Challenging diagnosis and successful treatment of localised Mycobacterium avium subsp. hominissuis glossitis in a dog on long-term immunomodulatory therapy.

CASE HISTORY: A 3-year-old, intact female mixed-breed dog, weighing 7 kg, was presented with generalised swelling of the tongue, leading to impaired deglutition and episodes of dyspnoea. From the age of 2 years, the dog had been under immunosuppressive therapy due to atopic dermatitis. CLINICAL FINDINGS AND TREATMENT: Multiple nodular lesions at the apex of the tongue were noted as well as mandibular and retropharyngeal lymph node enlargement. Serum biochemistry results showed inflammatory changes. The results of several biopsies taken over 7 months indicated persistent pyogranulomatous and necrotising glossitis despite ongoing antimicrobial treatment, first with amoxicillin/clavulanic acid and then pradofloxacin. No foreign material, acid-fast bacteria or fungal hyphae were detected throughout. The final diagnosis of Mycobacterium avium subsp. hominissuis (Mah) was reached after PCR and bacterial culture were carried out on the third biopsy sample. Therapy was initiated with rifampicin, clarithromycin and doxycycline, leading to complete remission of the lesions. DIAGNOSIS: Severe chronic pyogranulomatous and necrotising glossitis associated with infection by Mah. CLINICAL RELEVANCE: This report describes challenges in the diagnosis and therapy of a localised Mah infection in an iatrogenically immunocompromised dog. Successful treatment was only achieved with a specific combination of antibiotics administered long-term. ABBREVIATIONS: AF: Acid-fast; ALP: Alkaline phosphatase; CT: Computed tomography; MAC: Mycobacterium avium complex; Mah: Mycobacterium avium subsp. hominissuis.

[Telemedicine in heart failure]. / Telemedizin bei Herzinsuffizienz.

Improved outpatient care of heart failure patients is considered crucial to avoiding unplanned cardiovascular hospitalizations and reducing mortality. Making up for regional and rural differences in heart failure care poses a further challenge. Telemedical care as a supplement to outpatient point-of-care medicine by the general practitioner and medical specialist is considered relevant to implementing this goal. This article presents the technical and organizational basics of telemedical methods in outpatient heart failure care. Current evidence on the efficacy of telemedical co-management is also explained based on the results from the nine most important randomized studies on telemedicine in heart failure. Particular attention is paid to the TIM-HF2 study published in 2018, which showed the superiority of telemedical co-management in terms of mortality and morbidity following recent hospitalization for heart failure. Pre-stratified subgroup analysis revealed no significant interactions in terms of the primary endpoint between urban and rural regions. Scalability is required in order to translate the telemedical study concept from TIM-HF2 to a nationwide care program for all patients in Germany. Telemed5000 is the first project to set its goal as the development of a telemedicine center for the telemedical co-management of up to 5000 patients using artificial intelligence. It is being funded by the Federal Ministry of Economics and Technology for the period 2019-2022.

Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog.

Neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases that have been described in a variety of dog breeds, where they are caused by different mutations in different genes. However, the causative gene defect in the breed Alpenländische Dachsbracke remained unknown so far. Here we present two confirmed cases of NCL in Alpenländische Dachsbracke dogs from different litters of the same sire with a different dam harboring the same underlying novel mutation in the CLN8 gene. Case 1, a 2-year-old male Alpenländische Dachsbracke was presented with neurological signs including disorientation, character changes including anxiety states and aggressiveness, sudden blindness and reduction of food intake. Magnetic resonance imaging (MRI) scans showed cerebral atrophy with dilation of all cerebral ventricles, thinning of the intermediate mass of the thalamus and widening of the cerebral sulci. Postmortem examination of the central nervous system (CNS) showed neuronal loss in the cerebral cortex, cerebellum and spinal cord with massive intracellular deposits of ceroid pigment. Additional ceroid-lipofuscin deposits were observed in the enteric nervous system and in macrophages within spleen, lymph nodes and lung. Ultrastructural analyses confirmed NCL with the presence of osmiophilic membrane bounded lamellar-like structures. Case 2, a 1,5-year old female Alpenländische Dachsbracke was presented with progressive generalized forebrain disease including mental changes such as fearful reactions to various kinds of external stimuli and disorientation. The dog also displayed seizures, absence of menace reactions and negative cotton-ball test with normal pupillary light reactions. The clinical and post mortem examination yielded similar results in the brain as in Case 1. Whole genome sequencing of Case 1 and PCR results of both cases revealed a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form observed in both cases. The deletion follows recessive inheritance since the dam and a healthy male littermate of Case 1 were tested as heterozygous carriers. This is the first detailed description of CLN8 gene associated NCL in Alpenländische Dachsbracke dogs and thus provides a novel canine CLN8 model for this lysosomal storage disease. The presence of ceroid lipofuscin in extracerebral tissues may help to confirm the diagnosis of NCL in vivo, especially in new dog breeds where the underlying mutation is not known.

