Fat Fraction Measurements Using a Three-Material Decomposition Dual-Energy CT Technique Accounting for Bone Minerals: Evaluation in a Bone Marrow Phantom Using MRI as Reference.

Conventional two-material dual-energy CT (DECT) decomposition is insufficient to model bone marrow, which contains three materials: bone minerals, red marrow (water), and yellow marrow (fat). We explore an image-domain three-material decomposition DECT technique accounting for bone minerals in a bone-water-fat phantom. Three-material decomposition fat fraction (FF3MD) exhibited stronger correlation than two-material decomposition fat fraction (FF2MD) with MRI-based fat fraction (r = 0.95 vs r = 0.69). With increasing bone minerals, correlation of FF3MD remained stable (r = 0.81-1.02), whereas correlation of FF2MD decreased (r = 0.21-0.65).

Anatomy of Hematopoiesis and Local Microenvironments in the Bone Marrow. Where to?

The shape and spatial organization -the anatomy- of a tissue profoundly influences its function. Knowledge of the anatomical relationships between parent and daughter cells is necessary to understand differentiation and how the crosstalk between the different cells in the tissue leads to physiological maintenance and pathological perturbations. Blood cell production takes place in the bone marrow through the progressive differentiation of stem cells and progenitors. These are maintained and regulated by a heterogeneous microenvironment composed of stromal and hematopoietic cells. While hematopoiesis has been studied in extraordinary detail through functional and multiomics approaches, much less is known about the spatial organization of blood production and how local cues from the microenvironment influence this anatomy. Here, we discuss some of the studies that revealed a complex anatomy of hematopoiesis where discrete local microenvironments spatially organize and regulate specific subsets of hematopoietic stem cells and/or progenitors. We focus on the open questions in the field and discuss how new tools and technological advances are poised to transform our understanding of the anatomy of hematopoiesis.

New light shed on the early evolution of limb-bone growth plate and bone marrow.

The production of blood cells (haematopoiesis) occurs in the limb bones of most tetrapods but is absent in the fin bones of ray-finned fish. When did long bones start producing blood cells? Recent hypotheses suggested that haematopoiesis migrated into long bones prior to the water-to-land transition and protected newly-produced blood cells from harsher environmental conditions. However, little fossil evidence to support these hypotheses has been provided so far. Observations of the humeral microarchitecture of stem-tetrapods, batrachians, and amniotes were performed using classical sectioning and three-dimensional synchrotron virtual histology. They show that Permian tetrapods seem to be among the first to exhibit a centralised marrow organisation, which allows haematopoiesis as in extant amniotes. Not only does our study demonstrate that long-bone haematopoiesis was probably not an exaptation to the water-to-land transition but it sheds light on the early evolution of limb-bone development and the sequence of bone-marrow functional acquisitions.

For many aquatic creatures, the red blood cells that rush through their bodies are created in organs such as the liver or the kidney. In most land vertebrates however, blood-cell production occurs in the bone marrow. There, the process is shielded from the ultraviolet light or starker temperature changes experienced out of the water. It is possible that this difference evolved long before the first animal with a backbone crawled out of the aquatic environment and faced new, harsher conditions: yet very little fossil evidence exists to support this idea. A definitive answer demands a close examination of fossils from the water-to-land transition including lobe-finned fish and early limbed vertebrates. To support the production of red blood cells, their fin and limb bones would have needed an internal cavity that can house a specific niche that opens onto a complex network of blood vessels. To investigate this question, Estefa et al. harnessed the powerful x-ray beam produced by the European Synchrotron Radiation Facility and imaged the fin and limb bones from fossil lobe-finned fish and early limbed vertebrates. The resulting three-dimensional structures revealed spongy long bones with closed internal cavities where the bone marrow cells were probably entrapped. These could not have housed the blood vessels needed to create an environment that produces red blood cells. In fact, the earliest four-legged land animals Estefa et al. found with an open marrow cavity lived 60 million years after vertebrates had first emerged from the aquatic environment, suggesting that blood cells only began to be created in bone marrow after the water-to-land transition. Future work could help to pinpoint exactly when the change in blood cell production occurred, helping researchers to identify the environmental and biological factors that drove this change.

