“
“A middle-aged male patient with a right orbital comminuted fracture underwent computer tomography scanning, and a three-dimensional finite element model of the eyes and relevant tissues was established. Optic nerve stress in a

hyperbaric oxygen environment was simulated and analyzed by changing the elastic modulus and external pressure of the skull at the damage side. Results showed that stress maximized at the contact site of the optic nerve and the eyeball in the damaged and intact eye orbits. Optic nerve stress at the damaged orbit significantly increased; however, stress in the intact orbit only slightly changed with decreased elastic modulus of the skull while external pressure remained unchanged. Maximum optic nerve stress increased in the damaged and intact side, along with increased external pressure, while elastic modulus remained unchanged. These experimental findings suggested that the optic nerve was compressed under hyperbaric selleck inhibitor oxygen and optic nerve stress was greater in the damaged orbit than in the intact orbit.”
“Purpose: To study the effect of patient education and the TravAlert((R))-Eyot((R)) drop guider on intraocular pressure (IOP) and adherence

in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT) monitored with the TravAlert((R)) dosing aid. Methods: Multicentre, randomized, controlled clinical trial among 18 Dutch hospitals. Patients were randomized to one of the four study arms: (1) use of the dosing aid, (2) use of the dosing aid with the drop guider, (3) use of the dosing aid together with patient education GSK1210151A or (4) use of the dosing aid and drop guider together with patient education. IOP was recorded at baseline and after 3 and 6months. Data on adherence generated by the dosing aid were collected and studied at the end of the study. Results: Mean IOP dropped from 20.35.7mmHg

at baseline to 16.3 +/- 4.0mmHg (right eye) after 6months and from 20.2 +/- 5.9mmHg to 16.4 +/- 4.1mmHg (left eye). The mean adherence rate was 0.91 +/- 0.1. IOP and adherence rate were not statistically different between the study arms. Autophagy Compound Library Patients with drug holidays’ had a significantly higher mean IOP after 6months. Patients who used the drop guider were less adherent. A lower adherence level was also associated with new patients with glaucoma and patients with a lower level of knowledge on glaucoma. Conclusion: Patient education is especially useful for new patients with glaucoma. The use of a drop guider does not improve adherence. Especially patients with drug holidays’ are at risk for developing uncontrolled IOP levels.”
“The minimum inhibitory concentrations of 23 Bacteroides fragilis clinical isolates from Cape Town, South Africa, were established using the E-test method. Eight percent of the strains were found to be highly resistant to metronidazole (>= 256 mg/L) imipenem and cefoxitin.

Previously treated patients were instructed to discontinue their prior medications at the first visit. All the patients were dosed with travoprost 0.004% once-daily at 8 p.m. in both eyes for 12 weeks. Efficacy and safety evaluations were conducted at week 4 and 12. IOP measurements were performed at the same time of day at the follow-up visits.\n\nResults For patients transitioned to travoprost, mean IOP reductions from baseline in untreated and treated patients with different prior medications at week 12 were: latanoprost, (4.3+/-4.6) mmHg; beta-blocker, (6.3+/-4.0) mmHg; a-agonist, (7.5+/-4.3) mmHg; topical

carbonic anhydrase inhibitors, (8.0+/-4.9) mmHg. All mean IOP changes from baseline were statistically significant (P <0.001). No treatment-related

selleckchem serious www.selleckchem.com/products/AG-014699.html adverse events were reported in this study.\n\nConclusions In patients treated with other hypotensive medications or untreated, the IOP reduction with travoprost was significant. The results of this study demonstrated the potential benefit of using travoprost as a replacement therapy in order to ensure adequate IOP control. Travoprost administered once daily was safe and well tolerated in patients with glaucoma or ocular hypertension. Chin Med J 2010;123(11):1417-1421″
“Isolated endobronchial inflammatory myofibroblastic tumor is an unusual diagnosis among endobronchial masses in childhood. The presenting signs and symptoms may mimic asthma. Rigid bronchoscopy is effective for the diagnosis and

