gamma secretase inhibitors This might result in a local elimination of MAP

This might result in a local elimination of MAP that could lead to a complete recovery from MAP infection as has been reported in a few animals (Sigurðardóttir et al., 1999; Dennis et al., 2011). On the other hand, new infection of the mucosa may occur by dissemination of MAP from other sites, e.g. caseous necrosis in mesenteric lymph nodes (Corpa et al., 2000; Lybeck et al., 2013; Krüger et al., 2014) or granulomatous vasculitis in the submucosa (Krüger et al., 2014). The focal to multifocal granulomatous lesions (score 1) observed particularly frequent in goats 6 and 9 mpi may represent these sites of new infection. Comparable lesion have been described in experimentally infected goats (Valheim et al., 2004), whereas equal numbers of CD4+ and CD8+ T lymphocytes were found in this type of lesion in naturally infected goats (Lybeck et al., 2013). They may be precursors of the extensive granulomatous lesions (score 2) described above.
In three goats, lesions characterized by increased numbers of epitheloid gamma secretase inhibitors and MAP developed. They were no longer limited to GALT, but also affected intestinal mucosa. The increased number of MAP was associated with an overall lower number of lymphocytes in the granulomatous infiltrate. The reduced number of CD25+ cells not only within lesions, but throughout the intestinal wall indicates a decreased IL-2-mediated activation and proliferation of T and B lymphocytes (Rossi et al., 2009; Robinson et al., 2011). In spite of the overall decreased numbers of lymphocytes, many CD4+ T lymphocytes were still present within lesions, but apparently not able to control the proliferation of MAP.
This may be due to a decreased IFN-γ release by CD4+ T lymphocytes or the resistance of infected macrophages to activation by IFN-γ (Simutis et al., 2007). Mycobactericidal activity and antigen presentation of macrophages might be inhibited by anti-inflammatory cytokines like TGF-β and IL-10 which may be increased in animals with clinical paratuberculosis (Smeed et al., 2007; Munoz et al., 2009; Rossi et al., 2009; Redford et al., 2011; Lybeck et al., 2013). A balance between pro- and anti-inflammatory cytokines is critical for a protective immune response while preventing severe immune-mediated tissue destruction. It can be speculated that switching from a pro-inflammatory to an anti-inflammatory microenvironment before the elimination of MAP is complete might result in uncontrolled mycobacterial proliferation and multibacillary lesions.
In conclusion, a sequential development of lesions was observed in the GALT of goats after experimental infection with MAP. It resulted either in an almost complete local elimination of MAP or an uncontrolled mycobacterial proliferation at 9 to 12 mpi. Both outcomes were characterized by marked, but distinctly different inflammatory infiltrates. MAP–host interactions during the clinically inapparent phase of paratuberculosis have a major influence on the eventual outcome of the infection with MAP. The infection model in goats allowed to observe the complex cellular immune reactions postulated for the pathogenesis of paratuberculosis in situ.

Conflict of interest statement


As a part of the outer membrane of Gram-negative bacteria, LPS or endotoxin is involved in many infectious bovine diseases (Radostitis et al., 2007). Particularly in calves, which are physiologically extremely sensitive to LPS, Gram-negative bacteria such as Escherichia coli, Mannheimia haemolytica and Pasteurella multocida play a crucial role in the most frequent and economically important calf diseases, namely neonatal diarrhoea and respiratory disease (Michaels and Banks, 1988; Constable, 2004; Pardon et al., 2012). Also in septicaemia, which continues to be a life-threatening condition with high mortality risks, especially in calves with failure of passive transfer, the vast majority of isolates is Gram-negative (Fecteau et al., 2009).
Intravascular or peripheral exposure of host cells to LPS is a possible trigger of a complex series of non-specific, predetermined and well-orchestrated reactions, intending to control the Gram-negative bacterial infection (Conner et al., 1989; Baumann and Gauldie, 1994). This acute-phase response (APR) is initiated by the release of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, and other inflammatory mediators, including prostaglandins (PGs) (Werling et al., 1996). The APR is characterized by fever, tachycardia, leukocyte activation, mobilization of phagocytes, altered plasma concentrations of zinc, iron, calcium and copper, synthesis of acute-phase proteins (APPs) including serum amyloid A (SAA) and haptoglobin (Hp) by hepatocytes, and behavioural changes such as depression, anorexia and hyperalgesia (Watkins et al., 1994; van Miert, 1995; Zebeli et al., 2010). Nevertheless, the response can be excessive and subsequently result in detrimental effects to the host, like sepsis and septic shock (Peri et al., 2010).

ikk inhibitor This section first describes our

This section first describes our NMF model, some basic concepts, and update rules for low rank matrices and parameters. The detailed derivation of all update rules is described in the Supplementary Material. The experimental procedures for STEM-EELS/EDX-SI are described in detail in later subsections.