Structural organization of the bone marrow and its role in hematopoiesis.

PURPOSE OF REVIEW: The bone marrow is the main site for hematopoiesis. It contains a unique microenvironment that provides niches that support self-renewal and differentiation of hematopoietic stem cells (HSC), multipotent progenitors (MPP), and lineage committed progenitors to produce the large number of blood cells required to sustain life. The bone marrow is notoriously difficult to image; because of this the anatomy of blood cell production -- and how local signals spatially organize hematopoiesis -- are not well defined. Here we review our current understanding of the spatial organization of the mouse bone marrow with a special focus in recent advances that are transforming our understanding of this tissue. RECENT FINDINGS: Imaging studies of HSC and their interaction with candidate niches have relied on ex-vivo imaging of fixed tissue. Two recent manuscripts demonstrating live imaging of subsets of HSC in unperturbed bone marrow have revealed unexpected HSC behavior and open the door to examine HSC regulation, in situ, over time. We also discuss recent findings showing that the bone marrow contains distinct microenvironments, spatially organized, that regulate unique aspects of hematopoiesis. SUMMARY: Defining the spatial architecture of hematopoiesis in the bone marrow is indispensable to understand how this tissue ensures stepwise, balanced, differentiation to meet organism demand; for deciphering alterations to hematopoiesis during disease; and for designing organ systems for blood cell production ex vivo.

Pearls and Pitfalls in Imaging Bone Marrow in Pediatric Patients.

Magnetic resonance is a noninvasive, nonionizing modality used in the detection and evaluation of marrow lesions, as well as surgical planning and treatment follow-up. Since the distribution of red and yellow marrow occurs in a predictable sequence according to age, understanding this sequence is essential in establishing an accurate and timely diagnosis. This article provides an overview of the normal appearance of bone marrow in healthy children as well as focal and diffuse marrow abnormalities. Imaging pitfalls unique to children and solutions to use in difficult cases will be described.

Age- and BMI-related variations of fat distribution in sacral and lumbar bone marrow and their association with local muscle fat content.

This analysis investigated the age- and BMI-related variations of fat distribution in sacral and lumbar bone marrow and their association with local muscle fat content in order to detect fat distribution patterns and variations in healthy adults using proton density fat fraction (PDFF) measurements. A six-echo 3D spoiled gradient-echo sequence was used for chemical shift encoding-based water-fat separation at the sacral and lower lumbar region in 103 healthy volunteers. PDFF values of the sacrum, 5th lumbar vertebral body, the gluteal and paraspinal muscles were determined. Correlation with age was significant (p < 0.05) for PDFF of the sacrum (men (m): r = 0.58; women (w): r = 0.54), L5 (m: r = 0.58; w: r = 0.54), the gluteal (m: r = 0.51; w: r = 0.44) and paraspinal (m: r = 0.36; w: r = 0.49) muscles in both genders. BMI correlated significantly with the paraspinal musculature in men (r = 0.46) and women (r = 0.33). Correlation testing revealed significant correlations (p < 0.05) between the two osseous (m: r = 0.63, w: r = 0.75) and the muscle compartments (m: r = 0.63, w: r = 0.33) in both genders. Bone marrow and muscle fat infiltration patterns were not significantly associated with each other at the sacral and lower lumbar spine region. The presented data suggest that the two compartments may have distinct pathophysiological fat infiltration patterns. However, further clinical studies are needed to support the results.

Biological and structural effects after intraosseous infiltrations of age-dependent platelet-rich plasma: An in vivo study.

