A Neurocritical Case Study of Intracerebral Hemorrhage Unveiling Multiple Myeloma Through the Lens of Hickam's Dictum.

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells in the bone marrow, often leading to various end-organ damages. Here, we report the case of a 73-year-old previously healthy woman who was initially diagnosed with an intracerebral hemorrhage secondary to a potential hypertensive emergency. However, further evaluation revealed a diagnosis of MM. This case points out the importance of comprehensive evaluations in neurocritical care and challenges the notion of simplistic diagnostic explanations, illustrating the relevance of Hickam's dictum in clinical practice. It highlights the need for clinicians to consider a broad range of potential etiologies in similar cases, ultimately leading to tailored management strategies and improved patient outcomes.

Cheminformatics and artificial intelligence for accelerating agrochemical discovery.

The global cost-benefit analysis of pesticide use during the last 30 years has been characterized by a significant increase during the period from 1990 to 2007 followed by a decline. This observation can be attributed to several factors including, but not limited to, pest resistance, lack of novelty with respect to modes of action or classes of chemistry, and regulatory action. Due to current and projected increases of the global population, it is evident that the demand for food, and consequently, the usage of pesticides to improve yields will increase. Addressing these challenges and needs while promoting new crop protection agents through an increasingly stringent regulatory landscape requires the development and integration of infrastructures for innovative, cost- and time-effective discovery and development of novel and sustainable molecules. Significant advances in artificial intelligence (AI) and cheminformatics over the last two decades have improved the decision-making power of research scientists in the discovery of bioactive molecules. AI- and cheminformatics-driven molecule discovery offers the opportunity of moving experiments from the greenhouse to a virtual environment where thousands to billions of molecules can be investigated at a rapid pace, providing unbiased hypothesis for lead generation, optimization, and effective suggestions for compound synthesis and testing. To date, this is illustrated to a far lesser extent in the publicly available agrochemical research literature compared to drug discovery. In this review, we provide an overview of the crop protection discovery pipeline and how traditional, cheminformatics, and AI technologies can help to address the needs and challenges of agrochemical discovery towards rapidly developing novel and more sustainable products.

Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.

Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 µg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.

Practical outcomes of applying ensemble machine learning classifiers to High-Throughput Screening (HTS) data analysis and screening.

Over the years numerous papers have presented the effectiveness of various machine learning methods in analyzing drug discovery biological screening data. The predictive performance of models developed using these methods has traditionally been evaluated by assessing performance of the developed models against a portion of the data randomly selected for holdout. It has been our experience that such assessments, while widely practiced, result in an optimistic assessment. This paper describes the development of a series of ensemble-based decision tree models, shares our experience at various stages in the model development process, and presents the impact of such models when they are applied to vendor offerings and the forecasted compounds are acquired and screened in the relevant assays. We have seen that well developed models can significantly increase the hit-rates observed in HTS campaigns.

Comparative study of machine-learning and chemometric tools for analysis of in-vivo high-throughput screening data.

High-throughput screening (HTS) has become a central tool of many pharmaceutical and crop-protection discovery operations. If HTS screening is carried out at the level of the intact organism, as is commonly done in crop protection, this strategy has the potential of uncovering a completely new mechanism of actions. The challenge in running a cost-effective HTS operation is to identify ways in which to improve the overall success rate in discovering new biologically active compounds. To this end, we describe our efforts directed at making full use of the data stream arising from HTS. This paper describes a comparative study in which several machine learning and chemometric methodologies were used to develop classifiers on the same data sets derived from in vivo HTS campaigns and their predictive performances compared in terms of false negative and false positive error profiles.

On the increasing fragility of human teeth with age: a deep-UV resonance Raman study.

