[Hypereosinophilic syndrome and other rheumatic diseases with hypereosinophilia]. / Hypereosinophiles Syndrom und weitere rheumatische Erkrankungen mit Hypereosinophilie.

Among the eosinophilic diseases treated by rheumatologists other than eosinophilic granulomatosis with polyangiitis, there are further organ-related and systemic diseases with hypereosinophilia. Only the exact differential diagnostic demarcation of the diseases enables a pathogenetic oriented treatment. This article focuses on the hypereosinophilic syndromes. The potential differential diagnoses of Ig(immunoglobulin)G4-related disease, eosinophilic fasciitis and drug-induced vasculitis as well as eosinophilia-myalgia syndrome and toxic oil syndrome as historic drug-induced inflammatory rheumatic diseases are described and the clinical manifestations and treatment are summarized.

Pharmacokinetics, pharmacodynamics and clinical use of trazodone and its active metabolite m-chlorophenylpiperazine in the horse.

Trazodone is a serotonin receptor antagonist and reuptake inhibitor used extensively as an anxiolytic in human and small animal veterinary medicine. The aims of this study were to determine the pharmacokinetics of oral trazodone in experimental horses and to evaluate the effect of oral trazodone in clinical horses. Six experimental horses were administered trazodone at 7.5 or 10 mg/kg. Plasma concentrations of trazodone and its metabolite (m-CPP) were determined via UPLC-MS/MS. Noncompartmental pharmacokinetic analysis, sedation and ataxia scores were determined. Trazodone was rapidly absorbed after oral administration with a maximum concentration of 2.5-4.1 µg/ml and half-life of the terminal phase of approximately 7 hr. The metabolite was present at low levels in all horses, representing only 2.5% of the total area under the curve. In experimental horses, concentration-dependent sedation and ataxia were noted, lasting up to 12 hr. For clinical cases, medical records of horses treated with trazodone for various abnormal behaviours were reviewed and data were summarized. Trazodone was successful in modifying behavioural problems to some degree in 17 of 18 clinical cases. Tolerance and subsequent lack of drug effect occurred in two of 18 clinical cases following 14 or 21 days of use. In both populations of horses, adverse effects attributed to trazodone include oversedation, muscle fasciculations and transient arrhythmias.

Ionization of pyridine: Interplay of orbital relaxation and electron correlation.

The valence shell ionization spectrum of pyridine was studied using the third-order algebraic-diagrammatic construction approximation scheme for the one-particle Green's function and the outer-valence Green's function method. The results were used to interpret angle resolved photoelectron spectra recorded with synchrotron radiation in the photon energy range of 17-120 eV. The lowest four states of the pyridine radical cation, namely, 2A2(1a2-1), 2A1(7a1-1), 2B1(2b1-1), and 2B2(5b2-1), were studied in detail using various high-level electronic structure calculation methods. The vertical ionization energies were established using the equation-of-motion coupled-cluster approach with single, double, and triple excitations (EOM-IP-CCSDT) and the complete basis set extrapolation technique. Further interpretation of the electronic structure results was accomplished using Dyson orbitals, electron density difference plots, and a second-order perturbation theory treatment for the relaxation energy. Strong orbital relaxation and electron correlation effects were shown to accompany ionization of the 7a1 orbital, which formally represents the nonbonding σ-type nitrogen lone-pair (nσ) orbital. The theoretical work establishes the important roles of the π-system (π-π* excitations) in the screening of the nσ-hole and of the relaxation of the molecular orbitals in the formation of the 7a1(nσ)-1 state. Equilibrium geometric parameters were computed using the MP2 (second-order Møller-Plesset perturbation theory) and CCSD methods, and the harmonic vibrational frequencies were obtained at the MP2 level of theory for the lowest three cation states. The results were used to estimate the adiabatic 0-0 ionization energies, which were then compared to the available experimental and theoretical data. Photoelectron anisotropy parameters and photoionization partial cross sections, derived from the experimental spectra, were compared to predictions obtained with the continuum multiple scattering approach.

An experimental and theoretical study of the valence shell photoelectron spectra of 2-chloropyridine and 3-chloropyridine.