There are several local minima in the likelihood functions. The type of NMF algorithm appears to determine which minimum we eventually reach, although it is not mathematically possible to prove the dependence. Moreover, because of the computational cost, it is hard to obtain all of the local minima, even when we apply the spatial orthogonality constraint and sparse priors for the ARD effect, i.e. small value of K, in the data matrix. In the present NMF method, systematically varying the weight of the spatial orthogonality in the object function can minimize and extract the objective function of some particular solutions. In both of the EELS examples presented herein, an increase in w caused the resolved components to be distributed in more separate manners over the sample space and their spectral shapes to become less sparse (or orthogonal). This change in spectral shape, which is prone to be sparse under the basic NMF, is clearly resolved and exhibits more accurate composition when the orthogonal constraint is applied. Hence, the proposed NMF can identify chemical states from the resolved spectra more accurately than existing methods that do not use spatial orthogonality. In the case of the atomic ikk inhibitor SI of Mn3O4, the method resulted in physically meaningless solutions when we overestimated the spatial orthogonality. In general, we can reach solutions that are physically more realistic/interpretable, comparable to theoretical spectra predicted by first principles calculations or reference experimental spectra, by changing the value of w systematically and understanding how the spectral shapes and spatial distributions of the resolved components vary. This scheme seems much more effective and pragmatic than estimating the solution bounds by repeating the decomposition routines with many different initial random numbers in the loading or score matrices.
It can be controversial to subtract the spectral background before the statistical processing, depending on what type of spectral data are being treated. Although it is generally considered that background subtraction results in the loss of important spectral information, we believe that background subtraction is necessary in the present framework because our NMF assumes that no background structure is incorporated. As demonstrated in the Supplementary material, our proposed NMF did not provide the expected correct results for STEM-EELS SI without background subtraction, which thus poses further questions as to how a background structure can be incorporated into our model.


With the advent of aberration corrected electron microscopy [1,2], individual atoms of light elements can be directly imaged in atomic resolution [3–7] using electron energies below the knock-on damage threshold [8,9]. However, this only applies to certain materials, among organic materials most notably graphene or carbon nanotubes are not affected by other mechanisms of beam damage. The relative irradiation resilience of low dimensional carbon allotropes is strongly contrasted by virtually any other organic materials or molecules that are rapidly destroyed by electron irradiation: Atomic resolution images of a carbon material or molecule require a dose of several thousand e−/Å2, which exceeds the damage threshold of organic molecules by orders of magnitude [10,11].
A promising approach to circumvent the dose limitation is to distribute the required dose over many identical copies of a given object. This has been the basis for numerous successful object reconstruction schemes for biological electron microscopy [12–15]. If single objects can be identified and oriented in TEM micrographs, it is possible to recover a high signal-to-noise ratio image by superimposing all snapshots that correspond to the same orientation and conformation. However, for lowest doses and/or smaller objects, the alignment is problematic [16] or fails. A similar problem exists with x-ray diffraction data from individual molecules or nanocrystals as recorded with the recently developed pulsed x-ray beams from free electron lasers [17–19], where the orientation of the molecule in each snapshot is not known a priori[20,21]. The tasks of retrieving objects either from low-dose diffraction data or direct images are indeed closely related. The unknown parameters comprise in the former rotations and translations and in the latter only rotations. Powerful statistical approaches have been developed in order to recover the structure even when the dose is not sufficient for a straightforward assignment of these parameters [22–34].