Platelet-rich plasma (PRP) is an increasingly widespread treatment for joint pathologies. Its characteristics and administration route are variables that may influence the clinical outcome. The aim of this in vivo study was to analyze in aged rats the biological and structure effects of intraosseous infiltrations of two different types of PRP obtained from young and old donors. During 6 months intraosseous infiltrations were performed and 4 days after the last infiltration, animals were sacrificed, and bones were extracted for micro-computed tomography (micro-CT) and histological analysis. Molecular composition of the PRP of aged donors presented higher levels of proinflammatory molecules. The histological studies showed a greater cellularity of bone marrow in groups treated with PRP. Concerning micro-CT analysis, young PRP showed a better femoral bone structure according to values of percentage of trabecular bone, trabecular space, trabecular density, and subchondral bone plate volume. In summary, this study has demonstrated that intraosseous infiltrations of PRP from young donors prevent from age-related bone degeneration. This treatment could stimulate the biological processes that maintain homeostasis and bone structure and avoid osteoarticular pathologies.

Morphologic and quantitative evaluation of bone marrow aspirates from Hispaniolan Amazon parrots (Amazona ventralis).

BACKGROUND: Bone marrow aspirate assessments provide valuable information about hematopoietic status and hematologic disease. Hematopoietic cell differentials and morphologies have been anecdotally described in psittacines, but quantitative studies are lacking. OBJECTIVES: We aimed to determine differential cell counts and calculate granulocyte:erythroid (G:E) ratios in bone marrow aspirates from Hispaniolan Amazon parrots and report representative morphologies of the hematopoietic cells. METHODS: Bone marrow aspirates were collected from 32 clinically healthy, captive, parrots. Peripheral blood was obtained for CBCs. Bone marrow differential cell counts (%) were determined by counting 500 cells on modified Wright's-stained smears. G:E ratios were calculated. Representative images of hematopoietic cells at all stages of development were taken. RESULTS: Of the 32 parrots sampled, 17 bone marrow samples were of sufficient cellularity and quality for evaluation. Erythroid cells comprised 68.9 ± 8.6% (total ± SD) of the hematopoietic cells and consisted primarily of early- and late-stage polychromatophilic rubricytes (43.6 ± 2.1% of total erythroid cells). Granulocytic cells comprised 28.1 ± 3.8% of the hematopoietic cells and consisted primarily of mature and band heterophils (11.9 ± 5.2% and 6.5 ± 3.4%, respectively, of total granulocytic cells). A unique morphologic finding in avian progranulocytes was the presence of multiple different granules. The G:E ratio was 0.4 ± 0.2 (median 0.4, range 0.1-0.9). Thrombocyte lineage cells could not be reliably identified and were not counted. CBC results were largely within expected limits. CONCLUSIONS: The low G:E ratios observed could be normal in this species; however, these ratios could be affected by factors related to sampling and cell identification. These findings will be a valuable resource for the diagnostic evaluation of clinical bone marrow samples from Hispaniolan Amazon parrots and could serve as a general reference for psittacine bone marrow evaluation.

Bone Marrow Adipose Tissue Quantification by Imaging.

PURPOSE OF REVIEW: The significance and roles of marrow adipose tissue (MAT) are increasingly known, and it is no more considered a passive fat storage but a tissue with significant paracrine and endocrine activities that can cause lipotoxicity and inflammation. RECENT FINDINGS: Changes in the MAT volume and fatty acid composition appear to drive bone and hematopoietic marrow deterioration, and studying it may open new horizons to predict bone fragility and anemia development. MAT has the potential to negatively impact bone volume and strength through several mechanisms that are partially described by inflammaging and lipotoxicity terminology. Evidence indicates paramount importance of MAT in age-associated decline of bone and red marrow structure and function. Currently, MAT measurement is being tested and validated by several techniques. However, purpose-specific adaptation of existing imaging technologies and, more importantly, development of new modalities to quantitatively measure MAT are yet to be done.

