Our results indicate

that L fermentum NTD are distribute

Our results indicate

that L. fermentum NTD are distributed not only in the cytoplasm but also on AP24534 the cell wall surface, and further studies showed that surface-attached NTD can be released into the culture broth and conventional buffers. Lactobacilli can be divided into two groups depending on whether or not they require deoxyribonucleosides for growth (Kaminski, 2002). Most lactobacilli that utilize the salvage pathway degrade exogenous nucleosides to the nucleobase and pentose sugar via a nucleoside phosphorylase. Others possess a special salvage system based on a nucleoside deoxyribosyltransferase and require a deoxynucleoside in combination with purine and pyrimidine bases for their DNA synthesis (Kilstrup

et al., 2005). N-deoxyribosyltransferases (EC 2.4.2.6), also called trans-N-deoxyribosylases, catalyze the transfer of a 2′-deoxyribosyl group from check details a donor deoxynucleoside to an acceptor nucleobase (Anand et al., 2004). This enzyme was initially described for lactobacilli and has also been found in certain species of Streptococcus (Chawdhri et al., 1991) and in some protozoans such as Crithidia luciliae (Steenkamp, 1991). Two types of N-deoxyribosyltransferase have been described in lactobacilli: type I is purine deoxyribosyltransferase (PTD), specific for the transfer of deoxyribose between two purines; type II is nucleoside 2′-deoxyribosyltransferase (NTD), which catalyzes the transfer of deoxyribose between either purines

or pyrimidines (Holguin & Cardinaud, 1975; Miyamoto et al., 2007). Several dozen reports on lactobacilli N-deoxyribosyltransferase have been why published since the initial study by Macnutt (Macnutt, 1950). The three-dimensional structure of these enzymes has been solved, and their kinetic mechanisms as well as their catalytic and substrate binding sites have been well characterized (Armstrong et al., 1996; Anand et al., 2004). The transfer reactions, catalyzed by either PTD or NTD, proceed following a ping-pong bi-bi mechanism by formation of a covalent deoxyribosyl enzyme intermediate (Danzin & Cardinau, 1974; Danzin & Cardinaud, 1976). As NTD has broader substrate specificity than PTD, it has attracted more attention. NTD also has a hydrolase function such that, in the absence of an acceptor base, the nucleoside is converted to its base and deoxyribose (Smar et al., 1991). Most antiviral or anticancer drugs are analogues of naturally occurring nucleosides. The use of purified enzyme or intact bacterial cells containing NTD enables a one-pot transglycosylation reaction at high yields, providing an interesting alternative to traditional multistep chemical methods (Fernandez-Lucas et al., 2010). Stereospecific reactions and high tolerance for various modifications in the bases also make NTD ideally suited to serve as biocatalyst for the production of nucleosides and nucleoside analogues (Okuyama et al.

[26] The mortality rate of uterine corpus cancer in the USA is hi

[26] The mortality rate of uterine corpus cancer in the USA is high, being eighth among women’s cancers,[26] but in Japan it remains selleck chemicals llc low, ranking the 20th;[25] however, the mortality ratio is expected to increase.

Endometrioid adenocarcinoma is the most common epithelial malignancy of the endometrium, mimicking non-neoplastic endometrial glands. This tumor is usually graded by FIGO scale depending on the amount of solid components and cytological atypia. There is no substantial difference in the immunophenotype between differentiated endometrial carcinoma, namely, G1/2 EMA, and atypical endometrial hyperplasia. In general, EMA expresses common epithelial markers such as pancytokeratin, epithelial membrane antigen, epithelial antigen (BerEP4), B72.3 and carbohydrate antigen 125 (CA125). Carcinoembryonic antigen (CEA) expression is less striking compared to endocervical adenocarcinoma.