The valence shell photoelectron spectra of 2-chloropyridine and 3-chloropyridine have been studied both experimentally and theoretically. Synchrotron radiation has been employed to record angle resolved photoelectron spectra in the photon energy range 20-100 eV, and these have enabled anisotropy parameters and branching ratios to be derived. The experimental results have been compared with theoretical predictions obtained using the continuum multiple scattering Xα approach. This comparison shows that the anisotropy parameter associated with the nominally chlorine lone-pair orbital lying in the molecular plane is strongly affected by the atomic Cooper minimum. In contrast, the photoionization dynamics of the second lone-pair orbital, orientated perpendicular to the molecular plane, seem relatively unaffected by this atomic phenomenon. The outer valence ionization has been studied theoretically using the third-order algebraic-diagrammatic construction (ADC(3)) approximation scheme for the one-particle Green's function, the outer valence Green's function method, and the equation-of-motion (EOM) coupled cluster (CC) theory at the level of the EOM-IP-CCSD and EOM-EE-CC3 models. The convergence of the results to the complete basis set limit has been investigated. The ADC(3) method has been employed to compute the complete valence shell ionization spectra of 2-chloropyridine and 3-chloropyridine. The relaxation mechanism for ionization of the nitrogen σ-type lone-pair orbital (σN LP) has been found to be different to that for the corresponding chlorine lone-pair (σCl LP). For the σN LP orbital, π-π* excitations play the main role in the screening of the lone-pair hole. In contrast, excitations localized at the chlorine site involving the chlorine πCl LP lone-pair and the Cl 4p Rydberg orbital are the most important for the σCl LP orbital. The calculated photoelectron spectra have allowed assignments to be proposed for most of the structure observed in the experimental spectra. The theoretical work also highlights the formation of satellite states, due to the breakdown of the single particle model of ionization, in the inner valence region.

[Clinical spectrum of IgG4-related diseases and the connection to rheumatology]. / Klinisches Spektrum der IgG-4-assoziierten Erkrankungen und der Bezug zur Rheumatologie.

Rheumatologist should be familiar with the concept of IgG4-related disease (IgG4-RD). Due to the clinical spectrum IgG4-RD can fall directly within the scope of rheumatology and are often diagnosed primarily by rheumatologists. Furthermore, IgG4RD are relevant differential diagnoses for many other rheumatic conditions. Finally, there are an increasing amount of data suggesting an important role of immunological processes observed in IgG4-RD for other rheumatic diseases.

Pharmacokinetics and pharmacodynamics of three formulations of firocoxib in healthy horses.

The objectives of this study were to compare the pharmacokinetics and COX selectivity of three commercially available formulations of firocoxib in the horse. Six healthy adult horses were administered a single dose of 57 mg intravenous, oral paste or oral tablet firocoxib in a three-way, randomized, crossover design. Blood was collected at predetermined times for PGE2 and TXB2 concentrations, as well as plasma drug concentrations. Similar to other reports, firocoxib exhibited a long elimination half-life (31.07 ± 10.64 h), a large volume of distribution (1.81 ± 0.59L/kg), and a slow clearance (42.61 ± 11.28 mL/h/kg). Comparison of the oral formulations revealed a higher Cmax , shorter Tmax , and greater AUC for the paste compared to the tablet. Bioavailability was 112% and 88% for the paste and tablet, respectively. Maximum inhibition of PGE2 was 83.76% for the I.V. formulation, 52.95% for the oral paste formulation, and 46.22% for the oral tablet formulation. Pharmacodynamic modeling suggests an IC50 of approximately 27 ng/mL and an IC80 of 108 ng/ mL for COX2 inhibition. Inhibition of TXB2 production was not detected. This study indicates a lack of bioequivalence between the oral formulations of firocoxib when administered as a single dose to healthy horses.

[Polyarteritis nodosa: differential diagnostics and therapy]. / Polyarteriitis nodosa: Differenzialdiagnostik und Therapie.

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of medium size arteries that may affect various organs. The clinical appearance is very variable. The most common manifestations are of the skin, the peripheral nervous system presenting as mononeuritis multiplex and the mesenteric and renal blood vessels due to the development of stenoses and small aneurysms. Of the cases one third are estimated to be associated with hepatitis B virus (HBV). The therapy depends on the pathogenesis of the disease: primary PAN is treated with immunosuppressants, whereas patients with HBV-related PAN should receive antiviral therapy and plasmapheresis. Differentiating PAN from other forms of vasculitis can be difficult and requires complex differential diagnostics.

Transcatheter aortic valve implantation: alternative access options.

