Combining skin and olfactory α-synuclein seed amplification assays (SAA)-towards biomarker-driven phenotyping in synucleinopathies.

Seed amplification assays (SAA) are becoming commonly used in synucleinopathies to detect α-synuclein aggregates. Studies in Parkinson's disease (PD) and isolated REM-sleep behavior disorder (iRBD) have shown a considerably lower sensitivity in the olfactory epithelium than in CSF or skin. To get an insight into α-synuclein (α-syn) distribution within the nervous system and reasons for low sensitivity, we compared SAA assessment of nasal brushings and skin biopsies in PD (n = 27) and iRBD patients (n = 18) and unaffected controls (n = 30). α-syn misfolding was overall found less commonly in the olfactory epithelium than in the skin, which could be partially explained by the nasal brushing matrix exerting an inhibitory effect on aggregation. Importantly, the α-syn distribution was not uniform: there was a higher deposition of misfolded α-syn across all sampled tissues in the iRBD cohort compared to PD (supporting the notion of RBD as a marker of a more malignant subtype of synucleinopathy) and in a subgroup of PD patients, misfolded α-syn was detectable only in the olfactory epithelium, suggestive of the recently proposed brain-first PD subtype. Assaying α-syn of diverse origins, such as olfactory (part of the central nervous system) and skin (peripheral nervous system), could increase diagnostic accuracy and allow better stratification of patients.

Association between probable REM sleep behavior disorder and increased dermal alpha-synuclein deposition in Parkinson's disease.

INTRODUCTION: Many patients with Parkinson's disease suffer from REM sleep behavior disorder, potentially preceding the onset of motor symptoms. Phospho-alpha-synuclein is detectable in skin biopsies of patients with isolated REM sleep behavior disorder several years prior to the onset of manifest PD, but information on the association between dermal phospho-alpha-synuclein deposition and REM sleep behavior disorder in patients with manifest PD is limited. We therefore aimed to investigate the alpha-synuclein burden in dermal peripheral nerve fibers in patients with Parkinson's disease with and without REM sleep behavior disorder. METHODS: Patients with Parkinson's disease (n = 43) who had undergone skin biopsy for the immunohistochemical detection of phosphorylated alpha-synuclein were screened for REM sleep behavior disorder using RBDSQ and Mayo Sleep Questionnaire. Skin biopsies from 43 patients with isolated polysomnography-confirmed REM sleep behavior disorder were used as comparators. RESULTS: Dermal alpha-synuclein deposition was more frequently found (81.8% vs. 52.4%, p = 0.05) and was more abundant (p = 0.01) in patients with Parkinson's disease suffering from probable REM sleep behavior disorder compared to patients without REM sleep behavior disorder and was similar to patients with isolated REM sleep behavior disorder (79.1%). CONCLUSION: The phenotype of REM sleep behavior disorder is associated with high amounts of dermal alpha-synuclein deposition, demonstrating a strong involvement of peripheral nerves in patients with this non-motor symptom and may argue in favor of REM sleep behavior disorder as an indicator of a "body-predominant" subtype of Parkinson's disease.

Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson's disease - a randomized controlled trial.

BACKGROUND AND PURPOSE: Evidence for effective treatment options for orthostatic hypotension (OH) in Parkinson's disease (PD) is scarce. Elevation of cholinergic tone with pyridostigmine bromide has been reported as a way to improve blood pressure (bp) regulation in neurogenic hypotension without causing supine hypertension. METHODS: This was a double-centre, double-blind, randomized, active-control, crossover, phase II non-inferiority trial of pyridostigmine bromide for OH in PD (clinicaltrials.gov NCT01993680). Patients with confirmed OH were randomized to 14 days 3 × 60 mg/day pyridostigmine bromide or 1 × 0.2 mg/day fludrocortisone before crossover. Outcome was measured by peripheral and central bp monitoring during the Schellong manoeuvre and questionnaires. RESULTS: Thirteen participants were enrolled between April 2013 and April 2015 with nine participants completing each trial arm. Repeated measures comparison showed a significant 37% improvement with fludrocortisone for the primary outcome diastolic bp drop on orthostatic challenge (baseline 22.9 ± 13.6 vs. pyridostigmine bromide 22.1 ± 17.0 vs. fludrocortisone 14.0 ± 12.6 mmHg; P = 0.04), whilst pyridostigmine bromide had no effect. Fludrocortisone caused an 11% peripheral systolic supine bp rise (baseline 128.4 ± 12.8 vs. pyridostigmine bromide 130.4 ± 18.3 vs. fludrocortisone 143.2 ± 10.1 mmHg; P = 0.01) but no central mean arterial supine bp rise (baseline 107.2 ± 7.8 vs. pyridostigmine bromide 97.0 ± 12.0 vs. fludrocortisone 107.3 ± 6.3 mmHg; P = 0.047). Subjective OH severity, motor score and quality of life remained unchanged by both study interventions. CONCLUSIONS: Pyridostigmine bromide is inferior to fludrocortisone in the treatment of OH in PD. This trial provides first objective evidence of the efficacy of 0.2 mg/day fludrocortisone for OH in PD, causing minor peripheral but no central supine hypertension. In addition to peripheral bp, future trials should include central bp measurements, known to correlate more closely with cardiovascular risk.

