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Defects in Phosphate Acquisition and Storage Influence Virulence of <i>Cryptococcus neoformans</i>
Kretschmer, Matthias,Reiner, Ethan,Hu, Guanggan,Tam, Nicola,Oliveira, Debora L.,Caza, Melissa,Yeon, Ju Hun,Kim, Jeongmi,Kastrup, Christian J.,Jung, Won Hee,Kronstad, James W. American Society for Microbiology 2014 Infection and immunity Vol.82 No.7
<P>Nutrient acquisition and sensing are critical aspects of microbial pathogenesis. Previous transcriptional profiling indicated that the fungal pathogen <I>Cryptococcus neoformans</I>, which causes meningoencephalitis in immunocompromised individuals, encounters phosphate limitation during proliferation in phagocytic cells. We therefore tested the hypothesis that phosphate acquisition and polyphosphate metabolism are important for cryptococcal virulence. Deletion of the high-affinity uptake system interfered with growth on low-phosphate medium, perturbed the formation of virulence factors (capsule and melanin), reduced survival in macrophages, and attenuated virulence in a mouse model of cryptococcosis. Additionally, analysis of nutrient sensing functions for <I>C. neoformans</I> revealed regulatory connections between phosphate acquisition and storage and the iron regulator Cir1, cyclic AMP (cAMP)-dependent protein kinase A (PKA), and the calcium-calmodulin-activated protein phosphatase calcineurin. Deletion of the <I>VTC4</I> gene encoding a polyphosphate polymerase blocked the ability of <I>C. neoformans</I> to produce polyphosphate. The <I>vtc4</I> mutant behaved like the wild-type strain in interactions with macrophages and in the mouse infection model. However, the fungal load in the lungs was significantly increased in mice infected with <I>vtc4</I> deletion mutants. In addition, the mutant was impaired in the ability to trigger blood coagulation <I>in vitro</I>, a trait associated with polyphosphate. Overall, this study reveals that phosphate uptake in <I>C. neoformans</I> is critical for virulence and that its regulation is integrated with key signaling pathways for nutrient sensing.</P>
Alexander Kretschmer,Alexander Buchner,Benedikt Leitl,Markus Grabbert,Anne Sommer,Wael Khoder,Christian Gozzi,Christian G. Stief,Ricarda M. Bauer 대한배뇨장애요실금학회 2016 International Neurourology Journal Vol.20 No.4
Purpose: To evaluate long-term outcomes of AdVance and AdVanceXP male slings in patients with persistent stress urinary incontinence (SUI) after transurethral resection of the prostate (TURP). Methods: A total of 18 consecutive patients received AdVance (n=14) or AdVanceXP (n=4) male sling implantation between 2007 and 2013. Continence was determined by pad use, 24-hour pad testing and validated questionnaires (International Consultation on Incontinence Questionnaire Short Form, ICIQ-SF). Quality of life was evaluated by International Quality of Life (IQoL) score. Patient satisfaction was measured with patient’s global impression of improvement score. Cure was defined as 0–5 g in the 24-hour pad test. Statistical analysis included Fisher exact and Wilcoxon test (P<0.05). Results: Follow-up was available for 15 patients who underwent further analysis. After a median follow-up of 70 months (range, 18–83 months), mean daily pad usage was 1.8±2.1 pads (P=0.015 vs. baseline level). Mean IQoL score was 66.4±31.6 (P=0.050 vs. baseline level), and mean ICIQ-SF score was 9.5±6.6 (P=0.077 vs. baseline level). Based on 24-hour pad testing, mean daily urine loss was 31.2±64.5 g (median, 0 g; range, 0–209 g). Cure rate was 46.7%, and cure-and-improved rate was 60.0%. Assessing predictive features for success, better results were found in patients who needed up to 4 pads preoperatively (P=0.041) as well as for patients ≤71 years at the time of implantation (P=0.041). Conclusions: The findings indicate that AdVance and AdVanceXP implantation can be performed effectively and safely in men suffering from SUI after TURP. However, long-term success rates seem to be lower compared to SUI after radical prostatectomy and patients should be counseled accordingly.