Calcific aortic valve stenosis represents the most common acquired valvular heart disease in adults. Transcatheter aortic valve implantation (TAVI) has been established as a widely accepted therapeutic option in elderly and multimorbid patients with severe aortic stenosis not amenable to conventional surgery. Retrograde transfemoral and antegrade transapical approaches are commonly used for implantation. However, there are a certain number of patients who are not candidates for either approach due to poor vascular access, severe pulmonary dysfunction or other prohibitive chest pathologies. Recently, different alternative access route options have been proposed and described. These alternative access routes include approaches via the subclavian/axillary artery, the ascending aorta, the carotid artery, and the brachiocephalic artery.

[Peripartum cardiomyopathy: interdisciplinary challenge]. / Peripartale Kardiomyopathie: Interdisziplinäre Herausforderung.

Peripartum cardiomyopathy (PPCM) is a rare type of heart failure which presents towards the end of pregnancy or in the first 5 months after delivery. Depending on the geographical location the incidence is reported in the literature as 1:300 up to 1:15,000. There are a number of known risk factors, such as multiparity and age of the mother over 30 years. The symptoms of PPCM correspond to those of idiopathic cardiomyopathy. The diagnosis is mainly carried out using echocardiography which shows a clear reduction of systolic left ventricular function. The therapeutic approach is the same as for idiopathic cardiomyopathy and in this context it is absolutely necessary to show caution concerning the state of pregnancy and the resulting contraindications for therapeutic drugs. The prognosis is dependent on recovery from the heart failure during the first 6 months postpartum. The lethality of the disease is high and is given in the literature as up to 28 %. Because of its complexity PPCM is an interdisciplinary challenge. In the peripartum phase a close cooperation between the disciplines of cardiology, cardiac surgery, neonatology, obstetrics and anesthesiology is indispensable. For anesthesiology the most important aspects are the mostly advanced unstable hemodynamic condition of the mother and the planning and implementation of the perioperative management. This article presents the case of a patient in advanced pregnancy with signs of acute severe heart failure and a suspected diagnosis of PPCM. The patient presented as an emergency case and delivery of the child was carried out using peridural anesthesia with a stand-by life support machine.

[Chronic periaortitis]. / Chronische Periaortitis.

Chronic periaortitis is an inflammatory and fibrosing disease presenting as periaortal fibrosis and formation of aortic aneurysms which are mostly localized in the retroperitoneum and occasionally in the mediastinum. Inflammatory vasculitic involvement of large vessels is also possible. In addition to symptoms of systemic inflammation, mechanical complications also occur whereby obstruction of the ureter is the most frequent. The diagnosis is made by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and if the findings are atypical the diagnosis should be confirmed by biopsy. After exclusion of a secondary genesis, in which case therapy of the underlying illness would be necessary, idiopathic chronic periaortitis can be treated with steroids. In cases of refractory and relapsing courses the administration of further immunosuppressive medication can be necessary. Duration of therapy, dosage and indications for immunosuppressive medication are currently unclear and have to be defined in further randomized controlled trials with larger cohorts. If complications occur, interventional or operative treatment can be necessary; in cases of hydronephrosis the placement of double-J-stents is usually sufficient.

[EHEC-associated colon stenosis after ulcerous-chronic haemorrhagic colitis and consecutive resulting ileus]. / EHEC-assoziierte Kolonstenose nach ulzerös-chronisch hämorrhagischer Kolitis mit konsekutivem Ileus.

We report on the case of a segmentally emphasised, ulcerous chronic haemorrhagic colitis with the development of granulation tissue und scarred fibrosis with consecutive resulting stenosis of the colon. A 49-year-old male patient was infected with enterohaemorrhagic Escherichia coli bacteria during the EHEC-epidemic in northern Germany in early summer 2011. In the course of the infection the patient suffered from haemolytic uraemic syndrome (HUS) with acute renal failure and neurological symptoms. Haemodialysis and plasmapheresis had become mandatory. A simultaneous ileus was estimated to be of paralytic origin. One month after treatment of the acute phase of the infection a CT scan of the abdomen was performed and discovered a symptomatic stenosis of the proximal colon transversum. This obstruction needed to be treated by performing a right hemicolectomy with an ileo-transverso anastomosis. After surgery the patient recovered continuously. The histopathological examination verified an ulcerous-chronic haemorrhagic colitis on the background of an EHEC infection.

Simultaneous transcatheter aortic and mitral valve-in-valve implantation in a patient with degenerated bioprostheses and high surgical risk.