Squamous differentiation and morula formation with no or little proliferative activity, which are often observed in EMA, show CD10 (common p38 MAPK pathway acute lymphoblastic leukemia antigen) expression as well as high molecule cytokeratin such as cytokeratin (CK) 34βE12. Vimentin is regarded as one of the markers available for distinguishing EMA from cervical adenocarcinoma. As its histogenesis-associated markers, estrogen receptor (ER), progesterone receptor (PgR), p53, β-catenin, p16, phosphatase and tensin (PTEN), and DNA mismatch repair proteins, Farnesyltransferase such as MutL protein homolog 1 (MLH1), MutS protein homolog (MSH)2, MSH6, and postmeiotic segregation increased 2 (PMS2) are listed. β-Catenin is involved in cell adhesion and is a component of the Wnt signal transduction pathway. Nuclear expression of β-catenin is observed in as many as 50% of EMA,[27-31] but is rarely observed in SEA.[27, 28] PTEN homolog deleted on chromosome 10 is a tumor suppressor

gene involved in the tumorigenesis of 40–75% of EMA.[28, 32-37] Mutation in PTEN occurs at a similar frequency in atypical endometrial hyperplasia and EMA,[38, 39] resulting in an immunohistochemical negative reaction. While PTEN is significant in the development of endometrial hyperplasia, PIK3CA mutations are considered to play a role in the transition of atypical endometrial hyperplasia to EMA.[38, 39] DNA mismatch repair proteins are found to be deficient in tumor cell nuclei in up to 33% of EMA, caused by MLH1 promoter hypermethylation in most cases or in mutation of MLH1, MSH2, MSH6 and PMS2 in the remaining cases.[40-43] The preponderance of G1/2 EMA shows clear expression of ER and PgR. But, according to upgrading from G1/2 to G3, these expressions decline considerably. Overexpression of p53 tends to be more evident in G3 EMA. Cervical muscular involvement of the endometrial carcinoma is defined as stage II, according to the FIGO 2008 scale.

In addition, a relationship was demonstrated between the absence

In addition, a relationship was demonstrated between the absence of capsule and the incapacity to assign a known serotype to S. suis isolates. We are grateful to K. Kim (Johns Hopkins University School of Medicine) for providing the HBMEC. We wish to thank Sonia Lacouture, Louis Grignon, and Richard Janvier for their technical assistance. This study was supported by the Fond Québécois de la Recherche sur la Nature

MAPK Inhibitor Library manufacturer et les Technologies (FQRNT) and the Natural Sciences and Engineering Research Council of Canada (NSERC). All authors report no conflicts of interest related to their study. “
“In this study, we investigated the β-lactamase-encoding genes responsible for β-lactam resistance phenotypes detected among 56 Gram-negative isolates (Gamma- and Alpha-proteobacteria) recovered this website from wastewater, urban streams, and drinking water. The β-lactam resistance mechanisms detected in 36 isolates comprised the presence of class A (blaTEM-1, blaSHV-1, blaSHV-11, blaGES-5), class B (ImiS, L1), class C (blaCMY-2, blaCMY-34, blaCMY-65, blaCMY-89, blaCMY-90, blaACC-5, blaACT-13), and class D (blaOXA-309)β-lactamase-encoding genes, some variants described for the first time here. Notably, the results showed antimicrobial resistance genes related not only to commonly used antibiotics, but also to carbapenems, providing the first

description of a GES-5-producing Enterobacteriaceae. The importance of ubiquitous bacteria thriving in aquatic environments as reservoirs or carriers of clinically relevant resistance determinants was confirmed, and the need to monitor water habitats as potential sources for the emergence and/or spread of antibiotic resistance in the environment was highlighted. “
“Medizinische Fakultät, Klinik für Kinder-Onkologie-Hämatologie und Klinische Immunologie, Heinrich-Heine Universität

Düsseldorf, Düsseldorf, Germany Medizinische Fakultät, Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, Amino acid München, Germany The ubiquitous pathogen Listeria monocytogenes lives either saprophytically in the environment or within cells in a vertebrate host, thus adapting its lifestyle to its ecological niche. Growth experiments at 24 and 37 °C (environmental and host temperature) with ammonium or glutamine as nitrogen sources revealed that ammonium is the preferred nitrogen source of L. monocytogenes. Reduced growth on glutamine is more obvious at 24 °C. Global transcriptional microarray analyses showed that the most striking difference in temperature-dependent transcription was observed for central nitrogen metabolism genes, glnR (glutamine synthetase repressor GlnR), glnA (glutamine synthetase GlnA), amtB (ammonium transporter AmtB), glnK (PII regulatory protein GlnK), and gdh (glutamate dehydrogenase) when cells were grown on glutamine.