The IGFBP7 homolog Imp-L2 promotes insulin signaling in distinct neurons of the Drosophila brain.

In Drosophila, Insulin-like peptide 2 (Dilp-2) is expressed by insulin-producing cells in the brain, and is secreted into the hemolymph to activate insulin signaling systemically. Within the brain, however, a more local activation of insulin signaling may be required to couple behavioral and physiological traits to nutritional inputs. We show that a small subset of neurons in the larval brain has high Dilp-2-mediated insulin signaling activity. This local insulin signaling activation is accompanied by selective Dilp-2 uptake and depends on the expression of the Imaginal morphogenesis protein-late 2 (Imp-L2) in the target neurons. We suggest that Imp-L2 acts as a licensing factor for neuronal IIS activation through Dilp-2 to further increase the precision of insulin activity in the brain.

Acute metabolic, hormonal, and psychological responses to different endurance training protocols.

In the last years, mainly 2 high-intensity-training (HIT) protocols became common: first, a Wingate-based "all-out" protocol and second, a 4×4 min protocol. However, no direct comparison between these protocols exists, and also a comparison with high-volume-training (HVT) is missing. Therefore, the aim of the present study was to compare these 3 endurance training protocols on metabolic, hormonal, and psychological responses. Twelve subjects performed: 1) HVT [130 min at 55% peak power output (PPO)]; 2) 4×4 min at 95% PPO; 3) 4×30 s all-out. Human growth hormone (hGH), testosterone, and cortisol were determined before (pre) and 0', 30', 60', 180' after each intervention. Metabolic stimuli and perturbations were characterized by lactate, blood gas (pH, BE, HCO3⁻, pO2, PCO2), and spirometric analysis. Furthermore, changes of the person's perceived physical state were determined. The 4×30 s training caused the highest increases in cortisol and hGH, followed by 4 × 4 min and HVT. Testosterone levels were significantly increased by all 3 exercise protocols. Metabolic stress was highest during and after 4×30 s, followed by 4×4 min and HVT. The 4×30 s training was also the most demanding intervention from an athlete's point of view. In conclusion, the results suggest that 4×30 s and 4×4 min promote anabolic processes more than HVT, due to higher increases of hGH, testosterone, and the T/C ratio. It can be speculated that the acute hormonal increase and the metabolic perturbations might play a positive role in optimizing training adaptation and in eliciting health benefits as it has been shown by previous long term training studies using similar exercise protocols.

ECMO cannula review.

This paper reviews the basic fluid dynamics underlying extracorporeal membrane oxygenation (ECMO) cannula design. General cannula features and their effect on flow are discussed and the specific requirements of different ECMO circuits are explained. The current commercially available cannula options for veno-arterial and veno-venous circuits are reviewed and the main characteristics presented.

[Old and immobile in rural areas? Limited mobility of the elderly in the context of increasingly problematic health care in rural regions]. / Alt und immobil auf dem Land? Mobilitätseinschränkungen älterer Menschen vor dem Hintergrund einer zunehmend problematischen Gesundheitsversorgung in ländlichen Regionen.

Against the background of considerable population ageing processes in rural areas, it is expected that access to the health care system in these regions will deteriorate. Within this context, the question arises as to whether elderly people have the ability to overcome increasing distances in order to receive adequate medical care. Hence the objective of this study is an in-depth analysis of the everyday mobility of elderly people living in rural areas. The empirical analysis is based on the German National Travel Survey "Mobilität in Deutschland 2008". Findings show that older women in particular experience limitations in their mobility options. Only 63% of mobility-impaired women (aged > 75 years) were mobile outside their homes, and only 37% had access to a car, which can be regarded as the crucial factor for being mobile. It follows that older and mobility-impaired women have to cope with everyday life under difficult conditions. In the context of the growing problem of access to the health care system in rural areas, the challenge is to ensure adequate primary health care for a large proportion of the immobile elderly.

