Tecchio et al. (2010) employed AtDCS to upregulate M1 activity after practice to enhance consolidation of the practiced implicit BGJ398 solubility dmso sequence. This post-practice application of AtDCS may have specifically enhanced consolidation processes and improved offline learning. Nevertheless, our findings support the previously reported role of M1 in offline memory stabilization (Kantak et al., 2010; Kang & Paik, 2011). To our knowledge, our study is the first to investigate the effects of AtDCS applied over PMd during practice on performance and learning of an implicit SRTT sequence. Contrary to our hypothesis,

AtDCS applied over PMd did benefit motor performance during practice and at EoA compared with sham stimulation. Although not statistically significant, the effect size was high, indicating that the effect was likely to be real and may have reached significance with a larger sample size. There may be multiple mechanisms that may implement this effect. Although

we used a smaller anode than those previously used, evidence exists that AtDCS applied over PMd is known to increase the excitability within the M1 via corticocortical connections (Boros et al., 2008). Although it is not clear how explicit and implicit systems interact during practice at a neural substrate level, the behavioral evidence for the effect of explicit knowledge on implicit motor performance is also mixed. Although PMd is thought to be predominantly a part of the explicit memory system, there is evidence that it may be engaged during early performance of any sequence learning task that links the visuospatial Bortezomib nmr cues to compatible responses, an important

characteristic of our task (Grafton et al., 1998, 2002; van der Graaf et al., 2006). Our findings are different from those observed by Boyd & Linsdell (2009) who observed that enhancing PMd excitability during the immediate post-practice period led to better offline learning of a continuous tracking task. In our study, we applied AtDCS during practice of the implicit sequence task, therefore not directly affecting the motor memory consolidation phase. It is likely that AtDCS over PMd during practice led to a motor memory representation that did not Janus kinase (JAK) demonstrate offline stabilization. Although somewhat beneficial to online practice performance of the implicit motor sequence learning task, AtDCS over PMd attenuated offline stabilization of the implicit motor sequence compared with sham and M1 AtDCS. This emphasizes the well-known performance–learning distinction which suggests that factors that enhance practice performance may not always enhance retention of motor skills (Kantak & Winstein, 2011). Even after practice ends, functional properties and representation of the skill continue to evolve in the brain and help stabilize motor performance over the retention interval (online learning).

If the CD4 count falls below 200 cells/μL, Pneumocystis carinii pneumonia (PCP) prophylaxis should be considered. Cotrimoxazole may have haematological side effects and should be used at the lowest appropriate dosage. 5.3.4.4 Treatment duration. Early trials such as the APRICOT study recognized that this is

a ‘hard-to-treat’ group and opted for longer duration of therapy (48 weeks) for all patients whatever the genotype [194–196,200–202,205]. Detailed analysis of the RVR and EVR from various studies has helped predict the SVR for the individual patient and there is increasing use of ‘tailoring Daporinad chemical structure the regimen’ for the individual according to the genotype, baseline viral load and initial virological response [194–196]. 5.3.4.5 ‘Easier-to-treat’ genotypes. In patients with genotype 2 and 3 infection who have an RVR, a treatment duration of 24 weeks should be strongly considered [194–196]. In

patients who do not have an RVR but reach an undetectable Trametinib HCV viral load by 24 weeks, a 48-week course is recommended [194–196]. Treatment courses longer than 48 weeks are associated with poor compliance but may be considered in an individual patient with a slow but steady decline in the viral load who is tolerating therapy well [210,211,213]. 5.3.4.6 ‘Harder-to-treat’ genotypes. second In patients with genotypes 1 and 4, a 48-week course of treatment is recommended [194–196,200–202,205,206,210,211]. An extension to 72 weeks of therapy

should be utilized in patients not achieving an RVR but who have a 2 log10 drop at 12 weeks and become PCR negative at 24 weeks [210,211,213]. The Sustained Long-term Antiviral Maintenance with Pegylated Interferon in HCV/HIV-co-infected Patients (SLAM-C) study showed 65% completion and 51% SVR after 72 weeks of treatment. 5.3.4.7 Recommendations • Anti-HCV treatment should be started before the CD4 count falls below 350 cells/μL and before ART is started, if possible (I). There are limited data to guide re-treatment of nonresponders and relapsers in the setting of HIV [214]. In the HIV-negative population, re-treatment may be considered in individuals who have failed to respond with an SVR to non-gold standard therapy, i.e. nonpegylated interferon with or without ribavirin, or in individuals with progression of fibrosis [215,216]. Responses in all groups are less than in individuals receiving pegylated interferon and ribavirin de novo [214–216]. When re-treatment is considered, all modifiable factors known to affect response should be changed to meet optimal conditions, where possible. The factors optimized should include the following.