The recording time varied from 4 to 6 min, depending on each infa

The recording time varied from 4 to 6 min, depending on each infant’s attention to the stimuli. The behaviour of the infants was videotaped and off-line coded for EEG artefact rejection. High-density EEG was recorded using a 128-channel Hydrocel Sensor Net (EGI

Inc.) referenced to the vertex (Tucker, 1993). The EEG signal was amplified, digitized at 500 Hz and band-pass filtered from 0.1 to 200 Hz. The signal was off-line low-pass filtered at 30 Hz and segmented into epochs starting 100 ms before and ending 1,000 ms after the AV stimulus onset. Channels contaminated by eye or motion artefacts were rejected manually, and trials with > 20 bad channels were excluded. In addition, video recordings of the infants’ behaviour were coded frame-by-frame, and trials during which the infant did not attend to the face were excluded from further analysis. Following artefact rejection, the average number of trials for an individual infant accepted PF-02341066 concentration for further analysis was 37.4 for /ba/, 36.7 for /ga/, 37.6 for VgaAba and 37.8 for VbaAga. Although uncommon for adult ERP studies, this number of accepted trials has been proved to be sufficient in infant studies (Dehaene-Lambertz & Dehaene, 1994; Friederici et al., 2007; Kushnerenko et al., RG7204 in vitro 2008; Bristow et al., 2009; Guiraud et al., 2011). Artefact-free segments were re-referenced to the average

reference and then averaged for each infant within each condition. A baseline correction was performed by subtracting mean amplitudes in the 260–360 ms window from the video onset (i.e. immediately before the sound onset) to minimise the effects of any ongoing processing from the preceding stimulus. According to Kushnerenko et al. (2008) the AVMMR resembled the auditory mismatch response and was observed mainly over the right frontocentral area (between F4, C4 and Cz), commencing at ~ 290 ms from the sound onset

and lasting beyond the epoch of analysis. In this report AVMMR was observed only in response to apparent AV mismatch of speech cues (visual /ba/ auditory /ga/). In order to link individual differences in electrophysiological Succinyl-CoA mismatch response to the development of visual scanning, the mean amplitude between 290 and 390 ms after sound onset (650–750 ms from video onset) from the area between F4, C4 and Cz was entered into hierarchical linear regression as the dependent variable with looking times to articulating mouth and control demographic variables (age, gender and second-language experience) as predictors. (Second-language experience here is defined as experience of one or more languages spoken at home in addition to English.) For the comparison between age groups we also measured mean voltage between 140 and 240 ms from the sound onset, centred around the mean latency of the auditory infantile P2 (Kushnerenko et al., 2002a, 2007) over the frontal leads.

We found enhanced hippocampal CA1 long-term potentiation and redu

We found enhanced hippocampal CA1 long-term potentiation and reduced long-term depression but normal spatial learning and memory in adult rats that were subjected to experimental febrile Raf phosphorylation seizures on postnatal day 10. Furthermore, rats with experimental

febrile seizures showed modest but significant sprouting of mossy fiber collaterals into the inner molecular layer of the dentate gyrus in adulthood. We conclude that enhanced CA1 long-term potentiation and mild mossy fiber sprouting occur after experimental febrile seizures, without affecting spatial learning and memory in the Morris water maze. These long-term functional and structural alterations in hippocampal plasticity are likely to play a role in the enhanced seizure susceptibility in this model of prolonged human febrile seizures but do not correlate with overt cognitive deficits. “
“Glucocorticoids can cause depression CDK inhibitor and anxiety. Mechanisms for glucocorticoid effects on mood are largely undefined.

The dorsal raphé nucleus (DRN) produces the majority of serotonin in the brain, and expresses glucocorticoid receptors (GR). Because we previously showed that antidepressants used to treat depression and anxiety decrease check DRN GR expression, we hypothesized that deleting DRN GR would have anxiolytic- and antidepressant-like effects. We also hypothesized that DRN GR deletion would disinhibit activity of the hypothalamic–pituitary–adrenal (HPA) axis. Adeno-associated virus pseudotype AAV2/9 expressing either Cre recombinase (DRNGRKO mice) or GFP

(DRN-GFP mice) was injected into the DRN of floxed GR mice to test these hypotheses. Three weeks after injection, mice underwent 21 days of social defeat or control handling and were tested for anxiety-like behavior (open-field test, elevated-plus maze), depression-like behavior [sucrose preference, forced-swim test (FST), tail-suspension test (TST)], social interaction, and circadian and stress-induced HPA activity. DRN GR deletion decreased anxiety-like behavior in control but not in defeated mice. DRN GR deletion decreased FST and tended to decrease TST despair-like behavior in both control and defeated mice, but did not affect sucrose preference. Exploration of social (a novel mouse) as well as neutral (an empty box) targets was increased in DRNGRKO mice, suggesting that DRN GR deletion also promotes active coping. DRN GR deletion increased stress-induced HPA activity without strongly altering circadian HPA activity.

