Identification of genomic regions associated with resistance to gastrointestinal parasites in an indigenous sheep by single- and multiple-locus methods.

We investigated the association between 157 SNPs located in 75 candidate genes involved in the immune system and proxy traits for resistance to gastrointestinal nematodes in sheep. A total of 211 lambs from eight flocks were sampled. Nematode eggs per gram were counted and classified as: (i) Strongyles, (ii) Nematodirus spp., (iii) Trichuris spp. and (iv) Marshallagia marshalli. Single- and multiple-locus models were used to test the marker-trait associations. Seven significant SNPs were identified on chromosomes OAR6, 15, 16, and 19. These findings provide insights for breeding nemarode-resistant traits in low-input production systems. General linear model, fixed and random model circulating probability unification, and Bayesian-information and linkage-disequilibrium iteratively nested keyway analyses identified a significant association between the eggs per gram of Strongyles nematodes and a specific variant of the PRLR gene.

Vinorelbine in bladder-preserving multimodality treatment for muscle-invasive bladder cancer-a valid option for cisplatin-unfit patients?

PURPOSE: Treatment of muscle-invasive bladder cancer (MIBC) remains challenging, especially for elderly and/or comorbid patients. Patients who are unfit for or refuse surgery should receive bladder-preserving multimodality treatment (BPMT), consisting of transurethral resection of the bladder tumor (TURB) followed by combined chemoradiotherapy (CRT). We aimed to investigate the effectiveness of vinorelbine, a chemotherapeutic agent not routinely used for MIBC, in patients referred to CRT who are unfit for standard chemotherapy and would thus rely solely on radiotherapy (RT). METHODS: We retrospectively analyzed 52 consecutive patients with MIBC who received standard CRT with cisplatin (n = 14), CRT with vinorelbine (n = 26), or RT alone (n = 12). Primary endpoints were median overall survival (OS) and median cancer-specific survival (CSS). Secondary endpoints were median local control (LC), median distant control (DC), and OS, CSS, LC, and DC after 1, 2, and 3 years, respectively. RESULTS: Median OS and CSS were significantly higher for patients who received vinorelbine as compared to RT alone (OS 8 vs. 22 months, p = 0.003; CSS 11 months vs. not reached, p = 0.001). Median LC and DC did not differ significantly between groups. Vinorelbine was well tolerated with no reported side effects >grade II. CONCLUSION: Our results suggest that CRT with vinorelbine is well tolerated and superior to RT alone in terms of OS and CSS. Therefore, this treatment regime might constitute a new treatment option for patients with MIBC who are unfit for or refuse surgery or standard chemotherapy. This study encourages a randomized controlled trial to compare this new regime to current standard therapies.

A rare case of a 123I-MIBG SPECT/CT positive, but 68Ga-DOTA-TOC PET/CT negative pheochromocytoma of the bladder. / Caso infrecuente de feocromocitoma vesical positivo en la SPECT/TC con 123I-MIBG, pero negativo en la PET/TC con 68Ga-DOTA-TOC.

Pheochromocytoma (PHEO) is rare and belongs to the group of neuroendocrine tumours (NETs). These tumours can be found anywhere from the neck to the pelvis associated with sympathetic ganglia. Morphological imaging, for example CT, provides excellent anatomical detail and high sensitivity but lacks specificity as difficulties may occur when distinguishing between tumours derived from the sympathetic nervous system and other tumour entities. In contrast to anatomical imaging, functional imaging (123I-MIBG, 68Ga-DOTA-TOC PET) provides high sensitivity and specificity in detecting NETs. Early detection of PHEO is crucial and has a major effect on treatment and prognosis. This case report describes the important role of anatomical and functional imaging in a patient with a neuroendocrine tumour of unusual origin.

A hybrid, low-cost tissue-like epidural needle insertion simulator.

Epidural and spinal anesthesia are mostly performed "blind" without any medical imaging. Currently, training of these procedures is performed on human specimens, virtual reality systems, manikins and mostly in clinical practice supervised by a professional. In this study a novel hybrid, low-cost patient simulator for the training of needle insertion into the epidural space was designed. The patient phantom provides a realistic force feedback comparable with biological tissue and enables sensing of the needle tip position during insertion. A display delivers the trainee a real-time feedback of the needle tip position.

ProPSA and the Prostate Health Index as predictive markers for aggressiveness in low-risk prostate cancer-results from an international multicenter study.