The preferred regimen (see Table 3.3) is TMP-SMX, one double-strength tablet (960 mg TMP-SMX) [63] or one single-strength tablet (480 mg TMP-SMX)

once daily. These regimens have comparable efficacy but the 480 mg once daily regimen has a lower rate of side effects [62]. A Markov buy EX 527 decision model analysis, using data derived from a meta-analysis, showed that these regimens are superior to other regimens in terms of efficacy, but that as life expectancy with HIV-1 infection increases, the 480 mg once daily regimen may have advantages because of the lower rate of associated drug toxicity [64]. The regimen of TMP-SMX 960 mg three times a week has comparable efficacy to nebulized pentamidine or dapsone plus pyrimethamine prophylaxis [65] but may be less effective than 960 mg once daily as one randomised study showed

a greater rate of PCP in individuals taking TMP-SMX 960 mg three times a week, compared to the once-daily dosing in on-treatment analysis [66]. Cross-protection is also provided by TMP-SMX against toxoplasmosis and certain bacterial infections [63]. Other prophylactic regimens have been shown to have similar efficacy as either primary or secondary prophylactic agents [62,63,66–68]. However, some, such as dapsone, lack the selleck products benefits of broad cross-prophylaxis seen with TMP-SMX, whilst others, such as nebulized pentamidine, are less effective at low CD4 cell counts and following PCP, when

used as secondary prophylaxis [69]. Patients who have not tolerated treatment doses of TMP-SMX are often able to take the drug at the lower doses used for secondary Uroporphyrinogen III synthase prophylaxis [63]. The optimal management of patients who develop intolerance to co-trimoxazole is not determined. Desensitization is a frequently used strategy though equally effective strategies include treating through the rash or stopping and restarting at full dose. Desensitization can be attempted 2 weeks after a non-severe (grade 3 or less) co-trimoxazole reaction that has resulted in a temporary interruption of co-trimoxazole. It has been shown to be successful in most individuals with previous hypersensitivity and rarely causes serious reactions [70,71]. Desensitization should not be attempted in individuals with a history of grade 4 reactions to previous co-trimoxazole or other sulpha drugs. Various desensitization protocols exist. Table 3.4 is reproduced from the World Health Organization guidelines on the use of co-trimoxazole prophylaxis for HIV infection [72]. Early initiation of HAART is favoured in individuals with PCP (category IIb recommendation). The optimal time of initiation of HAART after PCP remains to be determined.

A pharmacokinetic study in healthy volunteers was reminiscent of the saquinavir study, and was terminated early because of high rates of severe transaminitis [101]. Recent data suggest that atazanavir with or without ritonavir boosting had unfavourable pharmacokinetics when administered with rifampicin [102–104]. Trough atazanavir check details concentrations were reduced by >80% [103]. Tipranavir concentrations were reduced by 80% by rifampicin [105]. The interaction between darunavir and rifampicin has not yet been investigated. In line with other PIs, it is currently recommended that darunavir should not be coadministered with rifampicin. The use of

rifabutin in treating TB in HIV-positive patients is discussed above (see ‘Use of rifapentine’ [EII]). Rifabutin can be administered RAD001 with unboosted PIs except saquinavir [106], although they will rarely be used in practice. The balance between rifabutin induction and PI inhibition of CYP3A4 means that the dose of rifabutin should be decreased from 300 to 150 mg daily to avoid toxicity [48,70]. If PIs are used with low-dose ritonavir boosting then the dose of rifabutin should be reduced to 150 mg three times per week [49,105]. This recommendation

is derived from pharmacokinetic studies and modelling. There are no clinical outcome data for either HIV or TB using this strategy. Adherence should be monitored closely as the dose of rifabutin would become inadequate if the boosted PI is not taken concomitantly. Where available, drug levels of the PI should be measured. There have been reports of acquired rifabutin resistance occurring even in patients taking rifabutin 150 mg three