41)] All

participants from this cohort also completed th

41)]. All

participants from this cohort also completed the cTBS paradigm. All participants gave informed consent to the study, which was reviewed and approved by the institutional review boards at each participating institution. Participants were recruited through local community advertisement and local Asperger’s Associations and clinics. All AS participants in both cohorts had an IQ > 80 based on the Weschler Abbreviated Scale of Intelligence (WASI) and a formal clinical diagnosis from an independent clinician prior to participation in the study. All met DSM-IV-TR criteria for Asperger’s Syndrome and met criteria for ASD on the Autism Diagnostic Observation Schedule, Module 4 (ADOS) (mean ± SD Social and Communication score, 10.2 ± 4.6). Additionally, the Autism Diagnostic

Interview Revised was completed selleckchem on 11 participants whose parents were available for interview. For these individuals the mean Social score was 18.2 ± 5.1, Communication score was 20.0 ± 2.6 learn more and Repetitive Behavior score was 6.0 ± 2.3. Cognitive and clinical evaluation was identical for the two cohorts, with Spanish-translated versions of the ADOS and WASI used for the participants in cohort two. Participants in the neurotypical group were healthy controls with no neurological or psychiatric disorders. This group was matched with respect to chronological age, gender and full-scale IQ with the AS group. All participants were given a comprehensive neurological exam by a board-certified neurologist to confirm normal gross motor and fine motor functioning. Lastly, all participants were screened following published recommendations (Rossi et al., 2009) to ensure that they did not have any condition that would put them at greater risk of an adverse event related to TMS (e.g. a personal or family history of epilepsy). Study procedures were identical

in the two study locations. The experimenters find more who collected the data at each location were trained by Dr Pascual-Leone and used the same equipment and procedures described herein. cTBS and iTBS were applied as described in Huang et al., 2005. The cTBS paradigm consisted of three pulses of 50 Hz stimulation repeated at 200-ms intervals for 40 s (for a total of 600 pulses) at an intensity of 80% of active motor threshold (AMT). In the iTBS paradigm participants received a 2-s train of TBS repeated every 10 s for a total of 190 s (600 pulses), also at an intensity of 80% of AMT (Fig. 1). Corticospinal excitability was assessed prior to and following cTBS or iTBS by measuring peak-to-peak amplitude of MEPs induced in the contralateral first dorsal interosseus (FDI) muscle in response to single-pulse TMS at a rate of approximately 0.1 Hz (a random jitter of ± 1 s was introduced to avoid any train effects). Three batches of 10 MEPs were recorded prior to cTBS or iTBS and used as a baseline. Following cTBS or iTBS, batches of 10 MEPs were measured at periodic intervals for a total of 120 min to track changes in MEP amplitude over time.

This

clustering is negatively modulated by up-stream neur

This

clustering is negatively modulated by up-stream neurexin sequences (Kang et al., 2008). A C-terminus binding motif Lenvatinib purchase is required for neurexin to leave the endoplasmic reticulum and for targeting to and insertion at synaptic plasma membranes. Neurexin is transported along the axon in vesicles that do not contain active zone precursor proteins, but which carry CASK (Calcium/calmodulin- dependent serine protein kinase), RIM1α (Regulating synaptic membrane exocytosis protein 1α) and calcium channels and possibly other elements of the transmitter release machinery (Fairless et al., 2008). Insertion of neurexin in the presynaptic plasma membrane is clearly important for binding essential components into the presynaptic release machinery. In addition, the interactions of neurexins with neuroligins promote