UNLABELLED: UV resonance Raman spectroscopy (UVRRS) using 244-nm excitation was used to study the impact of aging on human dentin. The intensity of a spectroscopic feature from the peptide bonds in the collagen increases with tissue age, similar to a finding reported previously for human cortical bone. INTRODUCTION: The structural changes that lead to compromised mechanical properties with age in dentin and bone are under intense study. However, in situ analyses of the content and distribution of the mineral phase are more highly developed at present than equivalent probes of the organic phase. MATERIALS AND METHODS: Thirty-five human molars were divided into three groups: young/normal (23.3 +/- 3.8 years); aged/transparent (74.3 +/- 6.0 years), which had become transparent because of filling of the tubule lumens with mineral deposits; and aged/nontransparent (73.3 +/- 5.7 years). Control experiments were performed by demineralizing normal dentin. RESULTS: Spectral features caused by both the amide backbone and resonance-enhanced side-chain vibrations were observed. This finding contrasts with reported Raman spectra of proteins in solution excited with similar UV wavelengths, where side chain vibrations, but not strong amide features, are observed. The strong intensity of the amide features observed from dentin is attributed to broadening of the resonance profile for the amide pi --> pi* transition caused by the environment of the collagen molecules in dentin. With increasing age, the height of one specific amide vibration (amide I) becomes significantly higher when comparing teeth from donors with an average age of 23 years to those of 73 years (p < 0.001). This trend of increasing amide I peak height with age is similar to that previously reported for human cortical bone. The amide I feature also increased in dentin that had been demineralized and dehydrated. CONCLUSIONS: The similar trend of increasing amide I peak height with age in the UVRR spectra of both teeth and bone is surprising, given that only bone undergoes remodeling. However, by considering those observations together with this study of demineralized/dehydrated dentin and our prior work on dentin dehydrated with polar solvents, a consistent relationship between changes in the UVRR spectra and the collagen environment in the tissue can be developed.

Sequential treatment of ovariectomized mice with bFGF and risedronate restored trabecular bone microarchitecture and mineralization.

Basic fibroblast growth factor (bFGF), a potent mitogen, has been found to restore trabecular bone mass and connectivity in osteopenic rats. The purpose of this study was to determine how sequential treatment of ovariectomized (OVXed) mice with bFGF followed by risedronate would restore trabecular microarchitecture and improve bone strength through alterations in bone mineralization. Six-month old female Swiss-Webster mice were OVXed or sham-operated and left untreated for 4 weeks to develop osteopenia. At week 5, a group of Sham and OVXed mice were treated with vehicle, and 3 other groups of OVXed mice were treated with bFGF (1 mg/kg daily, s.c., 5x/week) for 3 weeks. At week 8, one group of bFGF-treated mice was sacrificed and the other two bFGF-treated groups were treated with vehicle or risedronate (Ris, 5 microg/kg, s.c., 3x/week) for an additional 6 weeks. Study endpoints included trabecular microarchitecture by microCT, histomorphometry, bone turnover, degree of bone mineralization (DBM), and whole bone strength for the lumbar vertebral body. Compared to sham-operated animals, OVXed mice had significant reductions in trabecular bone volume, connectivity density, DBM, and bone biomechanical properties (P < 0.05). Treatment with bFGF resulted in higher trabecular bone structure and bone strength compared to pre-treatment sham control (P < 0.05). Treatment of OVXed mice with bFGF for 3 weeks followed by 6 weeks Ris maintained the trabecular microarchitecture gained by bFGF treatment, and DBM and bone strength were restored to baseline control levels. Also compared to Sham-operated animals, serum TGF-beta1 was transiently increased after OVX, increased an additional 100% after bFGF withdrawal, and decreased by 30% with risedronate. In addition, DBM was the strongest predictor for bone biomechanical properties (R2 > 0.7, P < 0.001). Serum TGF-beta1 correlated with bone turnover (DPD/Cr, osteocalcin) and was negatively correlated to DBM. Thus, in osteopenic mice, sequential treatment with bFGF followed by risedronate increased trabecular bone microarchitecture, DBM, and bone strength. In addition, suppression of the serum TGF-beta1 with risedronate was associated with increased DBM. Therefore, sequential treatment with bFGF and Ris restores trabecular architecture and allows mineralization of bone to increase, which appears to be beneficial to bone strength.

Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice.