Introduction Avian heterophils the counterparts of the

Avian heterophils, the counterparts of the mammalian neutrophils, are multinucleated leukocytes that play a critical role in the innate immune response. They are rapidly recruited to the inflammatory site of an infection in order to detect and destroy invading pathogens. Antimicrobial functions comprise not only the ingestion of the invaders and production of reactive oxygen species (ROS) or other toxic molecules, but also the degranulation of antibacterial substances directly from the intracellular heterophilic granules into the inflammatory environment (reviewed by (Genovese et al., 2013)). Beyond, yet another defense mechanism of granulocytes – the generation of extracellular traps (ETs) – was discovered 12 years ago (Brinkmann et al., 2004). The ET formation (ETosis) has been accepted as a specific cell death mechanism of granulocytes that differs from apoptosis and necrosis (Mesa and Vasquez, 2013). Actually, the ETosis is a functional instrument that allows granulocytes, monocytes and also macrophages (Boe et al., 2015) to entrap and kill pathogens outside the cell. The clue of this function is the release of a meshwork of thin, 5–17nm thick fibers from the cell after stimulation with a wide range of chemical substances (summarized by (Guimaraes-Costa et al., 2012)) or infectious agents, as Gram-negative or -positive bacteria, fungi, protozoa, parasites and viruses (summarized by (Vorobjeva and Pinegin, 2014)). The extruded fibers consist of a backbone of DNA decorated with histones, anti-microbial proteins and Octreotide acetate (summarized by (Vorobjeva and Pinegin, 2014)). The so formed extracellular scaffold serves as a death-trap that arrests and prevents pathogens from dispersing into the tissue and, moreover, can destroy pathogens by highly concentrated anti-microbial effectors. The capability to undergo ETosis has also been described for avian granulocytes, albeit only after in vitro activation with stimulants as phorbol myristate acetate (PMA) or hydrogen peroxide (H2O2) (Chuammitri et al., 2009, 2011; Redmond et al., 2011) as well as in virus-infected tracheas (Reddy et al., 2017). Whether heterophils can produce ETs after exposure with microorganisms, as Salmonella spp., still has to be investigated.
Originally, most of the studies on ETosis have been done by in vitro experiments. In the meantime, ET structures have also been detected in experimentally induced and naturally occurring infections of mammalians, as in experimental Shigella infection of rabbits or spontaneous appendicitis (Brinkmann et al., 2004) and periodontitis (Vitkov et al., 2009) in humans, bovine mastitis (Lippolis et al., 2006) as well as in the lungs of mice infected with Streptococcus pneumonia (Beiter et al., 2006). In regard to Salmonella, only in vitro studies using human or murine neutrophils have been done to demonstrate the potential of this pathogen to cause ETs (Brinkmann et al., 2004; Medina, 2009). However, it is unknown whether these facultative intracellular agents can induce ETosis also in vivo.
Salmonella represents an important zoonotic agent leading to human infection mainly by the consumption of contaminated animal food products, predominantly poultry-derived food. In young chicks aged between 1–5days, Salmonella serovars, as Salmonella Enteritidis or Typhimurium, cause gastroenteritis and diarrhea and can also lead to systemic infection (Barrow et al., 1987). In the initial immune response against Salmonella, heterophils are considered as crucial. Rapidly after oral infection of day-old chicks, numbers of heterophils migrate into the gut mucosa and lumen (Berndt et al., 2007; Cheeseman et al., 2008; Kogut et al., 1994). Once arrived there, heterophils help to fight against the pathogens by grabbing them from the mucosal or luminal site of infection and killing them with the means of reactive oxygen species and/or anti-microbial peptides (Kogut et al., 2001; Swaggerty et al., 2003; van Dijk et al., 2009; Wells et al., 1998). In vivo experiments have demonstrated a correlation between an increased influx of heterophils into the area of inflammation and a better resistance against the Salmonella infection in chicks (He et al., 2007; Swaggerty et al., 2005). Also, an association between the function of heterophils and an improved resistance to Salmonella has been suggested (Ferro et al., 2004; Swaggerty et al., 2006). Whether avian granulocytes are, however, able to produce anti-microbial traps after Salmonella exposure in gut, and whether the ET fibers might impact the course of the avian Salmonella infection is unknown hitherto.

Diagnosis of pancreatic metastasis is

Diagnosis of pancreatic order salvinorin a is suspected in front of every new pancreatic lesion in patients with initial history of RCC. An intense nodular enhancement mostly homogenous of pancreatic tumor at arterial and portal phases is found on CT scan. Even with central necrosis, aspect is different from primitive pancreatic tumors, which are typically hypovascularized at the arterial time. MRI describes the same hypervascular lesions. Differential diagnoses are the neuroendocrine tumor and an accessory spleen. Detection and diagnosis of small tumors may be difficult with standard imaging; it is often completed by an endoscopic ultrasonography with fine needle biopsy that allows the definitive diagnosis. In our results, biopsy was taken in 55% of cases with a sensitivity of 72%. Furthermore, peroperative pancreatic ultrasonography may reveal undiagnosed metastatic lesions and change the type of resection.
The site and the multiplicity of lesions of pancreatic metastases and the surgical technique seem to have no effect on the survival. Because of our lack of patients, no statistical significant difference between patients with unique and multiple metastasis was found, even if the tendency of our results did not show any difference between these 2 groups. Same results have been described in the literature. It seems that every pancreatic metastasis of CCRCC is eligible to a metastasectomy whenever possible, without much comorbidity.
Pancreatic metastasis from CCRCC has the same rate of postoperative complications as metastasis to the pancreas from other malignancies. Our rate of postoperative complications may appear high, but it is comparable with other studies in the literature. Complication rate after pancreatectomy for a metastatic disease is majored by patient\’s comorbidities, high-ASA score, and age.
These data suggest that surgical management could not be considered as the only available option in these fragile patients, even if pancreatic metastasis is resectable. Ablative treatment has been evaluated in these cases. Radiofrequency for pancreatic malignancies may be an option but has between 10% and 43% morbidity rate: acute pancreatitis, hemorrhage, sepsis, and abdominal pain are the main events, without real benefit on overall survival.
All patients treated by surgery for a single pancreatic metastatic localization had different medical treatment in association. Depending on period and the patient\’s general state, several medical adjuvant treatments have been administrated. First, 90% of cases (18 patients) had an inaugural pancreatic recurrence, 10% (2 patients) had a CCRCC metastasectomy in another site (thyroid and adrenal gland) before pancreatectomy, and only 1 of these 2 patients had a medical treatment before pancreatic recurrence (immunotherapy). Difference of efficiency of immunotherapies and targeted therapies makes an inevitable bias of comparison by the long period of this study (15 years). The outcome of surgical resection of pancreatic metastasis from CCRCC was highlighted when immunotherapy was the only choice of medical treatment, less effective than targeted therapies.
Targeted therapies (sunitinib, pazopanib, bevacizumab + interferon α) have shown efficiency on metastasis from CCRCC with an improvement on overall survival and reduction of metastatic size making surgery conceivable. In our study, 3 patients were treated by sunitinib and metastatic resection, whatever the site: all were alive at 60, 150, and 156 months. A multimodal approach may allow preoperative tumor size reduction to facilitate surgery and improve overall survival for pancreatic metastasis of CCRCC indicating the need of further studies to confirm the benefit of combined treatment.
As it is shown in our cohort for pancreatic metastasis, aggressive approach of metastasis from CCRCC in other metastatic sites are described; indeed, surgical treatment of these metastases (thyroid, vertebral, colon, and so forth), associated or not with a medical treatment, has proved showed a long-term disease-free interval for highly selected patients.