Naturally occurring compensated insulin resistance selectively alters glucose transporters in visceral and subcutaneous adipose tissues without change in AS160 activation.

Although the importance of adipose tissue (AT) glucose transport in regulating whole-body insulin sensitivity is becoming increasingly evident and insulin resistance (IR) has been widely recognized, the underlying mechanisms of IR are still not well understood. The purpose of the present study was to determine the early pathological changes in glucose transport by characterizing the alterations in glucose transporters (GLUT) in multiple visceral and subcutaneous adipose depots in a large animal model of naturally occurring compensated IR. AT biopsies were collected from horses, which were classified as insulin-sensitive (IS) or compensated IR based on the results of an insulin-modified frequently sampled intravenous glucose tolerance test. Protein expression of GLUT4 (major isoform) and GLUT12 (one of the most recently discovered isoforms) were measured by Western blotting in multiple AT depots, as well as AS160 (a potential key player in GLUT trafficking pathway). Using a biotinylated bis-mannose photolabeled technique, active cell surface GLUT content was quantified. Omental AT had the highest total GLUT content compared to other sites during the IS state. IR was associated with a significantly reduced total GLUT4 content in omental AT, without a change in content in other visceral or subcutaneous adipose sites. In addition, active cell surface GLUT-4, but not -12, was significantly lower in AT of IR compared to IS horses, without change in AS160 phosphorylation between groups. Our data suggest that GLUT4, but not GLUT12, is a pathogenic factor in AT during naturally occurring compensated IR, despite normal AS160 activation.

Chronic Fragmentation of the Daily Sleep-Wake Rhythm Increases Amyloid-beta Levels and Neuroinflammation in the 3xTg-AD Mouse Model of Alzheimer's Disease.

Fragmentation of the daily sleep-wake rhythm with increased nighttime awakenings and more daytime naps is correlated with the risk of development of Alzheimer's disease (AD). To explore whether a causal relationship underlies this correlation, the present study tested the hypothesis that chronic fragmentation of the daily sleep-wake rhythm stimulates brain amyloid-beta (Aß) levels and neuroinflammation in the 3xTg-AD mouse model of AD. Female 3xTg-AD mice were allowed to sleep undisturbed or were subjected to chronic sleep fragmentation consisting of four daily sessions of enforced wakefulness (one hour each) evenly distributed during the light phase, five days a week for four weeks. Piezoelectric sleep recording revealed that sleep fragmentation altered the daily sleep-wake rhythm to resemble the pattern observed in AD. Levels of amyloid-beta (Aß40 and Aß42) determined by ELISA were higher in hippocampal tissue collected from sleep-fragmented mice than from undisturbed controls. In contrast, hippocampal levels of tau and phospho-tau differed minimally between sleep fragmented and undisturbed control mice. Sleep fragmentation also stimulated neuroinflammation as shown by increased expression of markers of microglial activation and proinflammatory cytokines measured by q-RT-PCR analysis of hippocampal samples. No significant effects of sleep fragmentation on Aß, tau, or neuroinflammation were observed in the cerebral cortex. These studies support the concept that improving sleep consolidation in individuals at risk for AD may be beneficial for slowing the onset or progression of this devastating neurodegenerative disease.

Immunohistochemistry and pathology of multiple Great Lakes fish from mortality events associated with viral hemorrhagic septicemia virus type IVb.

A novel viral hemorrhagic septicemia virus (VHSV) (genotype IVb) has been isolated from mortality events in a range of wild freshwater fish from the Great Lakes since 2005. In 2005 and 2006, numerous new freshwater host species (approximately 90 fish from 12 different species) were confirmed to have VHSV by cell culture and reverse transcriptase polymerase chain reaction. A prominent feature observed in infected fish were the petechial and ecchymotic haemorrhages on the body surface and in visceral organs, as well as serosanguinous ascites; however, many fish had few and subtle, gross lesions. Histologically, virtually all fish had a vasculitis and multifocal necrosis of numerous tissues. Excellent correlation was found between the presence of VHSV IVb antigen detected by immunohistochemistry and the pathological changes noted by light microscopy. Intact and degenerate leukocytes, including cells resembling lymphocytes and macrophages, also had cytoplasmic viral antigen. By contrast, renal tubules and gonadal tissues (ovary and testis), were strongly immunopositive for VHSV IVb, but no lesions were noted.