times a week with boosted PIs. No rifabutin drug levels were available in those patients and, although there may have been other reasons for these failures, physicians may consider measuring the levels of rifabutin and its active metabolite 25-0-desacetyl rifabutin if results are available in a timely manner [107]. Complex nearly interactions may occur when a rifamycin is given with salvage regimens such as an integrase, boosted PI and an NNRTI. Rifabutin is safer than rifampicin, but there are few data to guide the clinician regarding dose modification. TDM is recommended. We recommend that PI/ritonavir combinations should not be given with rifampicin. [EII] If possible, the HAART regimen should be changed to avoid PIs. If effective HAART necessitates the use of PIs then rifabutin should be used instead of rifampicin. [AII] Raltegravir is metabolized by UGT1A1 glucuronidation. Rifampicin is an inducer of UGT1A1, and reduces trough levels of raltegravir by approximately 60% [108]. Because the antiviral activity of raltegravir 200 mg twice daily was very similar to that of the licensed dose (400 mg twice daily), an earlier recommendation was that standard doses of raltegravir should be used with rifampicin. There is at least one report of raltegravir failure when given like this with rifampicin (S.

coelicolor membrane; therefore, incorrect localization is not the reason for lack of complementation of the Δpmt mutation in IB25. Even though both genes were expressed from the strong and inducible PtipA promoter, hemagglutinin-tagged PmtMtu appeared to be less abundant than hemagglutinin-tagged PmtSco, when expressed in S. coelicolor under full induction PD-0332991 clinical trial (to ensure that this fainter band was not due to a difference in the amount of protein loaded, the membrane was stained with Coomassie brilliant blue, Fig. S3). In addition, there appeared to be limited degradation of this protein, presumably related to the fact the S. coelicolor has an abundance of extracellular proteases

(Jayapal et al., 2007). It is unlikely that this slightly lower abundance

is the reason for lack of complementation, because hemagglutinin-tagged PmtSco was able to complement the Δpmt mutation for φC31 plaque formation even in the absence of inducer when expression relied on background PtipA transcription levels, revealing that even low levels of functional Pmt are sufficient for complementation (Fig. S4). The previous result prompted us to look for differences between PmtSco and PmtMtu to search for clues to the nonfunctionality of PmtMtu in S. coelicolor. Protein mannosylation by PmtMtu requires Sec translocation, and it has been proposed that physical interactions between the Sec complex and Pmt explain this requirement (VanderVen et al., 2005); therefore, JQ1 supplier the nonfunctionality of PmtMtu in S. coelicolor could result from its inability to interact with the S. coelicolor Sec translocon. Upon alignment of the Pmt protein sequences from

mycobacteria and Streptomyces species, it was clear that the main difference is the presence in the Streptomyces Pmt sequences, including that of S. coelicolor, of an N-terminal extension. According to the prediction for topology of mycobacterial Pmt, this N-terminal extension should be located on the intracellular side of the membrane (Lommel & Strahl, Carnitine palmitoyltransferase II 2009; Fig. S5). Because this extension could prove important for Pmt function in S. coelicolor (if, for example, it is required specifically for interaction with the S. coelicolor Sec translocon), we constructed two modified versions of the Rv1002c gene to encode chimeric Pmt proteins and cloned them in pIJ6902; in the first construct (pBL20, Table 1), 55 amino acids of PmtSco were affixed to the N-terminus of PmtMtu, giving PmtMtu + 55, whereas in the second construct (pBL21, Table 1), 178 amino acids of PmtSco, which include the first extracellular loop where acidic residues essential for activity are localized (VanderVen et al., 2005), were substituted for the equivalent N-terminal region of PmtMtu (Fig. S5). When pBL20 was introduced into the Δpmt mutant IB25, no complementation was observed, either for φC31 plaque formation (Fig. 4a, plate 5) or for Apa glycosylation (Fig. 4b and c, lane 5).

, 2006). On the other hand, the results may indicate that a shift in the microbial community was already occurring due to an increasing complexity of the available substrate after 4 weeks (Poll et al., 2008). However,

increased proportions of Gram-negative bacteria (16:1ω7; 16:1ω11) might indicate high contents of labile compounds in the early stages of decomposition, which usually attracts fast-growing bacteria (Kuzyakov et al., 2000; Fioretto et al., 2005). After 12 weeks of incubation, a significant population shift in L. corniculatus treatments was observed on both principal PS-341 components PC1 and PC2. This shift was based on low proportions of short-chained iso- and anteiso-branched PLFA (iso15:0, ant15:0, iso16:0), which were, in some cases, below the detection limit and thus indicated a reduced Gram-positive bacteria population (Zelles, 1999).