treatment. Follow-up is mandatory to check for recurrent disease. Here in, the authors report on a 9-year-old girl with endobronchial inflammatory myofibroblastic tumor to emphasize the possibility of endobronchial lesion in children with longstanding obstructive symptoms.”
“The Glycemic Index (GI) is a measure of the extent of the change in blood glucose content (glycemic response) following consumption of digestible carbohydrate, relative to a standard such as glucose. We have explored whether the reported GIs of foods are a sufficient Omipalisib guide to a person wishing to avoid large glycemic responses and thereby avoid hyperglycemia. For this purpose, volunteers carried out multiple tests of four foods, following overnight fasting, measuring the glycemic response over 2 H. The areas under the blood glucose/time curves (AUCs) were compared. Each food tester displayed individual, characteristic glycemic responses to each food, unrelated to any other tester’s response. Wide variations (up to 5-fold) were seen between the average AUCs for the same test by different testers.

The main indication from the analysis of these data is that NSAIDs could be given in patients receiving opioids, evaluating their benefit and weight on opioid therapy in individual patients who have a favorable response to justify a prolonged use. (c) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Percutaneous endoscopic gastrostomy (PEG) is widely performed. However, despite its widespread use, complications often follow and some of them are life-threatening. We report on two patients who developed pseudoaneurysm

after PEG and how the bleeding was stemmed by transcatheter arterial embolization. Case 1 is an 84-year-old man. PEG by the pull method using Mdm2 inhibitor One Step Button 24 Fr was performed. Blood-laced vomiting, followed by hemorrhagic shock was observed on day 21. Pseudoaneurysm less than 10 mm in diameter was observed in the gastroepiploic artery by urgent percutaneous abdominal angiography. A microcatheter was advanced selectively and the affected area was embolized by metallic coils and n-butyl cyanoacrylate. Case 2 is an 89-year-old man. PEG by the pull method using One Step Button 24 Fr was performed. On day 28, bleeding from the gastrostomy portion occurred and the patient went into shock. On urgent percutaneous

abdominal angiography, pseudoaneurysm approximate to 5 mm in diameter was detected in the left gastric artery. A microcatheter click here was advanced selectively and the affected area was embolized by metallic coils and n-butyl cyanoacrylate. In the present two cases, gastrostomies were created in the anterior wall of the mid body portion as suitable for PEG position, but the bleedings occurred because of pseudoaneurysm formation accompanied by damage QNZ to the gastroepiploic or the left gastric artery. Those who perform PEG on a regular basis should be aware of the possibility of pseudoaneurysm as a serious adverse event. (C) 2013 Wolters

Kluwer Health vertical bar Lippincott Williams & Wilkins.”
“The global climate is changing rapidly and Arctic regions are showing responses to recent warming. Responses of tundra ecosystems to climate change have been examined primarily through short-term experimental manipulations, with few studies of long-term ambient change. We investigated changes in above- and belowground biomass of wet sedge tundra to the warming climate of the Canadian High Arctic over the past 25 years. Aboveground standing crop was harvested from five sedge meadow sites and belowground biomass was sampled from one of the sites in the early 1980s and in 2005 using the same methods. Aboveground biomass was on average 158% greater in 2005 than in the early 1980s. The belowground biomass was also much greater in 2005: root biomass increased by 67% and rhizome biomass by 139% since the early 1980s. Dominant species from each functional group (graminoids, shrubs and forbs) showed significant increases in aboveground biomass.

We repeated the experiment once in adjacent plots located within the same stands as above. Coppices were harvested annually for three years and evaluated for damage, height, branching, mortality, and biomass. Three treatments: insects, rust fungus, and their combination caused higher levels of coppice damage and mortality compared to controls; these three treatments also reduced plant height, branching, and biomass of surviving coppices. These impacts of insects and rust-fungus-combination were additive on cut-stump and coppice stem mortality, and reduction in height, branching,

leaf biomass, and total biomass of coppices. The rust fungus and psyllid showed better ability to co-attack the I��B/IKK inhibitor same leaf tissues compared to the rust fungus and the weevil. In conclusion, Duvelisib molecular weight overall effects

of the three natural enemies led to markedly reduced performance of the invasive tree melaleuca. Published by Elsevier Inc.”
“Previous field and laboratory studies have concluded that suspension-feeding detriti vorous fish such as gizzard shad Dorosoma cepedianum selectively ingest nutrient-rich particles using either mechanical sorting within the oropharyngeal cavity or behavioral selectivity within the environment, but none have distinguished between these hypothesized selection mechanisms. To determine whether mechanical selectivity occurs within the oropharyngeal cavity, gizzard shad were fed particles of standardized size but different carbon and nitrogen content in homogeneous particle suspensions