UNLABELLED: This study compares changes in bone microstructure in 6-month-old male GC-treated and female ovariectomized mice to their respective controls. In addition to a reduction in trabecular bone volume, GC treatment reduced bone mineral and elastic modulus of bone adjacent to osteocytes that was not observed in control mice nor estrogen-deficient mice. These microstructural changes in combination with the macrostructural changes could amplify the bone fragility in this metabolic bone disease. INTRODUCTION: Patients with glucocorticoid (GC)-induced secondary osteoporosis tend to fracture at higher bone mineral densities than patients with postmenopausal osteoporosis. This suggests that GCs may alter bone material properties in addition to BMD and bone macrostructure. MATERIALS AND METHODS: Changes in trabecular bone structure, elastic modulus, and mineral to matrix ratio of the fifth lumbar vertebrae was assessed in prednisolone-treated mice and placebo-treated controls for comparison with estrogen-deficient mice and sham-operated controls. Compression testing of the third lumbar vertebrae was performed to assess whole bone strength. RESULTS: Significant reductions in trabecular bone volume and whole bone strength occurred in both prednisolone-treated and estrogen-deficient mice compared with controls after 21 days (p < 0.05). The average elastic modulus over the entire surface of each trabecula was similar in all the experimental groups. However, localized changes within the trabeculae in areas surrounding the osteocyte lacunae were observed only in the prednisolone-treated mice. The size of the osteocyte lacunae was increased, reduced elastic modulus around the lacunae was observed, and a "halo" of hypomineralized bone surrounding the lacunae was observed. This was associated with reduced (nearly 40%) mineral to matrix ratio determined by Raman microspectroscopy. These localized changes in elastic modulus and bone mineral to matrix ratio were not observed in the other three experimental groups. CONCLUSIONS: Based on these results, it seems that GCs may have direct effects on osteocytes, resulting in a modification of their microenvironment. These changes, including an enlargement of their lacunar space and the generation of a surrounding sphere of hypomineralized bone, seem to produce highly localized changes in bone material properties that may influence fracture risk.

Elastic anisotropy of bone and dentitional tissues.

The calculation of the scalar compressive and shear anisotropy factors developed for single crystal refractory compounds has been adapted to the anisotropic elastic stiffness coefficients determined by a number of ultrasonic measurements of bone based on transverse isotropic symmetry. Later, this work was extended to include the ultrasonic measurements of bone based on orthotropic symmetry. Recently, the five transverse isotropic elastic constants for both wet and dry human dentin were determined using resonant ultrasound spectroscopy. The five transverse isotropic elastic constants for wet bovine enamel and dentin had been calculated based on modeling of ultrasonic wave propagation measurements and related data in the literature. The scalar compressive and shear anisotropy factors have been calculated from both these sets of data and are compared with a representative set from those published previously for both human and bovine bone and both fluoro- and hydroxyl-apatites.

A transmission electron microscopy study of mineralization in age-induced transparent dentin.

It is known that fractures are more likely to occur in altered teeth, particularly following restoration or endodontic repair; consequently, it is important to understand the structure of altered forms of dentin, the most abundant tissue in the human tooth, in order to better define the increased propensity for such fractures. Transparent (or sclerotic) dentin, wherein the dentinal tubules become occluded with mineral as a natural progressive consequence of aging, is one such altered form. In the present study, high-resolution transmission electron microscopy is used to investigate the effect of aging on the mineral phase of dentin. Such studies revealed that the intertubular mineral crystallites were smaller in transparent dentin, and that the intratubular mineral (larger crystals deposited within the tubules) was chemically similar to the surrounding intertubular mineral. Exit-wave reconstructed lattice-plane images suggested that the intratubular mineral had nanometer-size grains. These observations support a "dissolution and reprecipitation" mechanism for the formation of transparent dentin.

Raising sun protection and early detection awareness among Florida high schoolers.