In L. corniculatus treatments, a large decrease in the ubiquitous nor16:0 (Zelles, 1999) was observed, which was consistent with the decline in the microbial biomass that was discussed previously. In C. epigejos treatments, however, a decrease in the fungi PLFA 18:2ω6,9 was largely responsible for the treatment separation on PC1, whereas the proportions of Gram-positive PLFA did not change relative to the 4-week sampling time point. Obviously, fungi have outcompeted Gram-positive bacteria Dorsomorphin nmr for the available substrate, because both groups have been reported in association with complex substrates (Kuzyakov et al., 2000; Dilly et al., 2004; Rubino et al., 2010). At the end of the experiment, a similar microbial community structure was observed in the detritusphere of L. corniculatus and C. epigejos many treatments. High proportions of short-chained and iso-/anteiso-PLFA

were detected in both treatments. This result indicated that high proportions of Gram-positive bacteria were present in the microbial decomposer community and were utilizing recalcitrant plant litter compounds at the end of the experiment (Kuzyakov et al., 2000; Rubino et al., 2010). These results are in contrast to many studies where litter degradation in well-developed soil ecosystems has been investigated. In most of these studies, a clear increase of fungal biomass over time has been described (Aneja et al., 2006; Oyun et al., 2006; Williams et al., 2006). Obviously, fungi are highly dependent on N; hence, as in our study, N was limited in soil, there was a need to use plant-derived N. The low amounts of available N in C. epigejos litter material after 12 weeks and in both litter types after 40 weeks might therefore explain the reduced fungal biomass, from which Gram-positive bacteria could benefit. By investigating the 13C signature of the corresponding PLFA, the active microbial community structure directly involved in the litter decomposition was assessed. After 4 weeks of incubation, a similar 13C distribution was observed in L. corniculatus and C.

Median time to progression was 5.1 months and median overall

survival was 12.8 months from start of sorafenib. Toxicities, principally diarrhoea and hand–foot syndrome, were more severe than expected suggesting possible interaction with concomitant use of HAART [51]. Pharmacokinetic studies are of HAART and sorafenib are ongoing. Recommendations for screening for patients with hepatitis and HIV coinfection exist in BHIVA [52] as well as European Association for Study of the Liver (EASL) [53] and American Association for the Study of Liver Disease (AASLD) guidelines [54]. Screening programmes utilizing serum AFP and 6-monthly ultrasound scans have demonstrated improved survival in non-HIV-infected patients [55]. Although AFP may not add to the value of ultrasound scans if the latter is done twice or more a year, this frequency of scans is often impractical and therefore AFP is still used. HBV is potentially Selleck Lumacaftor oncogenic, and so even in the absence of cirrhosis it is advised that all HIV/HBV coinfected patients have 6-monthly ultrasound scans even in the absence of cirrhosis. Adherence to published guidelines is poor, and many at-risk cohorts do not receive adequate ultrasound screening [56]. Surveillance for HCC needs to be tailored to specific risk [57]. Some patients may warrant more

intensive surveillance with shorter frequency [58] or different imaging modalities as ultrasound screening is associated with an appreciable false-negative rate [59]. We suggest that people old living with HIV with HCC should be treated in a similar manner to their HIV-negative NVP-AUY922 manufacturer counterparts (level

of evidence 2C). We suggest that liver transplantation should be considered for appropriate cases, as in the HIV-negative population (level of evidence 2D). We suggest that sorafenib is a treatment option in advanced, nonoperable HCC (level of evidence 2D). Noncirrhotic HBV coinfected patients should be considered for HCC screening (GPP). We recommend HCC screening with liver ultrasound (level of evidence 1A) and suggest 6-monthly AFP (level of evidence 2C) be offered to all cirrhotic patients with HBV and HCV coinfections. The largest prospective study to date compared 136 asymptomatic HIV-positive patients to 272 HIV-negative patients and found an increased incidence of neoplastic lesions (adenomas, adenocarcinomas) in the former [60]. HIV-positive patients with colorectal adenocarcinoma were significantly younger, had more advanced disease and had an increased prevalence of right-sided tumours [60], all of which is in keeping with findings from smaller studies [61–63]. Evidence for the treatment of HIV-positive colorectal cancer (CRC) patients is limited to small retrospective case studies and so specific recommendations are not possible.