[Focal dose escalation in the treatment of prostate cancer : Long-term results of HDR brachytherapy]. / Fokale Dosiseskalation in der Therapie des Prostatakarzinoms : Langzeitergebnisse der HDR-Brachytherapie.

BACKGROUND: We prospectively examined the effect and the safety of intensity-modulated HDR brachytherapy (IMBT) with focal dose escalation. MATERIALS AND METHODS: A total of 139 patients undergoing primary therapy for prostate cancer and 11 patients with recurrence were included. Data analysis focused on the following factors: date of primary diagnosis, Gleason score, initial prostate-specific antigen (PSA) value, PSA nadir, volume of the prostate in the transrectal ultrasound, biopsy of the prostate gland, androgen deprivation, chemotherapy, uroflowmetry, pre- and postoperative post-void residual urine (PVR), number of the needles in the prostate lobes and analysis of follow-up data. RESULTS: In the primary therapy group, 87.6 % of the patients had a PSA of 0-4 ng/ml at the time of follow-up, while in the recurrence group 81.8 % of patients were within this range. Overall, 55.8 % of patients in the primary group had a PSA nadir under 0.1 ng/ml, 37.2 % under 1 ng/ml, 5.8 % under 5 ng/ml and 1.2 % (1 patient) over 5 ng/ml. In the recurrence group, 100 % had a PSA nadir under 0.1 ng/dl. Fifty patients of the primary group reported grade 1 toxicity (Common Toxicity Criteria): 29 localized to the bladder and 21 to the rectum. Seventeen patients had grade 2 toxicity of the bladder and 1 patient had grade 3 toxicity of the bladder. Finally there was one grade 4 toxicity due to perforation of the sigmoid colon. In the recurrence group, 3 patients with grade 1 toxicity were observed (2 bladder and 1 bowl). Also 3 patients had grade 2 toxicity of the bladder, 1 patient had a grade 3 bladder toxicity and 1 patient had grade 4 toxicity due to bowl fistula. There were no grade 5 toxicities. CONCLUSION: The modifications of the "Kiel method" with focal dose escalation was proven as effective in locally advanced prostate carcinoma and in local recurrences of the disease with low level toxicity.

Red fluorescent proteins for imaging Zymoseptoria tritici during invasion of wheat.

The use of fluorescent proteins (FPs) in plant pathogenic fungi provides valuable insight into their intracellular dynamics, cell organization and invasion mechanisms. Compared with green-fluorescent proteins, their red-fluorescent "cousins" show generally lower fluorescent signal intensity and increased photo-bleaching. However, the combined usage of red and green fluorescent proteins allows powerful insight in co-localization studies. Efficient signal detection requires a bright red-fluorescent protein (RFP), combined with a suitable corresponding filter set. We provide a set of four vectors, suitable for yeast recombination-based cloning that carries mRFP, TagRFP, mCherry and tdTomato. These vectors confer carboxin resistance after targeted single-copy integration into the sdi1 locus of Zymoseptoria tritici. Expression of the RFPs does not affect virulence of this wheat pathogen. We tested all four RFPs in combination with four epi-fluorescence filter sets and in confocal laser scanning microscopy, both in and ex planta. Our data reveal that mCherry is the RFP of choice for investigation in Z. tritici, showing highest signal intensity in epi-fluorescence, when used with a Cy3 filter set, and laser scanning confocal microscopy. However, mCherry bleached significantly faster than mRFP, which favors this red tag in long-term observation experiments. Finally, we used dual-color imaging of eGFP and mCherry expressing wild-type strains in planta and show that pycnidia are formed by single strains. This demonstrates the strength of this method in tracking the course of Z. tritici infection in wheat.