Changing adolescents' sun protection behaviors remains a challenge, and the need for effective interventions targeting this group is a priority, particularly in warmer climates where emphasis on appropriate sun protection remains a year-round concern. However, there has been little prospective research on the effect of school-based sun protection interventions, particularly on adolescents, especially teens aged 15 to 18. High school science students in Palm Beach County, Florida, received a seven-lesson sun protection and early detection curriculum preceded by pretests and followed with post-tests 6 months later. The main outcome measures were student knowledge and sun protection practices, including adherence to sunscreen recommendations. Of 344 students completing the baseline surveys, 184 students completed the postintervention questionnaire. Overall, there were significant improvements from baseline to follow-up for many of the knowledge questions. Greatest change scores were seen in the children's ability to correctly define the five rules of early detection of skin cancer (27-60%, p<0.001) with improved change scores by gender and race persisting after 6 months. No significant differences were found in reported use of sunscreen, hat wearing, or sunglasses, although there was a slight decrease in the reported use of always wearing sun protective clothing (p=0.03). In conclusion, in this study, a skin cancer prevention and detection curriculum integrated into high school biology, resulted in knowledge gains maintained at least 6 months after classroom teaching. For example, procedural knowledge (e.g., knowing ways to identify early malignant moles) obtained in this study improved in 6 months, and may lay the foundation for future behavioral change. Sun protection activities in the United States have met with many challenges and obstacles and thus, further work is needed to better understand what combination of knowledge-based information, activity-based education, school-wide changes, and community efforts, will create a long-term systemic improvement in sun protection habits in children.

An orientation distribution function for trabecular bone.

We describe a new method for quantifying the orientation of trabecular bone from three-dimensional images. Trabecular lattices from five human vertebrae were decomposed into individual trabecular elements, and the orientation, mass, and thickness of each element were recorded. Continuous functions that described the total mass (M(phi,theta)) and mean thickness (tau(phi,theta)) of all trabeculae as a function of orientation were derived. The results were compared with experimental measurements of the elastic modulus in three principal anatomic directions. A power law scaling relationship between the anisotropies in mass and elastic modulus was observed; the scaling exponent was 1.41 (R2=0.88). As expected, the preponderance of trabecular mass was oriented along the cranial-caudal direction; on average, there was 3.4 times more mass oriented vertically than horizontally. Moreover, the vertical trabeculae were 30% thicker, on average, than the horizontal trabeculae. The vertical trabecular thickness was inversely related to connectivity (R2=0.70; P=0.07), suggesting a possible organization into either few, thick trabeculae or many thin trabeculae. The method, which accounts for the mechanical connectedness of the lattice, provides a rapid way to both visualize and quantify the three-dimensional organization of trabecular bone.

Challenges to rebuilding the US food pyramid.

PURPOSE OF REVIEW: Twelve years have passed since the US Department of Agriculture introduced the Food Guide Pyramid as a single visual expression of the major food groups and their relative amounts in a healthy diet. Unfortunately, no regular review has been conducted to incorporate new knowledge. Some feel that the pyramid format is too limited for modern use, while others wish it to continue with new information. It seems timely to review what features of the pyramid design have been useful over past years and how it can be improved with new concepts while maintaining ease of understanding by the average consumer. RECENT FINDINGS: Examples are presented of adapting the pyramid to diets promoted by a special group or to support particular dietary beliefs, in contrast to the goal of seeking a single standardized format. Inherent limitations of the pyramid format are discussed. One proposal is discussed which seeks to redesign the pyramid into a modern educational tool presenting current concepts supported by recent studies and outcomes data. Popular beliefs about what is a healthy diet have perhaps never been as varied as now. This is partly due to sharply differing opinions about which highly publicized weight-loss diet is most effective. SUMMARY: The educational benefits of the pyramid format need objective study in view of the inherent limitations of that configuration. Only when the specific visual advantages for the consumer are shown can a decision be made as to the benefit of major new efforts to construct a single modern pyramid.

Repair of rabbit segmental defects with the thrombin peptide, TP508.