Nonproliferative and Proliferative Lesions of the Rat and Mouse Hematolymphoid System.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.

A GIS based approach to long bone breakage patterns derived from marrow extraction.

In archaeological assemblages the presence of percussion marks, on the surface of long bones, is an indicator of long bone marrow extraction. The form, quantity and distribution of percussion marks are analysed to gain a better understanding of the marrow extraction process. Patterns of bone percussion damage in archaeological assemblages may highlight standardized actions, possibly related to butchery traditions. However, additional factors could underlie these patterns and should also be considered. In this article we test intuitiveness as a factor in appearance of percussion mark patterns, to see if patterns can appear when bones are being fractured without prior experience with bone fracture properties. To test this hypothesis, for this study we selected a sample of 40 cattle (Bos taurus) long limb bones from a large bone breakage experiment (400 long limb bones), where participants had no previous experience in bone breakage and may thus have broken bones intuitively. We used Geographic Information System (GIS) software to analyse the distribution of percussion marks. Using ArcGIS Spatial Analysts tools, we identified and quantified significant concentrations of percussion marks. Results show that percussion mark patterns emerge for the same bone element, and that specific sides and zones were recurrently selected by experimenters. The distribution of patterns varies among the different long bone elements, and we attribute this variance to an adjustment to bone morphology. In addition, we calculated and identified bone damage patterns resulting from hammerstone percussion. Crossing bone survivorship with percussion mark patterns enabled us to recognise and evaluate the effects of fragmentation and surface visibility in controlled experimental conditions. The GIS method facilitates comparisons between different variables and provides a sophisticated visual representation of results. Enlarging the sample will allow to constitute a more substantial analogous model for fossil assemblages.

Proton density fat fraction MRI of vertebral bone marrow: Accuracy, repeatability, and reproducibility among readers, field strengths, and imaging platforms.

BACKGROUND: Chemical shift-encoding based water-fat MRI is an emerging method to noninvasively assess proton density fat fraction (PDFF), a promising quantitative imaging biomarker for estimating tissue fat concentration. However, in vivo validation of PDFF is still lacking for bone marrow applications. PURPOSE: To determine the accuracy and precision of MRI-determined vertebral bone marrow PDFF among different readers and across different field strengths and imager manufacturers. STUDY TYPE: Repeatability/reproducibility. SUBJECTS: Twenty-four adult volunteers underwent lumbar spine MRI with one 1.5T and two different 3.0T MR scanners from two vendors on the same day. FIELD STRENGTH/SEQUENCE: 1.5T and 3.0T/3D spoiled-gradient echo multipoint Dixon sequences. ASSESSMENT: Two independent readers measured intravertebral PDFF for the three most central slices of the L1-5 vertebral bodies. Single-voxel MR spectroscopy (MRS)-determined PDFF served as the reference standard for PDFF estimation. STATISTICAL TESTS: Accuracy and bias were assessed by Pearson correlation, linear regression analysis, and Bland-Altman plots. Repeatability and reproducibility were evaluated by Wilcoxon signed rank test, Friedman test, and coefficients of variation. Intraclass correlation coefficients were used to validate intra- and interreader as well as intraimager agreements. RESULTS: MRI-based PDFF estimates of lumbar bone marrow were highly correlated (r2 = 0.899) and accurate (mean bias, -0.6%) against the MRS-determined PDFF reference standard. PDFF showed high linearity (r2 = 0.972-0.978) and small mean bias (0.6-1.5%) with 95% limits of agreement within ±3.4% across field strengths, imaging platforms, and readers. Repeatability and reproducibility of PDFF were high, with the mean overall coefficient of variation being 0.86% and 2.77%, respectively. The overall intraclass correlation coefficient was 0.986 as a measure for an excellent interreader agreement. DATA CONCLUSION: MRI-based quantification of vertebral bone marrow PDFF is highly accurate, repeatable, and reproducible among readers, field strengths, and MRI platforms, indicating its robustness as a quantitative imaging biomarker for multicentric studies. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1762-1772.