An improved strip FRAP method for estimating diffusion coefficients: correcting for the degree of photobleaching.

Fluorescence recovery after photobleaching is a widely established method for the estimation of diffusion coefficients, strip bleaching with an associated recovery curve analysis being one of the simplest techniques. However, its implementation requires near 100% bleaching in the region of interest with negligible fluorescence loss outside, both constraints being hard to achieve concomitantly for fast diffusing molecules. We demonstrate that when these requirements are not met there is an error in the estimation of the diffusion coefficient D, either an under- or overestimation depending on which assumption is violated the most. We propose a simple modification to the recovery curve analysis incorporating the concept of the relative bleached mass m giving a revised recovery time parametrization tau=m(2)w(2)/4piD for a strip of width w. This modified model removes the requirement of 100% bleaching in the region of interest and allows for limited diffusion of the fluorophore during bleaching. We validate our method by estimating the (volume) diffusion coefficient of FITC-labelled IgG in 60% glycerol solution, D= 4.09 +/- 0.21 microm(2) s(-1), and the (surface) diffusion coefficient of a green-fluorescent protein-tagged class I MHC protein expressed at the surface of a human B cell line, D= 0.32 +/- 0.03 microm(2) s(-1) for a population of cells.

Fatal cowpox virus infection in captive banded mongooses (Mungos mungo).

Cowpox virus infections have been described in various domestic and exotic animal species. This report is the first on an outbreak of fatal generalized cowpox virus infection among captive banded mongooses (Mungos mungo, suborder Feliformia). All animals of a colony of 8 mongooses showed a fulminant course of disease. The whole population died (n=7) or was euthanized (n=1) within 11 days. Postmortem examinations were performed on 4 animals. All animals showed extensive necrotizing inflammation of retropharyngeal lymph nodes, typical poxviral skin lesions, and multiple necrotic foci in liver and spleen. Three animals exhibited an ulcerating stomatitis. Pulmonary lesions, a common feature of fatal cowpox virus infections in other feliform species, were not obvious. Histopathologically, characteristic cytoplasmic inclusion bodies were detected in all affected organs but the spleen. Based on transmission electron microscopy and cell culture, Orthopoxvirus was identified as the etiology. The virus was further characterized by polymerase chain reaction and sequence analysis, identifying it as cowpox virus. A survey in the habitat suggests wild brown rats (Rattus norvegicus) as the most likely source of infection.

Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer.

BACKGROUND: This phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed. PATIENTS AND METHODS: Pemetrexed 500 mg/m(2) with folic acid and vitamin B(12) was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1-15 without initial loading dose and 250 mg b.i.d. on days 16-30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d. RESULTS: Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (C(av,ss)) decreased by approximately 25% in the presence of pemetrexed. Enzastaurin C(av,ss) were approximately 40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST. CONCLUSIONS: Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.

Possible involvement of messenger RNA-associated proteins in protein synthesis.

Two distinct forms of globin messenger RNA were isolated from mouse spleen cells infected with Friend erythroleukemia virus: polyribosomal messenger ribonucleoprotein particles (15S mRNP), and their corresponding protein-free mRNAs obtained by chemical deproteinization. The translation efficiencies of both messenger forms were assayed in a Krebs II ascites cell-free system. Selective removal of RNA-binding proteins from the ascites cell lysate did not affect globin synthesis when the mRNA was supplied as 15S mRNP; deproteinized mRNA however was not translated. Only in the presence of two fractions of RNA-binding proteins was the protein-free mRNA translated. Some of the RNA-binding proteins have the same molecular weights and isoelectric points as the principal proteins of 15S mRNP.

Biochemical characterisation of TCTP questions its function as a guanine nucleotide exchange factor for Rheb.

Translationally controlled tumour protein (TCTP) is involved in malignant transformation and regulation of apoptosis. It has been postulated to serve as a guanine nucleotide exchange factor for the small G-protein Rheb. Rheb functions in the PI3 kinase/mTOR pathway. The study presented here was initiated to characterise the interaction between TCTP and Rheb biochemically. Since (i) no exchange activity of TCTP towards Rheb could be detected in vitro, (ii) no interaction between TCTP and Rheb could be detected by NMR spectroscopy, and (iii) no effect of TCTP depletion in cells on the direct downstream targets of Rheb could be observed in vivo, this study shows that TCTP is unlikely to be a guanine nucleotide exchange factor for Rheb.