br Bladder cancer BCa is a disease of

Bladder cancer (BCa) is a disease of the elderly, with probabilities of developing invasive disease increasing almost 4-fold after the age of 70 years. In fact, BCa is the fourth leading cause of cancer death in men aged 80 years and older. Therefore, it should be expected that a certain proportion of patients diagnosed with BCa who are eligible for surgical treatment will have a positive history for other oncologic diseases. At the same time, radiation therapy has become part of standard treatment for some of the most frequent cancers including prostate, cervix, and rectum.
In this context, many have questioned the relationship between prior pelvic irradiation and BCa. Issues raised range from higher risk of development of BCa after ionizing radiation to modifications in BCa biology toward a more aggressive phenotype. Significant alterations in SAG supplier markers have been found in the so-called Chernobyl cystitis, a preneoplastic condition described in survivors from the eponymous disaster, suggesting distinct BCa carcinogenesis in patients exposed to radiation. However, uncertainty remains whether differences exist in the biological behavior of BCa in irradiated vs nonirradiated patients, as only 2 groups have commented on survival. Moreover, radiation therapy has seen significant advances in the last decade, and more recent radiation therapy protocols may not have the same effect on urothelial mucosa as older techniques.
In the present study, we compare BCa characteristics and survival outcomes of contemporary patients with and without a history of pelvic irradiation who underwent radical cystectomy (RC) and perform multivariable analyses to determine whether prior pelvic irradiation is predictive of BCa recurrence or BCa-specific death. A secondary goal was to provide an updated, comprehensive evaluation of diversion-related complications in both groups, as sparse data focused only on specific complications exist.
Patients and Methods


Other authors have investigated similar questions in older series. Yee et al, comparing 83 BCa patients who had had prior radiotherapy and 61 patients who had undergone surgery or other management for prostate cancer, observed higher proportion of high-grade urothelial carcinoma (92% vs 77%, P = .0016) in irradiated patients. These patients also presented with higher rate of non–organ-confined disease, although trypanosomes did not reach conventional levels of significance (75% vs 46% for nonirradiated, P = .1). No significant difference in survival was observed. One notable difference with the design of the present study is that in the cohort of Yee et al, only 51% of patients underwent RC. Despite this, their findings essentially agree with ours. SAG supplier Bostrom et al, evaluating 31 patients who underwent RC after pelvic irradiation for prostate cancer, reported that 10 patients (32%) harbored T4 disease, which corroborates the present results (35%). In that study, cancer-specific survival was worse compared with that of age- and stage-matched control patients. However, a matched-pair analysis involving such a low number of patients is obviously subject to selection bias. Importantly, irradiated patients in that study underwent a limited PLND only, which may explain the observed differences in survival. In any case, future studies with larger sample sizes may have sufficient statistical power to detect survival differences, as evidenced by our wide CIs. Overall, our results underline the fact that surgery in irradiated patients remains challenging. PLND is not feasible in a high number of cases, and these patients are more likely to present with T4 disease. This is reflected in a higher rate of PSM, as all 5 irradiated patients with PSM had T4 disease. Interestingly, although the numbers are too small to allow definitive conclusions, we found that the proportion of nonurothelial carcinoma histology, particularly small cell carcinoma, was significantly higher in the irradiated group. Small cell carcinoma is an otherwise rare pathologic finding with poor prognosis, and further studies are needed to reproduce our findings.