Leukocyte Trafficking and Regulation of Murine Hematopoietic Stem Cells and Their Niches.

Hematopoietic stem cells (HSC) are the most powerful type of adult stem cell found in the body. Hematopoietic stem cells are multipotent and capable of giving rise to all other types of hematopoietic cells found in the organism. A single HSC is capable of regenerating a functional hematopoietic system when transplanted into a recipient. Hematopoietic stem cells reside in the bone marrow in specific multicellular structures called niches. These niches are indispensable for maintaining and regulating HSC numbers and function. It has become increasingly clearer that HSC and their niches can also be regulated by migrating leukocytes. Here we will discuss the composition of murine bone marrow niches and how HSC and their niches are regulated by different types of leukocytes that traffic between the periphery and the niche. Unless otherwise indicated all the studies discussed below were performed in mouse models.

Glucocorticoids and Body Fat Inversely Associate With Bone Marrow Density of the Distal Radius in Healthy Youths.

CONTEXT: Elevated bone marrow adipose tissue (BMAT) is associated with lower bone quality, higher fracture rates, and an unfavorable overall metabolic profile. Apart from age, particularly glucocorticoids (GC), body fat, and diet are discussed to influence BMAT. We hypothesized that already in healthy youths, higher fat intake, higher fat mass index (FMI), and higher GC secretion, still within the normal range, may associate with increased BMAT. DESIGN: In a subsample of healthy 6- to 18-year-old participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study, peripheral quantitative CT of the nondominant proximal forearm was used to determine bone marrow density of the distal radius as an inverse surrogate parameter for BMAT. In those participants (n = 172) who had collected two, 24-hour urines within around one year before bone measurement, major urinary GC metabolites were measured by gas chromatography-mass spectrometry and summed up to assess daily adrenal GC secretion (ΣC21). Dietary intake was assessed by 3-day weighed dietary records. FMI was anthropometrically calculated. Separate multiple linear regression models were used to analyze the relationships of ΣC21, FMI, and fat intake with BMAT. RESULTS: After controlling for confounders, such as age, energy intake, and forearm muscle area, ΣC21 (ß = -0.042) and FMI (ß = -0.002) showed inverse relationships with bone marrow density (P < 0.05), whereas fat intake did not associate significantly. CONCLUSION: Our results indicate that already a moderately elevated GC secretion and higher body fatness during adolescence may adversely impact BMAT, an indicator for long-term bone health.

The Site of Bone Marrow Acquisition Affects the Myeloid to Erythroid Ratio in Apparently Healthy Dogs.

Bone marrow (BM) cytology and histopathology are complementary tools used to investigate hematological diseases. The purpose of this study was to determine if there are site-dependent differences in the diagnostic quality, myeloid to erythroid ratio (MER), and discordant findings in samples from different sites in the same dog. Eighteen apparently healthy dogs were used in the study. The sequence of sample acquisition was randomized according to a Latin square, and samples for BM cytology and histology were collected from both humeri and both ilial crests immediately after death. Board-certified clinical and anatomical pathologists read the cytology and histology, respectively. The data were analyzed using a mixed-effect model. The site of BM acquisition did not affect BM sample quality. The rate of discordant clinical findings between sites was 0.05 (95% confidence interval, 0.01-0.13). In general, by cytology, the MERs were slightly but significantly greater in samples from the ilial crests than from the humeri ( P = .01). The measured MER for histology was nearly twice that for cytology for all sites ( P < .001). In conclusion, there was a low-rate, site-dependent discordance in diagnostic findings in BM samples and differences in MER between the ilial crest and the humerus. A similar study is justified in sick dogs with hematological disease to determine the effect of sampling site on discordant findings between sites.