vs. non-homogeneous particle distributions. By comparing foregut and epibranchial organ contents with the particles available in a homogeneous suspension, we demonstrated that the fish did not use mechanical selection for nutrient-rich particles. Previously published hypotheses for intraoral selection of nutrient-rich particles in gizzard shad using crossflow filtration or gustatory receptors were not supported. However, when particles with different nutrient content were allowed to settle GDC-0068 chemical structure in a heterogeneous distribution, the nutrients in the foregut and epibranchial organs were 1.5 times higher than those of particles in the water and 2.5 times higher than those of settled particles (p <= 0.0001). As a test of one potential behavioral mechanism of particle selection, disturbance of the sediment-water interface resulted in significantly higher organic carbon (p = 0.01) and nitrogen (p = 0.001) within 1 to 2 cm of the bottom compared to the overlying water and the bottom sediment. Thus, future laboratory and field studies should focus on potential behavioral mechanisms of particle selectivity in detritivorous fish suspension feeding on non-homogeneous distributions of small particles (<< 1 mm).

He was treated with pegylated interferon alpha and ribavirin, with the development of malabsorption symptoms during the therapy. Celiac disease was established by histological, histochemical and serological examinations. AC220 inhibitor oth, interferon alpha and ribavirin treatment as well as virus of hepatitis C may trigger coeliac disease in genetically predisposed individuals. The immunological mechanism of celiac disease include balance disruption between Th1 and Th2 immunological response with Th1 predominance. Only few similar cases have been published in the professional literature to date. Development

of celiac disease during interferon alpha therapy with haemophilia A was not published until now (Fig. 3, Ref. 13). Full Text in free PDF www.bmj.sk.”
“Introduction: Children with Down syndrome (DS) commonly have obstructive sleep apnea syndrome selleck screening library (OSAS) and may assume a unique sleeping position not systematically described previously. We describe this sleep position

in DS and explore its relationship with OSAS in comparison to control children (CC).\n\nMethods: Overnight video-polysomnograms (PSG) of consecutive children with DS (age 2-18 y), referred to our center between April 2008 and October 2009, were retrospectively analyzed by a single scorer (ES). CC group comprised age and gender matched, non-syndromic, neurologically intact children referred to us for suspected OSAS over the same period.\n\nResults: Each group had 17 subjects matched for age check details (median [IQR]; 6 [4-8]) and gender (65% female). DS group had higher BMI (median [IQR]; 18.8 [17.4-21.0]) than CC (17 [14.7-18.8]; p = 0.03). There were however no significant differences (median [IQR]) between DS and CC with respect to sleep time in minutes (460 [425-499] vs 424[410-483]), sleep efficiency (%) (90.9

[87.4-92.4] vs 88.6 [79.9-93.1]), REM time (%) (17.1 [14.2-22.1] vs 19.2 [14.9-22.1]), supine time (%) (40.7 [24.8-56.0] vs 15.8 [0.40-44.5], p 0.06), mean oxygen saturation (%) (95 [94-96] vs 96 [95-97]), oxygen saturation nadir (89 [86-91] vs 89[94-92]), or total apnea-hypopnea index (4.3 [3-7.8] vs 5.1[1.9-9.6]). Despite these similarities between the groups, 9 (53%) DS children slept seated bent forward with head resting on bed for at least part of the total sleep time (%) (7.8 +/- 10.9, range 0.8-35.7). This was absent in the CC group (p = 0.06).\n\nConclusion: Some DS children assume a peculiar body position, sitting cross-legged flopped-forward with head resting on bed while asleep. This is absent in age-and gender-matched controls showing otherwise similar PSG characteristics. The reason for this posture is unclear from this study. However, this novel report of a unique sleeping position would provide us with a basis to conduct a prospective study involving a larger population to ascertain the contribution of this position for OSAS protection or to determine if it may be forme fruste parasomnia.