postsynaptic differentiation, presumably because they help to stabilise both proteins and thereby their pre- and postsynaptic binding partners. These interactions and the influence they have are affected by the splice variants present. For example, NL1 lacking an insert in splice site B binds both α and β neurexin and, if overexpressed, has a more powerful effect on synaptic size than on number, unlike the variant with the insert, which affects synapse number more powerfully (Boucard et al., 2005). These studies have led to the suggestion that the combination of neurexin and neuroligin isoforms that is expressed influences a wide range of synaptic properties. The many binding partners and extensive alternative splicing of neurexins, the conservation of splice MI-503 price insert sequences

and positions across species, and the co-expression of several neurexin isoforms in single cells may suggest that they are mediators of synapse specificity and that from this specificity is important. How different splice variants may be concentrated at different presynaptic terminals remains to be established, but a mechanism shared with that underlying the specific localisation of certain release machinery components seems likely. Neuroligins (NL1, NL2 and NL3) are the postsynaptic neurexin interactors. They exhibit less extensive alternative splicing, which occurs at their single LNS domain and at the AChE (acetylcholine esterase)-homologous regions, but important selectivity nevertheless (Kang et al., 2008). NL2 promotes formation of and is localised to GABAergic synapses (Varoqueaux et al., 2004), while NL1 promotes glutamateric synapse formation. NL3 aggregates at subsets of both glutamatergic and GABAergic synapses, forming complexes with NL1 or NL2 (Budreck & Scheiffele, 2007). Without NL2, GABAAR clusters do form in the plasma membranes of transfected HEK 293T cells co-cultured with neurones. However, the clusters that form are reported to be small, functionally silent and labile, and do not recruit the scaffolding protein gephyrin.

This study has strengths and limitations Participants interviewe

This study has strengths and limitations. Participants interviewed were from a range of backgrounds and data saturation was achieved. Some participants had already worked in multidisciplinary

teams, thus offering a richness and diversity of views. Two GPs had previous experience working within pharmacy (one as a pharmacist, the other as a sales assistant). It may be that participants interviewed had a pre-existing interest in this topic; however, they expressed varying views, highlighting the complex and divisive nature of the subject. The majority of pharmacists interviewed were consultant pharmacists, accredited to undertake collaborative medicines management reviews. We believed that consultant click here pharmacists would be the most suitable candidates for a role in general practice

given their additional training and existing working relationship with GPs, and thus they were approached for this study. Although this may have introduced selection bias, the pharmacists interviewed had experience in multiple other roles within the profession, including traditional roles in community and hospital pharmacy, and thus were able to offer insights from different perspectives. The interviewer was a registered pharmacist but took care to remain neutral throughout the interview, learn more and did not emphasise the fact he was a pharmacist. Being a qualitative study, caution

should be exercised in generalising these results because of the non-probabilistic nature of the sample. Although this study explored the views of GPs and pharmacists, input from other stakeholders such as consumers and major professional organisations is critical before recommending any changes to the current model. Studies in other counties have shown that integrated pharmacists have been SSR128129E perceived by stakeholders to benefit both practice staff and pharmacists.[20, 21] Our study revealed some concerns about potential negative impacts of the role on the community pharmacist. Some GPs felt this new role may undermine the current role of the community pharmacist, possibly reflecting the positive relationship between these GPs and their local pharmacists; however, most pharmacists in our study, including those working within community pharmacy, felt the role would be beneficial to the pharmacy profession overall. The opinion that a non-dispensing, co-located practice pharmacist was more credible than a community pharmacist is a view shared by GPs in the UK.[22] Similarly to other studies, the GPs interviewed in our study felt that pharmacists mainly have a role in support and advisory functions.[14] Pharmacist participants, however, felt that role expansion and greater clinical involvement would be desirable and these views are reflected in the international literature.

057) A lower probability was observed for IDUs (OR 051; 95% CI

057). A lower probability was observed for IDUs (OR 0.51; 95% CI 0.36–0.73). Similar to the analysis of late diagnosis, the transmission groups showed characteristic evolutions of risk over time (Fig. 4). In 2001, the probability of late presentation for care was lowest for