cesium chloride Because of the uncertainty surrounding who will and

Because of the uncertainty surrounding who will and will not benefit from neuromodulation therapy, decisions to perform the test procedure are left to clinical judgment, which can be influenced by a variety of clinical and nonclinical factors given the limited evidence base. First and foremost, physicians may be motivated to help their patients who have failed to respond to other treatments. This impetus could prompt physicians to perform the test procedure in a marginal population, or among those patients less likely to respond to neuromodulation given the clinical context. This altruistic motivation, coupled with the low morbidity profile associated with the test procedure, has the potential to encourage high rates of testing. Second, financial incentives inherent in the fee-for-service system could potentially motivate physicians to perform higher rates of sacral neuromodulation test procedures, which are reimbursed 4-5 times more than the implant procedure. Furthermore, additional incentives may be garnered through physician ownership of facilities where these procedures can be performed, such as ambulatory surgery centers (ASCs).

The American Urological Association (AUA) and the American Society for Radiation Oncology (ASTRO) released a joint statement in 2013 recommending that adjuvant cesium chloride be discussed as a possible treatment option for men with pathologic T3 (pT3) or margin positive disease (SM+) after radical prostatectomy (RP). However, urologists and radiation oncologists often differ in their recommendations regarding adjuvant radiation. The results of a large, national survey of physicians found that radiation oncologists were significantly more likely to recommend adjuvant radiation, whereas urologists were more likely to advocate for observation, followed by early salvage radiation (if needed). This disparity has the potential to create confusion and uncertainty for patients regarding their treatment options.
Although 3 phase III trials have demonstrated that adjuvant radiation decreases the risk of recurrence in patients with positive surgical margins or pathologic T3 disease, radiation oncologists and urologists looking at the same standard clinical variables have not come to convergence on what constitutes the appropriate use of postprostatectomy adjuvant therapy. Among other factors, concerns regarding the potential of overtreatment of some patients to benefit others have prevented widespread adoption of adjuvant radiation. Thus, there is a need to identify subsets of patients at even higher risk for disease progression to guide recommendations regarding adjuvant treatment.
Several previous studies have shown that genomic features in the primary tumor provide a quantitative measure of biological potential for disease progression and metastasis. Recently, a ribonucleic acid (RNA)–based genomic classifier (GC) test (Decipher; GenomeDx Biosciences, San Diego, CA), which uses 22 markers derived from paraffin-embedded prostatectomy tissue, has been validated as a significant independent predictor of early metastasis after RP. In 1 cohort study, the GC test had an area under the curve of 0.79 for predicting metastases. In the same study, the GC test outperformed all clinical variables and other published gene signatures. As adjuvant radiation was reported in the 2006 publication of the Southwest Oncology Group 87-94 randomized trial to significantly reduce the risk of distant metastases, precise information about a patient\’s risk of distant metastasis from the GC test could be very helpful to clinicians trying to formulate adjuvant treatment recommendations after prostatectomy. We sought to determine whether information from the GC test influenced adjuvant treatment recommendations made by radiation oncologists and urologists and whether the GC results reduced disagreement in treatment recommendations between the 2 specialties.
Materials and Methods


This multicenter, prospective, decision impact study assessed the influence of a GC test on adjuvant treatment recommendations after prostatectomy for prostate cancer. Although adjuvant therapy may benefit some high-risk patients, not every patient with adverse pathology requires it. In support of adjuvant therapy, 3 randomized trials showed a near halving of the risk of biochemical recurrence with adjuvant radiation and 1 trial demonstrated a significant increase in metastasis-free survival. Therefore, physicians are often more inclined to recommend adjuvant therapy for patients with a high risk of recurrence. However, the exact risk of recurrence cannot always be predicted precisely using stage, sGS, and margin status alone. Furthermore, in clinical practice, variation has been observed both within and between disciplines, further complicating selection of the appropriate treatment strategy.

ascorbic acid Another aspect is that of

Another aspect is that of incontinence that may become apparent after surgery, may it be because of increased postvoid residue due to VUR or it may be inherent ascorbic acid neck insufficiency. However, in most of the studies the continence improved after surgery and most patients attained continence after surgery. Only two patients, one a case of penile epispadias and the other a case of penopubic epispadias, were incontinent. Only one case was a candidate for bladder neck procedures in previous studies.
The surgical steps used during surgery are standard steps done for epispadias repair. An isolated IPGAM can be used for glandular and coronal epispadias, and Cantwell-Ransley repair for other more severe varieties of epispadias.
Penile length is the basic grievance of a parent. We advise that all interventions described to gain length in cases of buried penis should be done for these children. These are fixing the tunica albuginea of the corpora to pubis at 3, 6, 9 o\’clock positions; cutting the suspensory ligament if it is defective and pulling the shaft inside the pelvis; removing the parasymphyseal fat and lengthening the dorsal skin. Sarin and Sinha have reported to save the prepuce and create a neo meatus by an isolated IPGAM procedure, but we advice a circumcision in the surgical approach as it gives an extra pacification about the length, in cases with small penile length (our first case). It also avoids another procedure in the future. Bos et al performed additional procedures in the form of ventral skin plasty, dorsal Z plasty, and circumcision. These could have been incorporated in the primary procedure to avoid extra surgeries and anesthesia. In cases of penis with good length, an isolated IPGAM procedure with preputioplasty is recommended, as was done in our second case.