Transcatheter valve-in-valve implantation is evolving as a promising alternative to reoperative valve replacement in selected high-risk patients, considering the increasing need for redo surgery due to bioprosthetic degeneration in the future. Reoperative double valve replacements are particularly associated with an elevated surgical risk. The transapical access provides the opportunity to approach the aortic and mitral valves during one intervention. We report the case of a successful transcatheter valve-in-valve implantation in the aortic and mitral position within a single procedure.

Early results of a real-world series with two transapical transcatheter mitral valve replacement devices.

AIMS: Transcatheter mitral valve replacement (TMVR) with dedicated devices promises to fill the treatment gap between open-heart surgery and edge-to-edge repair for patients with severe mitral regurgitation (MR). We herein present a single-centre experience of a TMVR series with two transapical devices. METHODS AND RESULTS: A total of 11 patients were treated with the Tendyne™ (N = 7) or the Tiara™ TMVR systems (N = 4) from 2016 to 2020 either as compassionate-use procedures or as commercial implants. Clinical and echocardiographic data were collected at baseline, discharge and follow-up and are presented in accordance with the Mitral Valve Academic Research Consortium (MVARC) definitions. The study cohort [age 77 years (73, 84); 27.3% male] presented with primary (N = 4), secondary (N = 5) or mixed (N = 2) MR etiology. Patients were symptomatic (all NYHA III/IV) and at high surgical risk [logEuroSCORE II 8.1% (4.0, 17.4)]. Rates of impaired RV function (72.7%), severe pulmonary hypertension (27.3%), moderate or severe tricuspid regurgitation (63.6%) and prior aortic valve replacement (63.6%) were high. Severe mitral annulus calcification was present in two patients. Technical success was achieved in all patients. In 90.9% (N = 10) MR was completely eliminated (i.e. no or trace MR). Procedural and 30-day mortality were 0.0%. At follow-up NYHA class was I/II in the majority of patients. Overall mortality after 3 and 6 months was 10.0% and 22.2%. CONCLUSIONS: TMVR was performed successfully in these selected patients with complete elimination of MR in the majority of patients. Short-term mortality was low and most patients experienced persisting functional improvement.

Pharmacokinetics and ex vivo anti-inflammatory effects of oral misoprostol in horses.

BACKGROUND: Misoprostol is an E prostanoid (EP) 2, 3 and 4 receptor agonist that is anecdotally used to treat and prevent NSAID-induced GI injury in horses. Misoprostol elicits anti-inflammatory effects in vivo in men and rodents, and inhibits TNFα production in equine leucocytes in vitro. OBJECTIVE: Define the pharmacokinetic parameters of oral misoprostol in horses, and determine the inhibitory effect of oral misoprostol administration on equine leucocyte TNFα production in an ex vivo inflammation model. STUDY DESIGN: Pharmacokinetic study, ex vivo experimental study. METHODS: Six healthy adult horses of mixed breeds were used. In phase one, horses were given 5 µg/kg misoprostol orally, and blood was collected at predetermined times for determination of misoprostol free acid (MFA) by UHPLC-MS/MS. Pharmacokinetic parameters were calculated. In phase two, horses were dosed as in phase one, and blood was collected at T0, 0.5, 1 and 4 h following misoprostol administration for leucocyte isolation. Leucocytes were stimulated with 100 ng/mL LPS, and TNFα mRNA concentrations were determined via quantitative real-time PCR. RESULTS: About 5 µg/kg oral misoprostol produced a rapid time to maximum concentration (Tmax ) of 23.4 ± 2.4 min, with a maximum concentration (Cmax ) of 0.29 ± 0.07 ng/mL and area under the curve (AUC0-∞ ) of 0.4 ± 0.12 h ng/mL. LPS stimulation of equine leucocytes ex vivo significantly increased TNFα mRNA concentrations, and there was no significant effect of misoprostol even at the Tmax . MAIN LIMITATIONS: Only a single dose was used, and sample size was small. CONCLUSIONS: Misoprostol is rapidly absorbed following oral administration in horses, and a single 5 µg/kg dose had no significant inhibitory effect on ex vivo LPS-stimulated TNFα mRNA production in leucocytes. Further studies analysing different dosing strategies, including repeat administration or combination with other anti-inflammatory drugs, are warranted.

Oral reserpine administration in horses results in low plasma concentrations that alter platelet biology.