Mucosal damage was determined under light microscopic evaluation. Immunohistochemistry was used to investigate epithelial expression of Ki-67 as a measure of cell proliferation rate and claudin-1, 2, 3, 4, 5, and 7 as elements of tight junctions. Results. In colonic biopsies, independent of the circuit type used, moderate mucosal damage was observed as indicated by focal epithelial damage, increased epithelial

cell proliferation and decreased expression of tight junction check details protein claudin-4. Conclusions. Colonic mucosal damage was observed similarly in MCPB and CCPB. Based on these results, the effects of MCPB on intestinal mucosal stability are similar to those of CCPB.”
“We present an integrative model predicting associations among epiphytism, the tank habit, entangling seeds, C-3 vs. CAM photosynthesis, avian pollinators, life in fertile, moist montane habitats, and net rates of species diversification in the monocot family Bromeliaceae. We test these predictions by relating evolutionary shifts in form, physiology, and ecology to time and ancestral distributions, quantifying patterns of correlated and contingent evolution among pairs of traits and www.selleckchem.com/erk.html analyzing the apparent impact of individual traits on rates of net species diversification and geographic expansion beyond the ancestral Guayana Shield. All predicted patterns of correlated evolution

were significant, and the temporal and spatial associations of phenotypic shifts with orogenies generally accorded with predictions. Net rates of species diversification were most closely coupled to life in fertile, moist, geographically extensive cordilleras, with additional significant ties to epiphytism, avian pollination, and the tank

habit. The highest rates of net diversification were seen in the bromelioid tank-epiphytic clade (D-crown = 1.05 My(-1)), associated primarily with the Serra do Mar and nearby ranges of coastal Brazil, and in the core tillandsioids (D-crown = 0.67 My(-1)), associated primarily with the Andes and Central America. Six large-scale adaptive radiations and accompanying pulses of speciation account for 86% of total species richness in the family. This study is among the first to test a priori hypotheses about the relationships among phylogeny, phenotypic evolution, geographic AG-881 spread, and net species diversification, and to argue for causality to flow from functional diversity to spatial expansion to species diversity. (C) 2013 Elsevier Inc. All rights reserved.”
“A highly efficient In(III) triflate-assisted method for the detritylation of O-trityl derivatives of carbohydrates, phenols, and alcohols using solvent-free mechanochemical method is described. In the case of carbohydrates, further reaction in the presence of an acceptor sugar leads to highly efficient glycosylation in the same pot resulting in the formation of the desired glycoside-product in very high yields.

4-terminal transfer and output measurements reveal that R-c decreases from 10(5)-10(6) Omega cm for 15 min air exposure to 3 x 10(3) Omega cm for at least 5 h air exposure of the gold electrodes before the flip-crystal FET is assembled. We conclude the reduction of R-c to be caused by a growing contamination layer on the gold electrodes that weakens the electrostatic coupling between rubrene crystal and gold learn more electrode, and lowers the Schottky contact diode parameter V-0. In channel-dominated (low R-c) FETs, the mobility is in the range of 10-17 cm(2)/(Vs);

in contrast, in contact-limited (high R-c) FETs, the apparent mobility decreases significantly with increasing contact resistance. The apparent mu – R-c dependence is not intrinsic, but rather the result of incorrect assumptions of the potential and the charge carrier density in the channel region. Thus, the development of high-mobility selleck kinase inhibitor organic semiconductors requires further efforts to improve contacts beyond traditional metal electrodes. (C) 2014 AIP Publishing LLC.”
“Choroideremia (CHM) is an X-linked retinal degeneration of photoreceptors, the retinal

pigment epithelium (RPE) and choroid caused by loss of function mutations in the CHM/REP1 gene that encodes Rab escort protein 1. As a slowly progressing monogenic retinal degeneration with a clearly identifiable phenotype and a reliable diagnosis, CHM is an ideal candidate for gene therapy. We developed a serotype 2 adeno-associated viral vector AAV2/2-CBA-REP1, which expresses REP1 under control of CMV-enhanced chicken beta-actin promoter (CBA) augmented by a Woodchuck hepatitis BIX 01294 virus post-transcriptional regulatory element. We show that the AAV2/2-CBA-REP1 vector provides strong and functional transgene expression in the D17 dog osteosarcoma cell line,