[Accidental destruction of stone trapping baskets: new knowledge on the interaction of baskets, stone trapping devices, guide wires and lithotriptors - a brief review]. / Akzidentielle Zerstörung von Steinfangkörben: Neue Erkenntnisse zur Interaktion von Körben, "Stone trapping devices", Guidewire und Lithotriptoren - eine Kurzübersicht.

There is a rise in the incidence of stone disease in the industrial nations. Due to this, the number of endurological procedures will also rise. Sometimes endourological instruments will be fragmented accidentally together with the destruction of the stone. A search for articles on this subject was performed. The aim of this article is to provide a review about the literature on this subject and how this subject can be managed today and in the future.

[Recurrent bladder cancer after BCG instillation therapy. Local therapy options?]. / Das Harnblasenkarzinomrezidiv nach BCG-Instillationstherapie. Lokale Therapieoptionen?

Patients with a so-called BCG failure (Bacillus Calmette-Guérin) constitute an inhomogeneous group of patients. Patients with BCG recurrence or BCG refractive tumors are real BCG failures. Therapeutic options are radical cystectomy and a conservative approach, depending on the individual risk of recurrence and progression. Intravesical chemotherapy with docetaxel or gemcitabine after BCG failure shows some promise whereas second line immunotherapy, the combination of BCG and interferon (INF)-α, is an effective regimen but results need to be confirmed. Device-assisted intravesical strategies, such as mitomycin-EMDA or chemohyperthermia are candidates to keep in mind for the near future. Finally, cystectomy results in the best disease-specific survival in patients with BCG failure.

[Non-muscle invasive transitional cell carcinoma of the bladder. New developments in diagnostics and therapy]. / Das nicht muskelinvasive Urothelkarzinom der Harnblase. Neuigkeiten in der Diagnostik und Therapie.

Due to the high incidence and recurrence rate non-muscle invasive bladder cancer (NMIBC) has a relevant impact. Raman spectroscopy and optical coherence tomography represent innovative diagnostic tools. Urine markers still play a minor role in the diagnostics of NMIBC. New therapeutic options are thermochemotherapy and mitomycin-C electromotive drug administration (MMC-EMDA) as well as gemcitabine and apaziquone for intravesical administration.

[Fluorescence diagnosis in patients with non-muscle invasive bladder cancer: results of a metaanalysis]. / Fluoreszenzdiagnostik bei Patienten mit nicht muskelinvasivem Harnblasenkarzinom: Ergebnisse einer Metaanalyse.

PURPOSE: Heterogeneous results of single studies with photodynamic diagnosis (PDD) in bladder cancer have been reported. A metaanalysis of prospective studies has now been performed. MATERIAL AND METHODS: The effect of PDD in addition to WLC on a) the diagnosis and b) the therapeutic outcome of primary or recurrent non-muscle invasive bladder cancer (NMIBC) investigated by cystoscopy or transurethral resection was analysed. An electronic database search was performed. Trials were included if they prospectively compared WLC with PDD in bladder cancer. Primary endpoints were additional detection rate, residual tumour at second resection and recurrence-free survival. RESULTS: Significantly more tumour-positive patients were detected with PDD in all patients with non-muscle invasive tumours (= 20 %) [95 % confidence interval (CI): 8 to 35 %] and in CIS patients (= 39 %) (CI: 23 to 57 %). Residual tumour was significantly less often found after PDD (odds ratio 0.28, CI: 0.15 to 0.52, p < 0.0001). Recurrence-free survival was significantly higher at 12 and 24 months in the PDD groups than in WLC only groups. CONCLUSIONS: More bladder tumour-positive patients are detected by PDD. Best results were found in CIS patients. Diagnosis with PDD results in a more complete resection and a longer recurrence-free survival.

[Stromal tumour of uncertain malignant potential of the prostate (STUMP) - a case report]. / Stromatumor der Prostata von ungewissem malignem Potenzial (STUMP) - Ein Fallbericht.