BACKGROUND: One of the major challenges in prostate cancer (PCa) treatment is distinguishing insignificant PCa from those forms that need active treatment. We evaluated the impact of PSA isoforms on risk stratification in patients with low-risk PCa as well as in active surveillance (AS) candidates who underwent radical prostatectomy. METHODS: A total of 112 patients with biopsy confirmed Gleason score (GS) 6 PCa of four different international institutions were prospectively enrolled in the study. Blood withdrawal was performed the day before radical prostatectomy. In addition, patients were classified according to the EAU and NCCN criteria for AS candidates. PSA, free PSA (fPSA) and proPSA were measured using dual monoclonal antibody sandwich immunoassays. In addition, the Prostate Health Index (PHI=proPSA/fPSA × âˆšPSA) was calculated. Final histology of the radical prostatectomy specimens was correlated to PSA, its isoforms and PHI. RESULTS: Serum proPSA levels were significantly elevated in those patients with an upgrade in final histology (GS⩾7). In addition, higher proPSA levels were predictive for extraprostatic extension (⩾pT3a) as well as for positive surgical margins. Interestingly, PHI had an even higher predictive power when compared with proPSA alone concerning GS upgrading, extraprostatic extension and surgical margins in both the total and the AS patient group. CONCLUSION: We showed in a multicenter study that proPSA is a valuable biomarker to detect patients with aggressive PCa in a cohort of GS 6 patients, who would benefit from active tumor therapy. Combining proPSA with the standard markers PSA and fPSA using PHI further increases the predictive accuracy significantly. Moreover, our data support the use of PHI for monitoring PCa patients under AS.

[Bevacizumab as first-line therapy in metastatic renal cell carcinoma: Progression-free survival for 3 years]. / Metastasiertes Nierenzellkarzinom unter Bevacizumab als Erstlinientherapie : Progressionsfreies Überleben seit 3 Jahren.

We report the case of a 72-year-old woman who was diagnosed in 2006 with renal cell cancer (RCC) and had undergone consecutive tumor nephrectomy (clear-cell RCC, Fuhrmann grade II, stage pT3a, R0). Over the years, the patient underwent several surgical and radiological interventions due to various metastatic lesions. This case report describes the 3-year progression-free survival in a patient who underwent first-line therapy with the monoclonal antibody bevacizumab. Except for hypertension, the patient does not suffer currently from any other side effects of bevacizumab therapy.

Rare clinical findings in a patient with sporadic hemiplegic migraine: FDG-PET provides diminished brain metabolism at 10-year follow-up.

BACKGROUND: Sporadic hemiplegic migraine (SHM) is defined as migraine attacks associated with some degree of motor weakness during the aura phase and where no first-degree relative has identical attacks. SHM has a wide inter- and intraindividual clinical spectrum and, in case of prolonged aura symptoms and disturbed consciousness, can mimic several other acute neurological diseases. CASE: In 1996, during his wedding night, a 28-year-old man developed left face, arm and leg weakness, nausea and a throbbing headache. Neurological examination on presentation revealed stupor, fever, meningism and left hemiplegia. There were no abnormalities on emergency magnetic resonance. Lumbar puncture showed mild lymphocytic pleocytosis and slightly elevated protein. He received symptomatic treatment. Subsequent genetic analysis revealed the T666M mutation in the CACNA1A gene of chromosome 19. He was diagnosed with SHM. In 2005, at the end of another episode of hemiplegic migraine (HM), he for the first time developed an episode of paranoid psychosis with anxiety and visual hallucinations. The psychiatric symptoms resolved within a week. DISCUSSION: All perfusion SPECT and transcranial Doppler studies performed in the first days of HM attacks were consistent with hyperemia of the hemisphere contralateral to the neurological signs. FDG-PET/CT in January 2013 revealed a diffusely reduced glucose metabolism of the supratentorial cortex and marked asymmetric hypometabolism of the left cerebellum. The finding of progressive cortical metabolic dysfunction over years appears as a new finding. Glucose hypometabolism may indicate primary neuronal dysfunction as the cause of the prolonged deficits.

[-2]proPSA is an early marker for prostate cancer aggressiveness.

BACKGROUND: The aim of the study was to evaluate the correlation between preoperative [-2]proPSA, the Gleason Score (GS) and the risk of non-organ-confined (NOC) disease in patients undergoing radical prostatectomy (RP). METHODS: Beckman Coulter Access immunoassay was used to study serum specimens of 381 patients enrolled in a prostate cancer (PCa) early detection program. Inclusion criteria were three or more available serum specimens over 4 years before diagnosis. The values obtained were correlated with the GSs and pathological stages of specimens obtained at RP. RESULTS: [-2]proPSA levels were significantly higher in the cancer group (n=208) than in the benign group (n=173). Already 4 years before diagnosis [-2]proPSA differed significantly between PCa and benign prostate in all measured time points, however, highest prediction value was 2 and 1 years before diagnosis (P<0.001). When stratified [-2]proPSA levels according to GS of RP specimens, [-2]proPSA was highest in patients with ≥GS8 and lowest in those with ≤GS6.The difference in [-2]proPSA values between GS≥8 and GS≤7 was highly significant (P<0.01) already 3 years before diagnosis. Investigating the correlation between extraprostatic extension and the preoperative [-2]proPSA levels we found preoperative [-2]proPSA values significantly higher in men with NOC PCa compared with organ-confined (OC) cancers.The highest predictive value of [-2]proPSA to differ between OC and extraprostatic extension was found 3 and 2 years before RP. CONCLUSIONS: Patients with high [-2]proPSA levels in the years before cancer diagnosis are at a higher risk of having aggressive PCas. Thus, the [-2]proPSA should be included in the treatment decision-making for managing screen-detected PCa.