CHM patient fibroblasts and CHM mouse RPE cells in vitro and in vivo. The ability to transduce human photoreceptors highly effectively with this expression cassette was confirmed in AAV2/2-CBA-GFP transduced human retinal explants ex vivo. Electroretinogram (ERG) analysis of AAV2/2-CBA-REP1 and AAV2/2-CBA-GFP-injected wild-type mouse eyes did not show toxic effects resulting from REP1 overexpression. Subretinal injections of AAV2/2-CBA-REP1 into CHM mouse retinas led to a significant increase in a- and b-wave of ERG responses in comparison to sham-injected eyes confirming that AAV2/2-CBA-REP1 is a promising vector suitable for choroideremia gene therapy in human clinical trials.”
“We evaluated if repeated stress modulates mucociliary clearance and inflammatory responses in airways of guinea pigs (GP) with chronic inflammation. The GP received seven exposures of ovalbumin or saline 0.9%. After 4th inhalation, animals were submitted to repeated forced swim stressor protocol (5x/week/2 weeks). After 7th inhalation, GP were anesthetized.

These mostly very expensive books contain splendid and scientifically adequate anatomic descriptions and illustrations, but knowledge of physiology

and pathogenesis was virtually inexistent. Descriptions of pathological conditions are succinct and often inadequate. CA3 Due to the lack of a formal form of veterinary education, traditional handbooks, as we know them nowadays, did not exist before 1750.”
“The application of chondrocyte-based cartilage tissue engineering is limited because of the lack of autologous cartilage sources and chondrocyte dedifferentiation after in vitro expansion. Coculture of bone marrow mesenchymal stem cells (BMSCs) and chondrocytes has been a promising strategy for cartilage engineering as chondrocytes can provide a chondrogenic environment for BMSCs. However, there are no systematic Selleck NVP-LDE225 comparison studies for engineered cartilage constructed using different mixing ratios of BMSCs and chondrocytes, and the most effective mixing ratio with the lowest number of chondrocytes is unknown. Here, we seta gradient of mixing ratios of BMSCs to chondrocytes for an in vitro coculture

system and compared the shape retention and quality of the engineered cartilage using macroscopic and histological assays, glycosaminoglycan content assessment and immunohistochemical staining of type II collagen, biomechanical evaluation and hypertrophy-related gene expression analysis. The results showed that at least 30% chondrocytes were required to generate cartilage tissue with satisfactory shape and quality. Therefore, we preliminarily assessed the feasibility of engineering a human ear-shaped substitute using a coculture system with a 7:3 ratio of BMSCs to chondrocytes. After 8 weeks of in vitro culture, the precise architecture of the human ear-shaped construct was well maintained with the typical cartilaginous composition confirmed by histological assays. (C)

2014 S. Karger AG, Basel”
“The relative utility of conventional and novel risk factors in predicting cardiovascular disease (CVD) in relation VX-809 cell line to age remains unclear. We examined the discriminative ability of C-reactive protein (CRP) and Framingham risk score across young (35 to 50 years), middle (51 to 65 years), and older (>= 65 years) aged participants from the Scottish Health Surveys (n = 5,944, 44.5% men). CRIP data and conventional risk factors were collected at baseline. During an average follow-up of 7.1 years, 308 CVD events (a composite of fatal and nonfatal events incorporating acute myocardial infarction, coronary artery bypass surgery, percutaneous coronary angioplasty, stroke, and heart failure) occurred. The log CRP/SD predicted the risk of CVD events in middle-age (hazard ratio 2.20, 95% confidence interval 1.34 to 3.61) and older (hazard ratio 1.

We compared natural enemy to pest ratios between field with hedgerows and fields with weedy margins by sampling beneficial insects and key pests of vegetables on sticky cards. We used biweekly vacuum samples to measure the distribution of key insect taxa among native perennial plant species with respect to the timing and intensity of bloom. Sticky cards indicated a trend that field margins with hedgerows support a higher ratio of natural enemies to pests compared with weedy borders. Hedgerow learn more plant species hosted different relative densities of a generally overlapping insect community, and the timing and intensity of bloom only explained