The thermal conductivity of cortical and cancellous bone.

Surgical interventions close to vulnerable structures, such as nerves, require precise handling of surgical instruments and tools. These tools not only pose the risk of mechanical damage to soft tissues, but they also generate heat, which can lead to thermal necrosis of bone or soft tissues. Researchers and engineers are trying to improve those tools through experimentation and simulations. To simulate temperature distributions in anatomical structures, reliable material constants are needed. Therefore, this study aimed at investigating the thermal conductivity of cortical and cancellous bone. Accordingly, a custom-made steady-state experimental setup was designed and validated. 6 bovine and 3 human cortical bone samples, as well as 32 bovine cancellous bone samples, with variable bone volume fraction were tested. The cancellous bone samples were scanned by micro-computed tomography (µCT) and micro-finite element (µFE) voxel models were created to calculate iteratively the thermal conductivity of the bone marrow. The experimental results provided 0.64 ± 0.04 W/mK for bovine cortical bone and 0.68 ± 0.01 W/mK for human cortical bone. A linear dependency of thermal conductivity on bone volume fraction was found for cancellous bone [R-square (R2) = 0.8096, standard error of the estimates (SEE) = 0.0355 W/mK]. The thermal conductivity of the bone marrow was estimated to be 0.42 ± 0.05 W/mK. These results will help to improve thermal finite element simulations of the human skeleton and aid the development of new surgical tools or procedures.

Contrast-enhanced MRI findings of the knee in healthy children; establishing normal values.

OBJECTIVES: To define normative standards for the knee in healthy children using contrast-enhanced MRI, focusing on normal synovial membrane thickness. Secondly, presence of joint fluid and bone marrow oedema was evaluated. METHODS: For this study, children without disorders potentially resulting in (accompanying) arthritis were included. Patients underwent clinical assessments, followed by contrast-enhanced MRI. MRI features were evaluated in consensus using the Juvenile Arthritis MRI Scoring (JAMRIS) system. Additionally, the presence of joint fluid was evaluated. No cartilage lesions or bone abnormalities were observed. RESULTS: We included 57 healthy children. The overall mean thickness of the normal synovial membrane was 0.4 mm (min-max; 0.0-1.8mm). The synovium was thickest around the cruciate ligaments and retropatellar and suprapatellar regions. The mean overall diameter of the largest pocket of joint fluid was 2.8 mm (min-max; 0.9-8.0mm). Bone marrow changes were observed in three children (all in the apex patellae). CONCLUSIONS: The normal synovial membrane was maximally 1.8 mm thick, indicating that the JAMRIS cut-off value of 2 mm can be considered a valid measure for evaluating synovial hypertrophy. Some joint fluid and bone marrow changes suggestive of bone marrow oedema in the apex patellae can be seen in healthy children. KEY POINTS: • Knowledge on the normal synovial appearance using contrast-enhanced MR is lacking. • In healthy children, normal synovial membrane is maximally 1.8 mm thick. • Normal synovium is thickest around the cruciate ligaments, retropatellar and suprapatellar. • Bone marrow oedema in the apex patellae is seen in healthy children.

Initial experience with synthetic MRI of the knee at 3T: comparison with conventional T1 weighted imaging and T2 mapping.