[A biomechanical analysis of cyclical hand motor function: a pilot study in different Parkinsonian syndromes]. / Biomechanische Analyse zyklischer Handfunktionen : Eine Pilotstudie bei unterschiedlichen Parkinson-Syndromen.

INTRODUCTION: Clinical assessment of hand bradykinesia in Parkinson's disease (PD) focuses mainly on the frequency, amplitude and rhythm of movements, thereby subjectively evaluating the correct performance of hand movements. The aim of the study was to quantify hand bradykinesia with kinematic data in different Parkinsonian syndromes. PATIENTS AND METHODS: This retrospective study compared patients with idiopathic PD (IPD, n = 18), atypical Parkinson's syndrome (APS, n = 17), secondary Parkinson's syndrome (SPS, n = 18) and healthy controls (C, n = 18). All patients were receiving the best medical treatment. Hand movements were recorded using an ultrasound-system (Zebris®, Isny, Germany). Subjects were asked to perform pronation/supination of the forearm (diadochokinesis), flexion/extension of the hand (hand tapping) and tapping of the index finger. Mean amplitude, mean frequency and mean variability of movements were determined. RESULTS: APS patients had significant complex hand movement disability with reduced amplitude and frequency in combination with increased motion variability in all movement tasks. The key disturbance in the IPD group concerned the rhythm in hand tapping and index finger tapping in combination with moderately reduced velocity and range of motion in all conditions. The cyclical hand movement characteristics in SPS patients showed movement slowness with normal amplitude and variability in all motor conditions. CONCLUSION: Our results suggest that computerized quantitative analysis of cyclical hand movements can characterize and identify different representations of hand bradykinesia in different Parkinsonian disorders and hence may help clinicians to accurately assess therapeutic targets and outcome of interventions.

Proteinuria in diabetic kidney disease: a mechanistic viewpoint.

Proteinuria is the hallmark of diabetic kidney disease (DKD) and is an independent risk factor for both renal disease progression, and cardiovascular disease. Although the characteristic pathological changes in DKD include thickening of the glomerular basement membrane and mesangial expansion, these changes per se do not readily explain how patients develop proteinuria. Recent advances in podocyte and glomerular endothelial cell biology have shifted our focus to also include these cells of the glomerular filtration barrier in the development of proteinuria in DKD. This review describes the pathophysiological mechanisms at a cellular level which explain why patients with DKD develop proteinuria.

Optimizing processing parameters for signal enhancement of oligonucleotide and protein arrays on ARChip Epoxy.

Signal enhancement of oligonucleotide and protein arrays on ARChip Epoxy was achieved by optimizing chip processing parameters. The parameters investigated were fabrication, blocking and guide dot concentration, probe concentration and modification, print buffer, humidity during arraying, slide agitation, spot volume and spotter compatibility. The optimum oligonucleotide concentration was 20 microM, while the optimum protein concentration was 0.05 mg/ml. Amino-modified oligonucleotides were best able to be bound to the resin's epoxy groups at pH 8, whereas thiol-modified oligonucleotides displayed an optimum coupling value of pH 7. So as to avoid background (BG) contamination of probes around bright guide dots, the concentration of fluorescent guide dots was set to 1 muM. The most suitable print buffers for oligonucleotide arrays using both piezo- and contact-printing systems proved to be 3 x SSC/1.5 M betaine and commercial ArrayLink. When 0.01% monochlortriazinyl-beta-cyclodextrin sodium salt (MCT) was added, the hybridization signal doubled in strength as compared to plain buffer. The optimum print buffer for proteins was 0.1 N phosphate buffer, pH 8/10% glycerine. The optimum humidity for arraying oligonucleotides was 60% and for proteins 40%. Initially agitating slides for 15 min was found just as effective as agitating slides over the total hybridization period (2.5 h), and this resulted in a three times stronger signal.

Soluble tumour necrosis factor-alpha receptor I and interleukin-6 as markers of activity in thyrotoxic Graves' disease.