A prostatic stromal tumour of uncertain malignant potential (STUMP) is a non-epithelial, mesenchymal spindle-cell tumour that can be classified as a specialised stromal tumour of the prostate. Although in most cases STUMP is not of an aggressive nature, occasional cases have been documented with an extension into adjacent tissues or recurrence after resection. A minority of cases develop a sarcomatous dedifferentiation.We report the case of a 53-year-old male with symptoms of febrile prostatitis. After consolidation we performed TUR-P due to urinary retention. Finally, we made the pathological diagnosis of prostatic STUMP. The patient is being seen -frequently in our clinic to take prostate biopsies to exclude a progression into a stromal sarcoma (active surveillance). After 13 months the STUMP is still detectable, but with no signs of sarcoma.

[Postoperative polyuria after laparoscopic adrenalectomy for pheochromocytoma]. / Postoperative Polyurie nach laparoskopischer Adrenalektomie wegen Phäochromozytom.

Disturbances of osmoregulation leading to polyuria are well known complications after operations in the sella region. In contrast, increased urinary output following adrenalectomy is rare. We report a case of postoperative polyuria after laparoscopic adrenalectomy for pheochromocytoma with urine output up to 15 l per day. Treatment included careful monitoring of the patient and intravenous and oral replacement of fluids and electrolytes. In our case a normalisation of the urine output was observed after few days. A further treatment with vasopressin was not undertaken as the osmolality at all times was in normal range.

[Penile skin necrosis after application of a ring and defect coverage by a skin mesh graft]. / Penishautnekrose nach Ringanlage und Defektdeckung mittels Spalthauttransplantation.

INTRODUCTION: Penile strangulations are rare and always need an individual emergency treatment. Functional impairment and loss of organ integrity are the most serious complications. CASE REPORT: A 43-year-old man came to our ambulance with a penile skin necrosis and a penile abscess. This was caused by a heating pipe that he had put on his penis six weeks ago. We first removed the pipe and performed a necrosectomy in a second step a skin mesh graft was applied. Six months later we observed a satisfactory cosmetic and good functional result. CONCLUSION: Even in serious penile injuries caused by strangulation a penectomy can be avoided by means of an individually planned emergency treatment.

[Vaccine therapy of prostate cancer]. / Vakzinetherapie des Prostatakarzinoms.

Vaccine therapy of prostate cancer has been increasingly studied in trials over the past few years. The different vaccine techniques are quite variable and are predominantly used in patients with advanced hormone-refractory prostate cancer. In this review, vaccine techniques using tumor cells, dendritic cells or poxvirus are analyzed. For theses approaches phase-III trials are being planned, have been initiated or are already completed. Many trials demonstrate the efficacy with regard to endpoints such as stimulation of the immune system and/or biochemical response and/or clinical response. Recently, one vaccine approach using autologous dendritic cells demonstrated a statistically significant prolongation of overall survival compared to placebo in patients with hormone-refractory prostate cancer. Side effects of vaccination are generally mild. At present, there are trials are being planned or are already ongoing that combine vaccine with other treatment strategies or enroll patients with earlier disease stages.

Ketoprofen-induced cyclooxygenase inhibition in renal medulla and platelets of rats treated with caffeine.

It has been suggested that caffeine can augment analgesic activity and aggravate side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of the present study was to investigate a possible interaction between ketoprofen and caffeine on prostaglandin (PG) biosynthesis and cyclooxygenase (COX) mRNA expression in the rat renal medulla ex vivo. Treatment of rats with ketoprofen (60 min before) resulted in a dose-dependent (estimated ID(50) 0.3 mg/kg p.o.) reduction of PGE(2) biosynthesis in renal medulla ex vivo. Ketoprofen (0.3 mg/kg)-induced inhibition of PGE(2) biosynthesis was stable between 30 and 180 min and still detectable 300 min after drug administration. Caffeine (10 mg/kg) did not cause a detectable effect on its own, nor did it significantly affect ketoprofen-induced inhibition of renal medullary PGE(2) biosynthesis. Similar results were obtained with repeated daily drug administration for 1 week: there was no significant effect of caffeine on ketoprofen-induced inhibition of renal medullary PGE(2) biosynthesis. The absence of significant caffeine effects on ketoprofen-induced inhibition of renal medullary PGE(2) biosynthesis was paralleled by experiments showing no significant effect of caffeine on ketoprofen-induced inhibition of platelet thromboxane (TX)B(2) biosynthesis. Additional experiments showed increased COX-2 mRNA expression in the renal medulla 60 min after ketoprofen administration, that was not significantly influenced by concomitant caffeine treatment. Treatment of rats with ketoprofen for 1 week had no significant effects on COX-2 mRNA expression. The present results show that ketoprofen caused inhibition of PGE(2) biosynthesis in the rat renal medulla ex vivo with a potency similar to that reported for in vivo models suggesting that the ex vivo approach is a valid model to test a possible interference of caffeine with ketoprofen-induced COX inhibition. The absence of detectable effects of caffeine on time course or magnitude of ketoprofen-induced suppression of PGE(2) biosynthesis in this model indicates, therefore, that possible adverse actions of co-administered caffeine on renal function are not related to interference with renal COX inhibition.

Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis.

BACKGROUND: Coronary in-stent restenosis might be triggered by contact allergy to nickel, chromate, or molybdenum ions released from stainless-steel stents. We investigated the association between allergic reactions to stent components and the occurrence of in-stent restenosis. METHODS: Patients with coronary stainless-steel stents who underwent angiography for suspected restenosis were consecutively included in this study. Quantitative coronary angiography for analysis of percentage diameter stenosis was done on 131 patients (mean age 62 years [SD 9]) with 171 stents 6.1 months (2.7) after stent implantation. All patients underwent epicutaneous patch tests (Finn chamber method) for nickel, chromate, molybdenum, manganese, and small 316L stainless-steel plates. Patch tests were assessed by independent dermatologists after 48 h, 72 h, and when necessary 96 h of contact with the potential allergen. FINDINGS: In-stent restenosis (> or =550% diameter stenosis) occurred in 89 patients. All ten patients with positive patch-test results had restenoses (p=0.03). Four male patients had positive reactions to molybdenum, and seven patients (four male, three female) had reactions to nickel. No patient with an allergic reaction to the standard test substances had a positive reaction to the stainless-steel plates. All patients with positive results had recurrent angina pectoris and needed target-vessel revascularisation. INTERPRETATION: Patients with allergic patch-test reactions to nickel and molybdenum had a higher frequency of in-stent restenoses than patients without hypersensitivity. Allergic reactions to nickel and molybdenum released from stents may be one of the triggering mechanisms for in-stent restenosis.

[Absenteeism due to alcoholism in a federal installation]. / Alkoholismusbedingter Absentismus in einem Bundesbetrieb.

Absence due to sickness of 25 chronic alcoholics in a Swiss Federal company was compared with that of 75 control subjects parallelized as far as possible. Only those alcoholics were studied who worked in the company throughout the observation period (1966-1975) and whose records with the Federal Medical Service bore the diagnosis "chronic alcoholism". Through shortterm absences (up to 3 days) the alcoholics lost 1.7 days annually compared with 0.9 days for the control group. The average number of shortterm absences among the alcoholics was 0.8 and 0.4 in the control group. Through absences due to illness or accidents (absences of more than 3 days) the alcholics lost 22.3 days annually compared with 7.0 days for controls. The average number of longterm absences was 0.7 for alcoholics and 0.4 for controls. The average cost of absenteeism was 3193.10 Swiss francs for the alcholics and 790.80 Swiss francs for each member of the control group. First notification of alcohol problems of an employee came from within the company in 80% of cases. Striking features were mainly drinking before and during work and erratic time-keeping. In 88% of cases the treatment was disulfiram cure and supportive psychotherapy in 12%. In the next 3 years 4 alcoholics (30.7%) had further episodes of drinking, while 9 (69.3%) showed no sign of alcohol abuse. 12 alcoholics could not be assessed asfollow-up was too short.

[Morbidity of alcoholic employees. Examples from 2 public facilities in Switzerland]. / Morbidität von alkoholkranken Mitarbeitern. Beispiele aus zwei öffentlichen Betrieben der Schweiz.

Morbidity of of alcoholic employees. Results of a case/control study on 2 samples of civil servants. The data of this retrospective study were obtained mainly from files kept at the centralized medical service. The observation period was 10 years. The alcoholics (n = 64) lost in the average 19.3 or 16.1 days more per year through sickness absence and they spent considerably more days in hospitals than their control groups. Significant differences occurred also concerning frequences of medical diagnoses.