IDUs and increased steadily from 45% to almost 60% in 2009 in this subgroup. In contrast, the probability of late presentation decreased markedly in MSM from over 60% in 2001 to approximately 45% in 2009 and remained somewhat stable in migrants and heterosexuals, who had similar evolutions and would overlap in Figure 4. Patients with unknown transmission risk had no significant interaction with date of diagnosis. Female heterosexuals (OR 0.59; 95% CI 0.46–0.75)

and female migrants (OR 0.72; 95% CI 0.54–0.97) had lower probabilities of late presentation for care GSI-IX cell line compared with their male counterparts. Late presentation is associated with a substantially higher risk of mortality and morbidity. The risk increases with lower CD4 cell counts at ART initiation and remains elevated even years after initiation of ART [13, 14]. This argues for early diagnosis and treatment of HIV infection, before patients enter advanced stages of immunodeficiency. In contrast to many developing countries, access to HIV testing Regorafenib and treatment currently is not limited by economic constraints in industrialized countries such as Germany. As a basis for targeted interventions, we tried to identify this website groups at risk for late diagnosis and care in a specialized treatment centre in this setting. Data sources were chosen with a view to data completeness and generalizability, and represent different time-points. Data from the national case surveillance provide representative data on the first HIV diagnosis, whereas the ClinSurv cohort provides data on the

first presentation in specialized HIV treatment centres representing almost complete data for approximately 20% of all treated HIV-infected patients in Germany. According to the national case surveillance, in the years 2001–2010 a significant number of patients (49.5%; 95% CI 48.7–50.3%), on first being diagnosed with HIV infection, met the new consensus definition of late presentation. This proportion remained relatively stable over the years and no clear trend towards an earlier presentation in more recent years was noted. Despite intensive efforts to encourage earlier testing, this situation is currently also found in other European countries [20], although most studies have not yet started to use the new cut-off of 350 cells/μL for the definition of late presentation [21]. With regard to the transmission risk, the proportion of late presenters for diagnosis remained steady for heterosexuals. Migrants from high-prevalence countries according to the World Health Organization (WHO) definition [22] were the group with the highest proportion of patients with late diagnosis.

057) A lower probability was observed for IDUs (OR 051; 95% CI

057). A lower probability was observed for IDUs (OR 0.51; 95% CI 0.36–0.73). Similar to the analysis of late diagnosis, the transmission groups showed characteristic evolutions of risk over time (Fig. 4). In 2001, the probability of late presentation for care was lowest for

IDUs and increased steadily from 45% to almost 60% in 2009 in this subgroup. In contrast, the probability of late presentation decreased markedly in MSM from over 60% in 2001 to approximately 45% in 2009 and remained somewhat stable in migrants and heterosexuals, who had similar evolutions and would overlap in Figure 4. Patients with unknown transmission risk had no significant interaction with date of diagnosis. Female heterosexuals (OR 0.59; 95% CI 0.46–0.75)

and female migrants (OR 0.72; 95% CI 0.54–0.97) had lower probabilities of late presentation for care see more compared with their male counterparts. Late presentation is associated with a substantially higher risk of mortality and morbidity. The risk increases with lower CD4 cell counts at ART initiation and remains elevated even years after initiation of ART [13, 14]. This argues for early diagnosis and treatment of HIV infection, before patients enter advanced stages of immunodeficiency. In contrast to many developing countries, access to HIV testing MLN0128 manufacturer and treatment currently is not limited by economic constraints in industrialized countries such as Germany. As a basis for targeted interventions, we tried to identify Liothyronine Sodium groups at risk for late diagnosis and care in a specialized treatment centre in this setting. Data sources were chosen with a view to data completeness and generalizability, and represent different time-points. Data from the national case surveillance provide representative data on the first HIV diagnosis, whereas the ClinSurv cohort provides data on the

first presentation in specialized HIV treatment centres representing almost complete data for approximately 20% of all treated HIV-infected patients in Germany. According to the national case surveillance, in the years 2001–2010 a significant number of patients (49.5%; 95% CI 48.7–50.3%), on first being diagnosed with HIV infection, met the new consensus definition of late presentation. This proportion remained relatively stable over the years and no clear trend towards an earlier presentation in more recent years was noted. Despite intensive efforts to encourage earlier testing, this situation is currently also found in other European countries [20], although most studies have not yet started to use the new cut-off of 350 cells/μL for the definition of late presentation [21]. With regard to the transmission risk, the proportion of late presenters for diagnosis remained steady for heterosexuals. Migrants from high-prevalence countries according to the World Health Organization (WHO) definition [22] were the group with the highest proportion of patients with late diagnosis.