Male epispadias is a rare and challenging diagnosis within the exstrophy-epispadias complex. The author presents management of a case of distal epispadias. Management is as per contemporary understanding and technique for distal epispadias with intact prepuce. The status of the prepuce is not of supreme importance here or in any boy with epispadias. What is most important is characterizing the scope and severity of other manifestations, if present, of the field defect in this epispadias, and for epispadias of any level. The authors also provide a thorough review of the literature regarding this entity. One difference of opinion from the authors is that it is my strong belief based on references reported in the manuscript and personal experience (unpublished data) that a boy with epispadias at any level deserves evaluation with cystourethroscopy and voiding cystourethrogram, and potentially urodynamics as well, in addition to renal and bladder ultrasound. Epispadias is a spectrum (in and of itself) within the exstrophy-epispadias complex—in other words, epispadias is a spectrum within a spectrum and associated anomalies and manifestations of epispadias are a spectrum regardless of the level of the defect. Epispadias is typically classified by level; penopubic, penile, or glanular. This classification fails to include some of the associated malformations that may be present such as pubic diastasis, bladder neck abnormalities, and vesicoureteral reflux (VUR). There is a significant incidence of VUR in these boys. Some may have abnormality in pubic diastasis, with potential repercussions regarding urinary continence. Careful preoperative evaluation should allow the identification of these associated abnormalities, some that will be observed, and some that will help lead to appropriate successful surgical management based on the clinical history, imaging, urodynamic, and physical findings. Clinical follow-up with progress regards toilet training; successful, delayed, or not attained at all, along with noninvasive or invasive assessment of voiding parameters/function as needed, based on clinical impression. Follow-up with physical examination is also important to assess for potential development of significant dorsal penile curvature. All of the above, VUR, impaired urinary continence, and development of dorsal penile curvature, are possible and these possibilities should be discussed with the parent/caregiver(s) of a boy with epispadias, regardless of level, penopubic, penile, or glanular. This commitment to the care of these boys and their future should not be overly taxing, given the rarity of epispadias of any severity. These rare and, at times, challenging patients deserve utmost attention regarding evaluation and care.

Several types of electronic retinal implants have either been

Several types of electronic retinal implants have either been approved as commercial products such as Argus II, (Second Sight, Sylmar, CA, see Humayun et al., 2012) and Alpha IMS (Retina Implant AG, Reutlingen, Germany, see Stingl et al., 2013b) or are under development (Ayton et al., 2014; Guenther, Lovell, & Suaning, 2012; Luo & da Cruz, 2014; Menzel-Severing et al., 2012; Stingl & Zrenner, 2013; Zrenner, 2013) for the treatment of hereditary retinal degenerations. Their aim is to restore some vision in end-stage disease for patients who are completely blind or who have light perception without light localization. All of these implants consist of a light-capturing unit (an external camera or an intraocular photodiode array) and an electrode array for stimulation of retinal neurons, mostly those in the inner retina. By electrically stimulating the remaining neurons, the implants initiate a visual percept, replacing to some extent the lost photoreceptor function with artificial vision.
A consortium led by the University of Tübingen has been developing various types of active subretinal visual implants since the 1990s (Zrenner, 2002; Zrenner et al., 1999). After preclinical biocompatibility, safety, and biostability tests (Gekeler et al., 2007; Guenther et al., 1999; Kohler et al., 2001; Schwahn et al., 2001), a first wire-bound version of the subretinal implant with 1500pixels was tested in a pilot study in 11 blind volunteers, where a retroauricular transdermal cable connected the visual implant with an external battery supply. Surprising functional outcomes in three of the subjects, allowing for recognition of unknown objects and even reading large letters, including the detection of spelling errors, were published (Stingl et al., 2013c; Zrenner et al., 2011). Subsequently, a version with wireless transmission of power and signals (transdermally via coils in the retroauricular region, see Figs. 1 and 2), the subretinal implant Alpha IMS of Retina Implant AG, Reutlingen, Germany was implanted in further 29 eyes of 29 blind participants with degeneration of the outer terbinafine hcl in an ongoing clinical trial that consists of module 1 (a single centre study in Tübingen) and module 2 (a multicentre trial at authors’ sites). Primary efficacy endpoints were a significant improvement of activities of daily living and mobility shown via activities of daily living tasks, recognition tasks, mobility, or a combination thereof. Secondary efficacy endpoints were a significant improvement of visual acuity/light perception and/or object recognition (, NCT01024803). Results from the nine participants in module 1 have been published (Stingl et al., 2012, 2013b,c). This manuscript describes the results obtained in the multicentre trial, with a combined analysis of the original nine module-1-participants and the additional 20 participants recruited in module 2.