Advanced age in horses affects divisional history of T cells and inflammatory cytokine production.

A number of model systems have been employed to investigate age-associated changes in immune function. The purpose of the current study was to characterize senescent T cells and to investigate the inflamm-aging phenomenon both in vitro and in vivo using the old horse as a model. We examined whether decreased T cell proliferation induced by Con A is caused by increased apoptosis. We also utilized intracellular CFSE to analyze changes within each round of cell proliferation, in particular cytokine production. Intracellular staining with flow cytometry, RT-PCR, and ELISA were used to measure pro-inflammatory cytokines both in vitro and in vivo. While lymphocytes from old horses exhibit decreased proliferation, this is not the result of increased apoptosis. Instead, a larger percentage of the T cells remain in the parent generation and produce significant amounts of IFNgamma. Likewise, old horses have increased frequency of CD8-IFNgamma+ T cells and TNFalpha producing cells. We also show that old horses have elevated levels of IL-1beta, IL-15, IL-18 and TNFalpha gene expression in peripheral blood and significant levels of TNFalpha protein in serum, all characteristics of inflamm-aging.

A complex malformation in a pig: case report and review of the literature.

Congenital defects like myofibrillar dysplasia (splayleg), umbilical and inguinal hernias, cryptorchism, intersexes, and anal atresia occur relatively frequently in swine. On the other hand, some developmental anomalies like double monsters are very rare. The present paper reports a rare case of a congenital complex malformation including polymelia, duplicitas coli partialis et recti, atresia ani et fistula rectogenitalis, duplicitas corpori uteri, cervicis, vaginae et vulvae and duplicitas vesicae, urethrae et renalis. A plausible interpretation concerning the etiology is that the anomalies arose from unequal partial twinning. The pig has been healthy and inconspicuous. Although no anus was formed defecation took place via a fistula to one of the vaginas. Posture and behaviour of the pig were normal. Cytogenetic analysis of blood lymphocytes revealed no numerical or gross structural anomalies. There have been no further piglets with developmental disorders in the same litter, in a second litter of the same parents and in other twelve litters by the same boar.

Calicivirus co-infections in herpesvirus pneumonia in kittens.

Felid herpesvirus-1 (FeHV-1) and feline calicivirus (FCV) are the most important infectious causes of respiratory disease in cats. FeHV-1 and FCV co-infections are common in cats with upper respiratory tract disease, but it is unknown whether such co-infections also occur in cats with pneumonia. This study examined the lungs of naturally infected cats with FeHV-1 pneumonia for FCV co-infection by histopathology and immunohistochemistry. The frequency of FCV (13/21, 62%) in this group of cats suggests that co-infection is common in kittens with FeHV-1 pneumonia. FCV infected macrophages were often found in the lumen of FeHV-1 affected airways. In 8/13 (62%) cats, typical FCV lesions were distant from changes induced by FeHV-1. FCV infection of type II pneumocytes/alveolar macrophages was apparent in histologically unaltered areas. It is likely that damage to airways induced by FeHV-1 facilitates secondary infection with FCV due to reduced mucociliary clearance and impaired immune defences.

Rheumatic Heart Disease: Pathogenesis and Vaccine.

Rheumatic fever (RF) and rheumatic heart disease (RHD) follow untreated S. pyogenes throat infections in children who present susceptible genes that favor the development of autoimmune reactions. In this review, we focus on the genes that confer susceptibility and on the autoimmune reactions that occur due to molecular mimicry between human-tissue proteins and streptococcal M protein. Polyarthritis is the initial manifestation, which can evolve to carditis and severe valve damage; these culminate in rheumatic heart disease (RHD) or Sydenham's chorea, which affects the central nervous system. A perspective on vaccine development to prevent the disease is also discussed.

Tunable, Single-frequency, Diode-pumped 2.3mum VECSEL.

We report high-performance single-frequency operation of a directly diode-pumped GaSb-based vertical-external-cavity surface-emitting laser (VECSEL) at 2.3mum. Tunability of 70nm and a maximum single frequency output of 0.68W is demonstrated.