Autoimmune thyroid diseases are thought to be mediated by pro-inflammatory cytokines such as TNFalpha and IL-6. Serum levels of cytokines may indicate activity levels of immune functions. We investigated serum levels of IL-6 and of the soluble receptor of TNFalpha in patients with newly diagnosed onset of Graves' hyperthyroidism. The predominantly female group consisted of 39 patients, mean fT4 was 47.6 pg/ml (normal values 7.5=19.0 pg/ml). After diagnosis, all patients were treated with anti-thyroid drugs. Soluble Tumour Necrosis Factor Receptor I (TNF-RI) serum levels were found significantly increased (mean 3.7+/-1.3 ng/ml; p<0,01) compared to a matched group of apparent healthy individuals (mean sTNF-RI 1.8+/-0.5 ng/ml) and to a matched group of patients with treated Graves' disease (mean sTNF-RI 1.9+/-0.6 ng/ml). When IL-6 was assessed only 4 of the 39 patients exhibited increased serum levels. Our finding may indicate that sTNF-RI and possibly its ligand, TNFalpha, could play an important role in the onset of the acute stage of Graves' disease.

[Diagnosis and therapy of Graves' ophthalmopathy--consensus guidelines]. / Diagnostik und Therapie der endokrinen Orbitopathie--Konsensusrichtlinien.

On 22-09-2001 the VIth Grazer Hormonsymposion took place. Diagnosis and therapy of Graves' Ophthalmopathy was discussed in an interdisciplinary way by endocrinologists, surgeons and ophthalmologists. The results of the round-table discussion and the consensus talk are presented.

[Subacute thyroiditis with cell destruction and temporary hyperthyroidism in Graves'disease--case report]. / Subakute Thyreoiditis mit Zellzerfall und passagerer Hyperthyreose in einer Basedow-Struma--Fallbericht.

We present the case of a 60-year old woman with painful swelling of the thyroid gland and temporary thyrotoxicosis. 30 years ago she had experienced a period of hyperthyroidism because of Graves' disease. This time thyrotropin-receptor-antibodies were negative, Tc-99 m scan revealed decreased uptake in both lobes (this pattern normalised later on) and fine needle aspiration presented leucocyte infiltration of the thyroid. Three months later hypothyroidism was observed requiring treatment with levothyroxine. The development of subacute thyroiditis and Graves' disease in the same person is rare, autoimmune factors and a possible relationship are discussed.

[Therapy with somatostatin analogs in patient with orbitopathy and positive Octreoscan]. / Therapie der endokrinen Orbitopathie mit Somatostatin-Analoga bei Patienten mit positivem Octreo-Scan.

We prospectively evaluated 28 persons with active endocrine ophthalmopathy and positive sonographic criteria (A-mode) on extraocular eye muscles. To evaluate somatostatin-receptor status SPECT of the orbits was performed with a double-headed rotating gamma camera after application of 110 MBq 111-In-Pentreotide. 9 patients (12/56 eyes respectively) showed a marked uptake ratio (> 2 in circular ROIs by semiquantitative calculation) and were selected for lanreotide (30 mg i.m. every 14 d) treatment. 5 individuals had control scan after clinical progression which became positive in two of them. All but one tolerated modest side-effects of lanreotide treatment (diarrhea). Therapy was discontinued after 3-10 months when thyroid eye disease had lead to fibrotic stage. This subgroup, with the exception of two women, who received corticosteroids additionally, presented stable disease. One of those had to be sent to surgery because of endangered optical nerve. Clinical ophthalmological control showed promising results in patients receiving somatostatin analogues at early stage when positive on octreo-scan.

Recurrent infectious mononucleosis caused by Epstein-Barr virus with persistent splenomegaly.

We present the clinical case of a 20-year-old male soldier who appeared in general good physical condition. He suffered from infectious mononucleosis caused by Epstein-Barr virus that had recurred 2 years after the first serologically documented episode. The detected splenomegaly persisted in the healthy young man, who otherwise showed no apparent immune deficiency. To our knowledge, this is an extremely rare condition.

Enterovirus infection--a possible trigger for Graves' disease?

Viruses are potential environmental factors in autoimmune disease. Some evidence suggests a relationship between enteroviral infection (especially Coxsackie B virus) and autoimmunity. We investigated 21 individuals with recent onset of Graves' hyperthyroidism in regard of (subclinical) enterovirus infection. Thyrotoxic symptoms had started about two months before blood sample collection. The patients were from Upper Austria and mainly female (17/21). Their mean free thyroxin levels in blood were twice the maximum normal value and the majority achieved a euthyroid state 1 1/2 years later, after antithyroid medication. We employed a nested PCR reaction with primers of the enterovirus genome on blood samples. All were negative for RNA of the enterovirus group. Coxsackie and related viruses were not identified as a trigger factor in autoimmune thyrotoxic disease.