Material and methods

Twenty-one participants (72%) reached the primary efficacy endpoints as set in the study protocol (“significant improvement of activities of daily living and mobility shown via activities of daily living tasks, recognition tasks, mobility, or a combination thereof”). Twenty-five participants (86%) reached the secondary endpoints (“significant improvement of visual acuity/light perception and/or object recognition”). The following paragraphs give details on the performance for the particular tests. For summary of results with the implant switched on for each patient see Table 1.

Vision with a subretinal implant differs from natural vision in a healthy eye in several ways. Firstly, there is limited spatial resolution. The distance between the light-sensitive photodiodes is 70μm in a square-shaped-array, allowing for a theoretical maximum VA of approximately 20/250. Preclinical work (Stett et al., 2000) indicates that a distance of less than 50μm between the single planar electrodes does not improve spatial resolution without additional measures, due to the dissipation of electrical currents within the retinal tissue. Grating acuity and VA results from some of our participants show that the measured VA comes close to this theoretical limit; one participant achieved a grating acuity of 3.3 cycles per degree, corresponding to 20/200. Optotype and grating acuity, however, should not be directly compared (Katz & Sireteanu, 1989), because grating acuity relies on cues derived from angles of lines across a large visual field (even when lines are interrupted), whereas optotype VA depends terbinafine hcl on the recognition of single optotype features in a very small visual field. The best Landolt C-rings acuity of the same participant was 20/546.

In the present study we aimed to investigate how

In the present study, we aimed to investigate how non-human primates visually perceive and categorize materials humans encounter in daily life. We tested this ability in tufted capuchin monkeys (Cebus apella), a species of New World monkeys that separated from Old World monkeys about 40 million years ago (Kiesling, Yi, Xu, Sperone, & Wildman, 2014). Although capuchin monkeys are phylogenetically more distant from humans than are Old World monkeys such as macaques, they show habitual tool-using behavior such as cracking nuts with stones (Ottoni & Izar, 2008) and use visual information effectively to conduct various tasks (Paukner, Huntsberry, & Suomi, 2009; Wright, 1999). They also show remarkable omnivorous tendency; feed on small-sized species of Zalcitabine and reptiles, young birds and birds’ eggs, as well as various kinds of fruit and insects (Izawa, 1975, 1978). Therefore, they may benefit from recognizing materials such as stones and textures of foods with cryptic coloration visually. They share many perceptual properties with humans (e.g., preference for regularity, perceptual completion) (Anderson, Kuwahata, Kuroshima, Leighty, & Fujita, Zalcitabine 2005; Fujita & Giersch, 2005), but a difference has also been detected (e.g., perceptual grouping) (Spinozzi, De Lillo, & Castelli, 2004). Because of moderate similarity and differences between two species, they are good candidates to compare visual material perception from an evolutionary perspective. In this study, we observed how similarly (or differently) monkeys and humans behave in visual matching task based on material properties and discussed what kind of factors, e.g., visual features, saliency and experience, influence their performance. The comparison between the two species would shed light on the evolutionary processes of material perception in primates.

Experiment 1

Experiment 2

General discussion


This work was supported by a Grant-in-Aid for JSPS Fellows (No. 10J04395) to C. Hiramatsu and JSPS Grants-in-Aide for Scientific Research Nos. 20220004 and 25240020 to K. Fujita. We thank the anonymous reviewers for their valuable comments and suggestions to improve the manuscript. We are grateful to H. Kuroshima, T. Matsuno and A. Takimoto for initial training of the matching-to-sample task for the monkeys; to T. Matsuno for providing a program for the task; to N. Goda for providing programs for the analysis; and to H. Komatsu for helpful comments and discussions.