OBJECTIVE: To assess the feasibility and accuracy of synthetic MRI compared to conventional T1 weighted and multi-echo spin-echo (MESE) sequences for obtaining T2 values in the knee joint at 3 Tesla. METHODS: This retrospective study included 19 patients with normal findings in the knee joint who underwent both synthetic MRI and MESE pulse sequences for T2 quantification. T2 values of the two sequences at the articular cartilage, bone marrow and muscle were measured. Relative signal intensity (SI) of each structure and relative contrast among structures of the knee were measured quantitatively by T1 weighted sequences. RESULTS: The mean T2 values for cartilage and muscle were not significantly different between MESE pulse sequences and synthetic MRI. For the bone marrow, the mean T2 value obtained by MESE sequences (124.3 ± 3.6 ms) was significantly higher than that obtained by synthetic acquisition (73.1 ± 5.3 ms). There were no significant differences in the relative SI of each structure between the methods. The relative contrast of bone marrow to muscle was significantly higher with conventional T1 weighted images, while that for bone marrow to cartilage was similar for both sequences. CONCLUSION: Synthetic MRI is able to simultaneously acquire conventional images and quantitative maps, and has the potential to reduce the overall examination time. It provides comparable image quality to conventional MRI for the knee joint, with the exception of the bone marrow. With further optimization, it will be possible to take advantage of the image quality of musculoskeletal tissue with synthetic imaging. Advances in knowledge: Synthetic MRI produces images of good contrast and is also a time-saving technique. Thus, it may be useful for assessing osteoarthritis in the knee joint in the early stages.

Phytochemical Modulation of Apoptosis and Autophagy: Strategies to Overcome Chemoresistance in Leukemic Stem Cells in the Bone Marrow Microenvironment.

Advances in scientific research and targeted treatment regimes have improved survival rates for many cancers over the past few decades. However, for some types of leukemia, including acute lymphoblastic and acute myeloid leukemia, mortality rates have continued to rise, with chemoresistance in leukemic stem cells (LSCs) being a major contributing factor. Most cancer drug therapies act by inducing apoptosis in dividing cells but are ineffective in targeting quiescent LSCs. Niches in the bone marrow, known as leukemic niches, behave as "sanctuaries" where LSCs acquire drug resistance. This review explores the role of the bone marrow environment in the maintenance of LSCs and its contribution to chemoresistance and considers current research on the potential use of phytochemicals to overcome chemoresistance through the modulation of signaling pathways involved in the survival and death of leukemic clonal cells and/or leukemic stem cells. Phytochemicals from traditional Chinese medicine, namely baicalein, chrysin, wogonin (constituents of Scutellaria baicalensis; huáng qín; ), curcumin (a constituent of Curcuma longa, jiang huáng, ), and resveratrol (a constituent of Polygonum cuspidatum; hu zhàng, ) have been shown to induce apoptosis in leukemic cell lines, with curcumin and resveratrol also causing cell death via the induction of autophagy (a nonapoptotic pathway). In order to be effective in eliminating LSCs, it is important to target signaling pathways (such as Wnt/ß-catenin, Notch, and Hedgehog). Resveratrol has been reported to induce apoptosis in leukemic cells through the inhibition of the Notch and Sonic hedgehog signaling pathways, therefore showing potential to affect LSCs. While these findings are of interest, there is a lack of reported research on the modulatory effect of phytochemicals on the autophagic cell death pathway in leukemia, and on the signaling pathways involved in the maintenance of LSCs, highlighting the need for further work in these areas.

Case Report: Severe and Complicated Cynomolgi Malaria in a Rhesus Macaque Resulted in Similar Histopathological Changes as Those Seen in Human Malaria.

Histopathological data collected from patients with severe malaria have been instrumental for studying malaria pathogenesis. Animal models of malaria are critical to complement such studies. Here, the histopathological changes observed in a rhesus macaque with severe and complicated Plasmodium cynomolgi malaria are reported. The animal presented with thrombocytopenia, severe anemia, and hyperparasitemia during the acute infection. The macaque was given subcurative antimalarial treatment, fluid support, and a blood transfusion to treat the clinical complications, but at the time of transfusion, kidney function was compromised. These interventions did not restore kidney function, and the animal was euthanized due to irreversible renal failure. Gross pathological and histological examinations revealed that the lungs, kidneys, liver, spleen, and bone marrow exhibited abnormalities similar to those described in patients with malaria. Overall, this case report illustrates the similarities in the pathophysiological complications that can occur in human malaria and cynomolgi malaria in rhesus macaques.