Alexander Kretschmer,Tanja Hüsch,Frauke Thomsen,Dominik Kronlachner,Alice Obaje,Ralf Anding,Tobias Pottek,Achim Rose,Roberto Olianas,Alexander Friedl,Wilhelm Hübner,Roland Homberg,Jesco Pfitzenmaier,F 대한배뇨장애요실금학회 2017 International Neurourology Journal Vol.21 No.2
Purpose: To analyze perioperative complications and postoperative explantation rates for selected readjustable male sling systems and the perineal single-cuff artificial urinary sphincter (AUS) in a large, contemporary, multi-institutional patient cohort. Methods: Two hundred eighty-two male patients who underwent implantation between 2010 and 2012 in 13 participating institutions were included in the study (n=127 adjustable male sling [n=95 Argus classic, n=32 Argus T], n=155 AUS). Perioperative characteristics and postoperative complications were analyzed. The explantation rates of the respective devices were assessed using the Fisher exact test and the Mann-Whitney U-test. A Kaplan-Meier curve was generated. Potential features associated with device explantation were analyzed using a multiple logistic regression model (P<0.05). Results: We found significantly increased intraoperative complication rates after adjustable male sling implantation (15.9% [adjustable male sling] vs. 4.2% [AUS], P=0.003). The most frequent intraoperative complication was bladder perforation (n=17). Postoperative infection rates did not vary significantly between the respective devices (P=0.378). Device explantation rates were significantly higher after AUS implantation (9.7% [adjustable male sling] vs. 21.5% [AUS], P=0.030). In multivariate analysis, postoperative infection was a strong independent predictor of decreased device survival (odds ratio, 6.556; P=0.001). Conclusions: Complication profiles vary between adjustable male slings and AUS. Explantation rates are lower after adjustable male sling implantation. Any kind of postoperative infections are independent predictors of decreased device survival. There is no significant effect of the experience of the implanting institution on device survival.
Horizontal mergers, involuntary unemployment, and welfare
( Oliver Budzinski ),( Jurgen-peter Kretschmer ) 한양대학교 경제연구소 2016 JOURNAL OF ECONOMIC RESEARCH Vol.21 No.3
Standard welfare analysis of horizontal mergers usually refers to two effects: the anticompetitive market power effect reduces wel-fare by enabling firms to charge prices above marginal costs, where-as the procompetitive efficiency effect increases welfare by reduc-ing the costs of production (synergies). However, well-accepted demand-side effects of synergies (income feedback effects, `Ford ef-fects`) are usually neglected in this literature. We introduce them into a standard oligopoly model of horizontal merger by assuming an (empirically supported) decrease in labour demand due to merg-er-specific synergies and derive welfare effects. We find that effi-ciency benefits from horizontal mergers are substantially decreased, if involuntary unemployment exists. However, in full employment economies, demand-side effects remain negligible. Eventually, poli-cy conclusions for merger control are discussed.
Influence of the laser pulse shape in the treatment of stones in the upper urinary tract
Abdulmajeed Alghamdi,Alexander Kretschmer,Christian G. Stief,Frank Strittmatter 대한비뇨의학회 2020 Investigative and Clinical Urology Vol.61 No.6
Purpose: Urinary stones can be successfully treated using a Holmium: Yttrium-Aluminum-Garnet (Ho: YAG) laser. Regarding success rates, laser pulse energy, frequency, and pulse width are well-known contributing factors. Whether the pulse shape might be a further factor influencing the laser efficiency is unclear. This study aimed to evaluate different modes of laser pulse shapes in a real-world setting. Materials and Methods: The Dornier Medilas® H Solvo (Weßling, Germany) was used in the treatment of ureter and kidney stones. Patients were randomized into standard pulse shape (SPS) and new pulse shape groups (NPS1; ureter) and (NPS2; kidney pelvis), depending on the stone localization. The primary endpoint was laser efficiency defined as mm3 stone destruction per overall operating time. Secondary endpoints encompassed number of stone recoveries and stone-free rate. Results: Altogether 145 patients (24 SPS vs. 32 NPS1; 51 SPS vs. 38 NPS2) were included. No differences in sex, age, body mass index, stone localization and stone composition were found, except for preoperative stone size (133±95 [SPS] vs. 197±139 [NPS1] mm3; p=0.023) and (348±298 [SPS] vs. 525±429 [NPS2] mm3; p=0.042). Regarding the primary endpoint, a significant increase in laser efficiency could be detected for the NPS1 and NPS2 groups compared to the SPS groups (39.9±44.9 vs. 28.8±30.2 and 51.7±61.3 vs. 22.4±24.2 mm3/min [mean±standard deviation]). No statistically significant differences were found for secondary endpoints and perioperative complication rates. Conclusions: Efficiency of the Ho: YAG laser can be positively influenced by different pulse shapes. This adds the variable of individualized intraoperative decision making.