a small proportion of the variation in insect abundance at plant species and among hedgerows, with the exception of Orius spp. on Achillea millefolium L. and Baccharis pilularis De Candolle. Indicator Species Analysis showed an affinity of parasitic Selleck TH-302 wasps, especially in the super-family Chalcidoidea, for B. pilularis whether or not it was in flower. A. millefolium was attractive to predatory and herbivorous homopterans; Heteromeles arbutifolia (Lindley) Roemer and B. pilularis to Diabrotica undecimpunctata undecimpunctata Mannerheim; and Rhamnus californica Eschsch to Hemerobiidae. Perennial hedgerows can be designed through species selection to support particular beneficial insect taxa, but plant resources beyond

floral availability may be critical in providing structural refuges, alternative prey, and other attractive qualities that are often overlooked.”
“The nuclear receptor ROR gamma plays a central role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including TH17 cells. ROR gamma-dependent inflammation

has been implicated in the pathogenesis of several major autoimmune diseases and thus ROR gamma is an attractive target for therapeutic intervention in these diseases. Starting from a lead biaryl compound 4a, replacement of the head phenyl moiety with a substituted aminopyrazole group resulted in a series with improved physical properties. Further SAR exploration led to analogues (e.g., 4j and 5m) as potent ROR gamma inverse agonists. (C) 2015 Elsevier Ltd. All rights buy SN-38 reserved.”
“Objectives\n\nThe aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains.\n\nMethods\n\nThe ethers were synthesized in a one-step process by coupling ethylene glycol moieties of various chain lengths to carbon C-10 of artemisinin. The aqueous solubility and log D values were determined in phosphate buffered saline (pH 7.4). The derivatives were screened for antimalarial activity alongside artemether and chloroquine against chloroquine-sensitive (D10) and moderately chloroquine-resistant (Dd2) strains of P.

In addition, the high-throughput capacity of the platform click here was tested using a dual-slide system that allowed rapid screening of the effects

of tretinoin and fibroblast growth factor-4 (FGF-4) on the pluripotency of mouse ES cells. This high-throughput platform is a powerful new tool for investigating cellular mechanisms involved in stem cell expansion and differentiation and provides the basis for rapid identification of signals and conditions that can be used to direct cellular responses. Biotechnol. Bioeng. 2010;106: 106-118. (C) 2010 Wiley Periodicals, Inc.”
“Background: Perinuclear anti-neutrophil cytoplasmic (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) have been studied extensively in Western countries. We determined the prevalence of pANCA and ASCA in the mainland Chinese population and the ability of pANCA

and ASCA to discriminate between ulcerative colitis (UC) and Crohn’s disease (CD).\n\nMethods: Two hundred-six unrelated patients with IBD (UC, n = 152: CD, n = 54), 60 patients with other gastrointestinal diseases, and 80 healthy controls were included. find more Sera pANCA and ASCA titers were determined by a standardized indirect immunofluorescence technique.\n\nResults: The sensitivity, specificity, positive and negative predictive values, and positive likelihood ratio of pANCA were calculated for differentiating UC from healthy controls (43.4%, 96.3%, 95.7%. 47.2%, and 11.7, respectively) and ASCA for differentiating CD from healthy controls and (46.3%, 96.3%, 89.3%, 72.6%. and 12.5, respectively). The combination of pANCA and ASCA did not result in greater diagnostic efficiency than either test alone. pANCA was more frequent see more in UC with extensive or severe phenotype than others. ASCA was associated with severe CD disease activity.\n\nConclusions:

pANCA and ASCA are useful in confirming the diagnosis of IBD and differentiating between UC and CD in an IBD cohort in central China. (C) 2010 Elsevier B.V. All rights reserved.”
“The immune system can be adversely affected by a variety of extrinsic factors, including immunosuppressive drugs, exposure to harsh environmental conditions, hereditary disorders other than primary immunodeficiencies, and acquired metabolic disorders such as diabetic mellitus, with all of these resulting in conditions known as secondary immunodeficiencies. Perhaps the most well known secondary immunodeficiency is caused by HIV infection; however, the most prevalent cause of immunodeficiency worldwide is severe malnutrition, which affects as much as 50% of the population in some impoverished communities. The abnormalities of the immune system induced by secondary immunodeficiencies affect both the innate and the adaptive immunity, may be subtle, and are usually heterogeneous in their clinical manifestations.