parathymic lymph nodes. The release of tumor cells from the primary kidney to the peritoneum was mimicked by the i.p. administration of ink particles. Ink particles deposited in the abdominal organs and in the thoracal lymph nodes, preferentially in parathymic lymph nodes, confirming the notion of lymphatic spread of metastasis.

The ultrastructure and flexibility of thylakoid membranes in leaves and isolated chloroplasts as revealed by small-angle neutron scattering.

We studied the periodicity of the multilamellar membrane system of granal chloroplasts in different isolated plant thylakoid membranes, using different suspension media, as well as on different detached leaves and isolated protoplasts-using small-angle neutron scattering. Freshly isolated thylakoid membranes suspended in isotonic or hypertonic media, containing sorbitol supplemented with cations, displayed Bragg peaks typically between 0.019 and 0.023Å(-1), corresponding to spatially and statistically averaged repeat distance values of about 275-330 Å⁻¹. Similar data obtained earlier led us in previous work to propose an origin from the periodicity of stroma thylakoid membranes. However, detached leaves, of eleven different species, infiltrated with or soaked in D2O in dim laboratory light or transpired with D2O prior to measurements, exhibited considerably smaller repeat distances, typically between 210 and 230 Å⁻¹, ruling out a stromal membrane origin. Similar values were obtained on isolated tobacco and spinach protoplasts. When NaCl was used as osmoticum, the Bragg peaks of isolated thylakoid membranes almost coincided with those in the same batch of leaves and the repeat distances were very close to the electron microscopically determined values in the grana. Although neutron scattering and electron microscopy yield somewhat different values, which is not fully understood, we can conclude that small-angle neutron scattering is a suitable technique to study the periodic organization of granal thylakoid membranes in intact leaves under physiological conditions and with a time resolution of minutes or shorter. We also show here, for the first time on leaves, that the periodicity of thylakoid membranes in situ responds dynamically to moderately strong illumination. This article is part of a special issue entitled: photosynthesis research for sustainability: keys to produce clean energy.

Severe skin inflammation and filaggrin mutation similarly alter the skin barrier in patients with atopic dermatitis.

BACKGROUND: Filaggrin (FLG) deficiency is a well-known predisposing factor for the development of atopic dermatitis (AD). Decreased FLG expression can be the result of haploinsufficiency or severe inflammation, which can cause acquired FLG alterations. FLG mutations are related to several clinical and laboratory parameters of AD; however, some recent data seem to contradict these associations. OBJECTIVES: Our aim was to determine which clinical and biochemical parameters are connected to FLG haploinsufficiency and which ones are also associated with acquired FLG alterations due to severe skin symptoms in patients with AD. METHODS: We introduced a novel classification of patients with AD, based on FLG mutations and SCORAD (SCORing Atopic Dermatitis). Based on these parameters, we created three groups of patients with AD: mild-to-moderate wild-type (A), severe wild-type (B) and severe mutant (C). In all groups, we assessed laboratory and clinical parameters and performed immunohistochemical analyses. RESULTS: Groups B and C contained patients with equally severe symptoms based on the SCORAD. The two severe groups did not differ significantly with respect to barrier-specific parameters, whereas group A had significantly better results for the barrier function measurements. However, significant differences were detected between groups B and C with respect to the allergic sensitization-specific parameters. CONCLUSIONS: These findings suggest that skin barrier function correlates with the severity of skin inflammation and can be equally impaired in patients with FLG mutant- and wild-type AD with severe symptoms. Nevertheless, our results also suggest that patients with FLG mutant-type AD may have a higher risk of allergic sensitization compared with patients with the wild-type.