Lukas John Hefermehl,Stefan Tritschler,Alexander Kretschmer,Vincent Beck,Christian G. Stief,Boris Schlenker,Frank Strittmatter 대한비뇨의학회 2020 Investigative and Clinical Urology Vol.61 No.3
Purpose: To report a single surgeon experience with one year follow-up after open ureteroplasty with buccal mucosa graft (OUBMG) in the rare situation of long segment proximal ureteral strictures. Materials and Methods: Four patients with long segment proximal ureteral stricture underwent OU-BMG between February and July 2017. Functional outcome was assessed by pre- and postoperative serum creatinine, ultrasound and renal scintigraphy as well as patient reported outcomes. Results: Four patients with an average stricture length of 4 cm underwent OU-BMG between February and July 2017. No major postoperative complications occurred. Retrograde uretero-pyelography 6 weeks postoperatively revealed a watertight anastomosis followed by immediate emptying of the renal pelvis and ureter in all four patients. Ureteroscopy at this time showed a wide lumen with well-vascularized pink mucosa. After a mean follow-up time of 12.5 (12–14) months, postoperative serum creatinine was unimpaired. Renal scintigraphy revealed no signs of renal obstruction. With regard to intraoral surgery, no difficulties with mouth opening or intraoral dryness or numbness were reported. Conclusions: For patients with long segment ureteral strictures OU-BMG is a safe technique with excellent surgical and functional outcomes. Hence, the application of this technique should be encouraged and regarded as one of the standard options in case of this rare problem.
Fabian Queissert,Tanja Huesch,Alexander Kretschmer,Ralf Anding,Martin Kurosch,Ruth Kirschner-Hermanns,Tobias Pottek,Roberto Olianas,Alexander Friedl,Jesco Pfitzenmaier,Carsten M. Naumann,Carola Wotzka 대한배뇨장애요실금학회 2019 International Neurourology Journal Vol.23 No.3
Purpose: The aim was to study the correlation between cuff size and outcome after implantation of an AMS 800 artificial urinary sphincter. Methods: A total of 473 male patients with an AMS 800 sphincter implanted between 2012 and 2014 were analyzed in a retrospective multicenter cohort study performed as part of the Central European Debates on Male Incontinence (DOMINO) Project. Results: Single cuffs were implanted in 54.5% and double cuffs in 45.5% of the patients. The cuffs used had a median circumference of 4.5 cm. Within a median follow of 18 months, urethral erosion occurred in 12.8% of the cases and was associated significantly more often with small cuff sizes (P<0.001). Multivariate analysis showed that, apart from cuff size (P=0.03), prior irradiation (P<0.001) and the penoscrotal approach (P=0.036) were associated with an increased erosion rate. Continence rate tended to be highest with median cuff sizes (4–5.5 cm). Conclusions: Apart from irradiation and the penoscrotal approach, small cuff size is a risk factor for urethral erosion. Results are best with cuff sizes of 4.5–5.5 cm.
Affinity for self antigen selects T<sub>reg</sub> cells with distinct functional properties
Wyss, Lena,Stadinski, Brian D,King, Carolyn G,Schallenberg, Sonja,McCarthy, Nicholas I,Lee, Jun Young,Kretschmer, Karsten,Terracciano, Luigi M,Anderson, Graham,Surh, Charles D,Huseby, Eric S,Palmer, E Nature Publishing Group, a division of Macmillan P 2016 NATURE IMMUNOLOGY Vol.17 No.9
<P>The manner in which regulatory T cells (T-reg cells) control lymphocyte homeostasis is not fully understood. We identified two T-reg cell populations with differing degrees of self-reactivity and distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) T-reg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR(lo)PD-1(lo)CD25(lo) (Triple(lo)) T-reg cells were less self-reactive and limited the development of colitis by promoting the conversion of CD4(+) T-conv cells into induced T-reg cells (iT(reg) cells). Although Foxp3-deficient (Scurfy) mice lacked T-reg cells, they contained Triple(hi)-like and Triple(lo)-like CD4(+) T cells with distinct pathological properties. Scurfy Triple(hi)CD4(+) T cells infiltrated the skin, whereas Scurfy. Triple(lo)CD4(+) T cells induced colitis and wasting disease. These findings indicate that the affinity of the T cell antigen receptor for self antigen drives the differentiation of T-reg cells into distinct subsets with non-overlapping regulatory activities.</P>
Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box
Kronstad, James W.,Attarian, Rodgoun,Cadieux, Brigitte,Choi, Jaehyuk,D'Souza, Cletus A.,Griffiths, Emma J.,Geddes, Jennifer M. H.,Hu, Guanggan,Jung, Won Hee,Kretschmer, Matthias,Saikia, Sanjay,Wang, J Nature Publishing Group, a division of Macmillan P 2011 Nature reviews. Microbiology Vol.9 No.3
Cryptococcus neoformans is generally considered to be an opportunistic fungal pathogen because of its tendency to infect immunocompromised individuals, particularly those infected with HIV. However, this view has been challenged by the recent discovery of specialized interactions between the fungus and its mammalian hosts, and by the emergence of the related species Cryptococcus gattii as a primary pathogen of immunocompetent populations. In this Review, we highlight features of cryptococcal pathogens that reveal their adaptation to the mammalian environment. These features include not only remarkably sophisticated interactions with phagocytic cells to promote intracellular survival, dissemination to the central nervous system and escape, but also surprising morphological and genomic adaptations such as the formation of polyploid giant cells in the lung.