A well-established theory of functional organization across visual brain areas suggests that visual information is processed within two distinct pathways: the ventral stream and the dorsal stream (Goodale & Milner, 1992). The ventral stream receives parvocellular input and includes V2, V4, and the inferior temporal cortex. The dorsal stream, on the other hand, receives magnocellular input and includes V2, V3a, V5 (the homolog of the macaque middle temporal area; MT), and the posterior parietal lobe (De Haan & Cowey, 2011; Goodale, 2013; Goodale & Milner, 1992; Grinter, Maybery, & Badcock, 2010). Functionally, the ventral stream has been shown to underpin object recognition, whereas the dorsal stream supports object localization and visuomotor control (Almeida, Mahon, & Alfonso, 2010; Goodale, 2013; Johnson & Grafton, 2003; Rizzolatti & Matelli, 2003), although there is significant cross-talk between the two pathways (Cloutman, 2013; Himmelbach & Karnath, 2005; Zanon, Busan, Monti, Pizzolato, & Battaglini, 2010).
The dorsal stream vulnerability hypothesis proposes that neurodevelopmental problems have a greater impact on dorsal than ventral stream development (Braddick, Atkinson, & Wattam-Bell, 2003; Spencer et al., 2000). Much of the evidence for this hypothesis comes from the measurement of global motion perception, which involves the integration of local motion signals. Global motion perception is measured typically using random dot kinematograms (RDKs), which consist of two populations of moving dots; a signal population that move in the same direction and a noise population that move randomly. The observer identifies the direction of the signal dots and the relative proportion of signal to noise in the stimulus is varied to measure a psychophysical ‘motion coherence’ threshold (Newsome & Pare, 1988). Neurophysiological (Andersen, 1997; Edwards & Badcock, 1994), neuroimaging (Braddick et al., 2001; Klaver et al., 2008), lesion (Newsome & Pare, 1988; Rudolph & Pasternak, 1999) and brain stimulation studies (Cai, Chen, Zhou, Thompson, & Fang, 2014; Kaderali, Kim, Reynaud, & Mullen, 2015; Salzman, Britten, & Newsome, 1990) have shown that the perception of global motion in RDKs involves dorsal stream extrastriate area MT/V5 in macaques and humans, although a range of other brain areas may also be involved (Braddick et al., 2001).

br Discussion Phenological data collected in spring in

Phenological data collected in spring 2012 in Florence were used to investigate the relationship between flowering, seasonal temperature variations and urban surface parameters and explore a potential application of the relationship between urbanization and flowering phenology. The main findings of this study can be summarized as follows:
Even if Tilia species are widely used in urban environment, only few studies focused on Tilia genus phenology. In a study about the phenology of four Tilia species in the city of Lublin (Poland), the flowering season of was averagely 16 days (Weryszko-Chmielewska and Sadowska, 2010). The flowering season length observed in Lublin and in Florence was similar (16 vs. 16.8 days): even though the start of the flowering season was later by two weeks in Lublin than in Florence due to cooler spring temperatures. According to our results (Table 1), the seasonal average difference between the coolest and the hottest station is around 1°C (1°C in winter and 1.2°C in spring) and the start and the end of flowering at the hottest site happen, respectively, 7 days and 8 days earlier than at the coolest one. These results are in line with studies that found a strong influence of temperature on several plant species (Estrella et al., 2007; Clark and Thompson, 2010). In Germany, an extensive study on the phenology of 78 agricultural and horticultural species over a order DMH-1 of more than 50 years, estimated that a mean temperature difference of 1°C in spring was estimated to advance plant phenology by almost 4 days (Estrella et al., 2007).
The increasing size of cities and the intensive land use change from green surfaces to impervious surfaces and buildings cause thermal difference between cities and the surrounding countryside (Urban Heat Island Effect), as well as between areas of the city characterized by different levels of urbanization (Petralli et al., 2011; Petralli et al., 2013). The thermal variability induced by urbanization can consequently affect plant development and phenology.
This study showed that impervious surfaces contribute to flowering date shifts among different part of the cities (R2SF=0.982; R2EF=0.881), and a variation of impervious surface between 23% and 72% among observation sites corresponds to a difference in SF and EF of 7 and 8 days, respectively. In Florence, IS varies between 78% and 0.04% and if the linear relationship is considered valid for almost the whole range of IS, we can assume an advance of 10.9 days of the most built-up area (IS=78%) with respect to the greenest area (IS=0.04%) in Florence. Many researchers have investigated the differences in phenological response between rural and urban areas, and evidence of an advance in the phenological phases has been found in urban areas (Neil and Wu, 2006; Mimet et al., 2009; Shustack et al., 2009). Only a few studies have investigated the relationship between phenology and the degree of urbanization: Shustack et al. (2009) found evidences of shifts in Lonicera maackii (Amur honeysuckle), an invasive exotic species, along the urbanization gradient. Jochner et al. (2012) investigated the role of elevation and urbanization in the shift of flowering phases of nine tree species, and an advance of 2.6–7.6 days was observed between an entirely rural area and an entirely urban one in five of these species in flowering dates according to urbanization (Jochner et al., 2012). It must be noted that the urban index they used was calculated on land use at a 2km scale while our IS was calculated with a finer resolution (250m).
No significant relationship was found between the start and the end of flowering and the distance from the city center. This result is seemingly in contrast with studies conducted in the United States (Zhang et al., 2004), where an increase in dormancy was found in relation to distance from the urban perimeter. This could be due to the shape of Florence urban area that is not compact, hence the boundaries of the urban area are not at the same distance from the city centre in all directions and built-up areas are spread discontinuously.