BACKGROUND: Reserpine is a popular drug in the equine industry for long-term tranquilisation. Clinical observations revealed that blood from horses receiving oral reserpine was hypercoagulable. No studies have documented the pharmacokinetics of orally administered reserpine nor the effects of reserpine on platelets in horses. OBJECTIVES: To evaluate the pharmacokinetics of oral reserpine in horses and the effects of clinically relevant concentrations of reserpine on platelet functionality in vitro. STUDY DESIGN: Experimental controlled study. METHODS: The pharmacokinetics of oral reserpine (2.5 mg/horse, once) were determined in six healthy adult horses. Plasma samples were collected and concentrations of reserpine were determined by UPLC-MS/MS. Using this data, the in vitro effects of reserpine on platelets were examined. Aggregation, adhesion and releasate assays for serotonin and thromboxane B2 were performed on platelets exposed to varying concentrations of reserpine (0.01-10 ng/mL), aspirin (negative control) and saline (unexposed control). RESULTS: Oral reserpine administration demonstrated low plasma concentrations with a Cmax of 0.2 ± 0.06 ng/mL and a prolonged half-life of 23.6 ± 6.24 h. Simulations over a dose range of 2-8 µg/kg predicted Cmax at steady state between 0.06-0.9 ng/mL. Platelets exposed to these reserpine concentrations in vitro displayed increased aggregation and adhesion compared to unexposed or aspirin-exposed platelets as well as compared to higher concentrations of reserpine. These functional changes correlated with lower concentrations of serotonin and higher concentrations of thromboxane B2 in the platelet suspension supernatant. MAIN LIMITATIONS: This study used a small number of horses and only in vitro platelet experiments. CONCLUSIONS: Oral reserpine demonstrates low plasma concentrations and a prolonged half-life in horses. At these concentrations, reserpine causes significant changes in platelet function, most likely due to serotonin release and re-uptake which primes platelets for activation and thromboxane B2 release. These findings suggest that clinicians should harvest blood for biological processing prior to the onset of reserpine administration.

Family, patients, and organ and tissue donation: who decides?

OBJECTIVE: To identify who is responsible for the decision to donate organs and tissues from a deceased donor. METHODS: This cross-sectional study was performed with 69 family members of deceased donors, identified by the Organ Procurement Organization. RESULTS: The decision of the family regarding the request for donation took place after they had enough time to reflect on the matter (81.8%). The decision was made by the family (43.5%), by both family and donor (76.8%), by the family with previous knowledge about their deceased relative's wish (63.2%), or only by the donor (11.6%). There was familial conflict after the decision in about 7.2% of donations; 63.2% of the families were aware of their deceased relative's wish, and 90.5% were aware that their relative's wish helped them make the decision. Women were most frequently responsible for the decision to donate (55%). CONCLUSION: The donation process is experienced by all the family, regardless of who signs the consent form. At times, it is precisely the discussion about what is conflicting that will enable the familial decision. The donor's autonomy alone was shown to be a poor indicator, as the ones who decide about the donation are the family. This, therefore, legitimizes the alteration made to Law No. 9,434/97, which gives family members the responsibility for the decision about organ and tissue donation from their deceased relatives.

Development of Routine Dental Care for Liver Transplant Outpatients.

BACKGROUND: Liver transplantation has become commonplace for patients with end-stage liver disease. The liver is a bodily organ of great importance, and its dysfunction can cause significant complications throughout the body. Patients with hepatic disease should be able to acquire knowledge of the physiology of the liver via the dental profession, and it is also necessary to modify some aspects of dental treatment even in healthy patients. Problems such as excessive bleeding and hepatotoxicity caused by some of the drugs used in dental treatment can lead to a decrease in systemic health. Otherwise, patients with liver disease will have poorer oral health than the general population. Thus, it is important to have well-established routine dental care in this patient group and offer management of oral health in view of the effects of liver disease. METHODS: The objective of this work was to undertake a bibliographic review of the dental approaches to patients with liver disease and liver transplant recipients and to propose a dental care routine for such patients in an outpatient setting. RESULTS: A search was carried out on the main scientific databases (PubMed, Medline, and SciELO) for publications related to this subject and, particularly those published after 2010. The articles selected describe poor oral hygiene among patients, independent of the etiology of their liver disease. These patients also had a high index of xerostomia, caries, periodontal disease, apical lesions, and fungical infections. To control bleeding during and after surgery, hemostatic measures must be understood and adopted. CONCLUSION: There are no data about routine dental care among liver disease/transplantation patients. Thus, our findings will hopefully encourage other services to structure their approaches and consider enhancing their dental care protocols for patients with liver-related complications.