After the training and the test sessions, the rats were dried and placed back in their home cages. The EPM test Nivolumab mw was used to assess anxiety-like and exploratory behaviors, and consisted of two opposite open arms and two opposite closed arms (45 × 15 cm) connected by a central area (15 × 15 cm), elevated 70 cm above the floor. The test was

performed under dim light conditions. The rat was placed in the central square, and its behavior was observed for 5 min. During that time, the number of entries into and the time spent in the open and closed arms were measured. After each rat had been tested, the EPM was cleaned with a 10% ethanol solution. This test was performed as previously described (Ennaceur et al., 2005), and consisted of two phases. On the first day, two identical objects were placed in the back corners of an open LY2157299 datasheet box made of PVC (width, 80 cm; length, 80 cm; height, 50 cm), 10 cm away from the sidewall, and the rats

were placed facing away from the objects. The rat was allowed to explore the box for 3 min, and placed back in its home cage. After a 15-min delay, it was replaced in the box and allowed to explore it for another 3 min. This process was repeated five times (3 min each), with a 15-min interval between exposures. The second phase, performed 24 h later, consisted of placing the rat in the box for 3 min, and, after a 15-min interval, placing one of the objects in a different location (diagonally), and analysing the frequency and total duration of approaches to each object. A discrimination index was also used to evaluate possible memory deficits, calculated with the following equation – [(TNP − TOP)/(TNP + TOP) × 100], where TNP is the time spent in the new position, and TOP is the time spent in the old position. The rats were decapitated, their brains were removed, and the hippocampi were dissected on a cold surface. The tissue samples were weighed individually, and homogenised by sonication in 500 mL of extraction solution Evodiamine (0.1 m perchloric acid containing

0.4 mm sodium metabisulfite and 0.2 mm EDTA) (Machado et al., 2008). The mobile phase was filtered through a 0.2-mm filter membrane, degassed under vacuum, and delivered at a flow rate of 1.2 mL/min (HITACHI Pump System L-7100; LaChrom Elite, USA). Each sample was analysed in duplicate for the concentrations of 5-HT and the metabolite 5-HIAA. Recovery of the analytes was determined by adding a fixed concentration of the internal standard dihydroxybenzylamine before tissue homogenisation. An automatic injector (HITACHI L-7250, cut injection method) was utilised to improve the reproducibility of injections. All standards and salts were purchased from Sigma (USA), and the solvents (high-performance liquid chromatography grade) were purchased from J. T. Baker (USA).

The overall mean length of hospital stay was 6.8 days. Small vessel vasculitis and Sjögren syndrome had the longest and the shortest hospital stays respectively (14.5 vs. 5.3 days). Hospital charges were highest among systemic vasculitis and DM-PM patients. The admission rate for SCNTD in Thailand was 141 per 100 000 admissions among which SLE was the most common. Overall hospital mortality was 4.1%. Although a lower prevalence was found among systemic vasculitis, it had a higher mortality rate, longer length of stay and greater Dabrafenib cost therapeutic cost. “
“Some studies have been performed to elucidate the

association between Fc gamma receptor 3B (FCGR3B) copy number (CN) and the risk of systemic lupus erythematosus (SLE) and/or lupus nephritis (LN), yet the results remain conflicting. Therefore,

we have undertaken a systematic review of all the studies published and carried out a meta-analysis to obtain a better understanding of the role of FCGR3B CN in the susceptibility of SLE and LN. A computerized literature search was conducted in databases of PubMed, ISI Web of Knowledge for all studies investigating the association between FCGR3B CN and SLE and/or LN, published up to May 2013. A total of six articles meeting all of the criteria were included in this study. There were five comparisons of SLE between 2490 patients and 4286 controls, and four comparisons of LN between 689 patients and 1924 controls. Our results showed that VX-770 purchase individuals with FCGR3B CN gain did not suffer an increased risk of SLE or LN as compared to the normal genotype in the total analysis (SLE: OR = 1.07, 95% CI = 0.79–1.45, P = 0.65; LN: OR = 0.83, 95% CI = 0.47–1.46, P = 0.52). However, individuals with FCGR3B CN loss exhibited an increased risk of SLE or LN (SLE: OR = 1.77, 95% CI = 1.51–2.06, P < 0.00001; LN:

OR = 2.02, 95% CI = 1.59–2.57, P < 0.00001). Our meta-analysis indicated that FCGR3B CN loss rather than Nintedanib (BIBF 1120) CN gain was associated with susceptibility to SLE and LN. “
“Juvenile idiopathic arthritis (JIA) is the commonest chronic rheumatic disease of childhood[1] and is an important cause of short- and long-term disability in children. It is not a single disease entity, but rather a group of ‘genetically heterogeneous’ and ‘phenotypically distinct’ disorders.[1, 2] The diagnosis of various subtypes of JIA is essentially clinical and laboratory parameters are only supportive. The International League of Associations for Rheumatology (ILAR) classifies JIA into seven subtypes: oligoarthritis, rheumatoid factor (RF)-positive polyarthritis, RF-negative polyarthritis, systemic onset JIA (SoJIA), enthesitis-related arthritis (ERA), psoriatric arthritis and undifferentiated arthritis. However, the ILAR classification carries several limitations. It is not user-friendly from the clinician’s point of view and one needs to exclude several other diseases before categorizing a given patient into one of the subtypes.

The overall mean length of hospital stay was 6.8 days. Small vessel vasculitis and Sjögren syndrome had the longest and the shortest hospital stays respectively (14.5 vs. 5.3 days). Hospital charges were highest among systemic vasculitis and DM-PM patients. The admission rate for SCNTD in Thailand was 141 per 100 000 admissions among which SLE was the most common. Overall hospital mortality was 4.1%. Although a lower prevalence was found among systemic vasculitis, it had a higher mortality rate, longer length of stay and greater LY2835219 order therapeutic cost. “
“Some studies have been performed to elucidate the

association between Fc gamma receptor 3B (FCGR3B) copy number (CN) and the risk of systemic lupus erythematosus (SLE) and/or lupus nephritis (LN), yet the results remain conflicting. Therefore,

we have undertaken a systematic review of all the studies published and carried out a meta-analysis to obtain a better understanding of the role of FCGR3B CN in the susceptibility of SLE and LN. A computerized literature search was conducted in databases of PubMed, ISI Web of Knowledge for all studies investigating the association between FCGR3B CN and SLE and/or LN, published up to May 2013. A total of six articles meeting all of the criteria were included in this study. There were five comparisons of SLE between 2490 patients and 4286 controls, and four comparisons of LN between 689 patients and 1924 controls. Our results showed that Selleck Rapamycin individuals with FCGR3B CN gain did not suffer an increased risk of SLE or LN as compared to the normal genotype in the total analysis (SLE: OR = 1.07, 95% CI = 0.79–1.45, P = 0.65; LN: OR = 0.83, 95% CI = 0.47–1.46, P = 0.52). However, individuals with FCGR3B CN loss exhibited an increased risk of SLE or LN (SLE: OR = 1.77, 95% CI = 1.51–2.06, P < 0.00001; LN:

OR = 2.02, 95% CI = 1.59–2.57, P < 0.00001). Our meta-analysis indicated that FCGR3B CN loss rather than Glutathione peroxidase CN gain was associated with susceptibility to SLE and LN. “
“Juvenile idiopathic arthritis (JIA) is the commonest chronic rheumatic disease of childhood[1] and is an important cause of short- and long-term disability in children. It is not a single disease entity, but rather a group of ‘genetically heterogeneous’ and ‘phenotypically distinct’ disorders.[1, 2] The diagnosis of various subtypes of JIA is essentially clinical and laboratory parameters are only supportive. The International League of Associations for Rheumatology (ILAR) classifies JIA into seven subtypes: oligoarthritis, rheumatoid factor (RF)-positive polyarthritis, RF-negative polyarthritis, systemic onset JIA (SoJIA), enthesitis-related arthritis (ERA), psoriatric arthritis and undifferentiated arthritis. However, the ILAR classification carries several limitations. It is not user-friendly from the clinician’s point of view and one needs to exclude several other diseases before categorizing a given patient into one of the subtypes.