The synthetic peptide, TP508 (Chrysalin), was delivered to rabbit segmental bone defects in biodegradable controlled-release PLGA microspheres to determine its potential efficacy for enhancing healing of non-critically and critically sized segmental defects. Non-critically sized radial defects were created in the forelimbs of New Zealand White rabbits, which were randomized into three treatment groups receiving 10, 50 and 100 microg doses of TP508 in the right radius and control microspheres (without TP508) in the left radius. Torsional testing of the radii at six weeks showed a significant increase in ultimate torque, failure torque, ultimate energy, failure energy, and stiffness when treated with TP508 compared to controls (p<0.01 for all measures). Thus, TP508 appeared to enhance or accelerate bone growth in these defects. In a second set of experiments, critically sized ulnar defects were created in the forelimbs of New Zealand White rabbits, which were randomized into two groups with each rabbit receiving microspheres with 100 or 200 microg of TP508 into the right ulnar defect and control microspheres (without TP508) alone into the left ulnar defect. Bone healing was evaluated with plain radiographs, synchrotron-based microtomography, and mechanical testing. Radiographs of the rabbit limbs scored by three blinded, independent reviewers demonstrated a significantly higher degree of healing when treated with TP508 than their untreated control limbs (p<0.05). Three-dimensional synchrotron tomography of a limited number of samples showed that the new bone in TP508-treated samples had a less porous surface appearance and open marrow spaces, suggesting progression of bone remodeling. Torsional testing of the ulnae at nine weeks showed a significant increase in maximum torque and failure energy when treated with TP508 compared to controls (p<0.01 for both measures). These results suggest that TP508 in a controlled release delivery vehicle has the potential to enhance healing of segmental defects in both critically and non-critically sized defects.

Nutritional frailty, sarcopenia and falls in the elderly.

PURPOSE OF REVIEW: There is currently intense interest in understanding why certain elderly individuals become frail and disabled with age whereas others do not. Is frailty the result of an acceleration of normal aging processes or is it the result of chronic medical conditions that are superimposed on the conventional mechanisms of aging? The clinical problem of falls has long been recognized as a threat to some elderly individuals, but too often is not considered worthy of objective study. The factors underlying falls are now being investigated as part of the increasing attention being paid to the evolution of frailty in the elderly. RECENT FINDINGS: Frailty in the elderly has been given many names, but increasing efforts are now being made to define frailty in a standardized way that would allow more objective study. The frail elderly patient usually shows loss of both neurological and muscle function. Falls in the elderly are an example in which deterioration may be present in both functions. Methods are being developed to separate the loss of muscle capacity from the associated loss of central and peripheral neurological function involved in gait and balance. SUMMARY: The definition of frailty has been centered around the onset of accelerated weight loss with an associated decrease of mass and strength of skeletal muscle. New studies are discussed that extend this definition. Methods for a more detailed analysis of the physiological and metabolic deficits leading to falls in the elderly may provide a better understanding of frailty in general.

Both hPTH(1-34) and bFGF increase trabecular bone mass in osteopenic rats but they have different effects on trabecular bone architecture.

UNLABELLED: Osteoporosis is a syndrome of excessive skeletal fragility that results from both the loss of trabecular bone mass and trabecular bone connectivity. Recently, bFGF has been found to increase trabecular bone mass in osteoporotic rats. The purpose of this study was to compare how trabecular bone architecture, bone cell activity, and strength are altered by two different bone anabolic agents, bFGF and hPTH(1-34), in an osteopenic rat model. MATERIALS AND METHODS: Six-month-old female Sprague-Dawley rats (n = 74) were ovariectomized (OVX) or sham-operated (sham) and maintained untreated for 2 months. Then OVX rats were subcutaneously injected with basic fibroblast factor (bFGF; 1 mg/kg, 5 days/week), human parathyroid hormone [hPTH(1-34); 40 microg/kg, 5 days/week], or vehicle for 60 days (days 60-120). Sham-operated and one group of OVX animals were injected with vehicle. Biochemical markers of bone turnover (urinary deoxypyridinoline cross-links; Quidel Corp., San Diego, CA, USA) and serum osteocalcin (Biomedical Technologies, Stroughton, MA, USA) were obtained at study days 0, 60, 90, and 120 and analyzed by ELISA. At death, the right proximal tibial metaphysis was removed, and microcomputed tomography was performed for trabecular bone structure and processed for histomorphometry to assess bone cell activity. The left proximal tibia was used for nanoindentation/mechanical testing of individual trabeculae. The data were analyzed with Kruskal Wallis and post hoc testing as needed. RESULTS: Ovariectomy at day 60 resulted in about a 50% loss of trabecular bone volume compared with sham-treated animals. By day 120 post-OVX, OVX + vehicle treated animals had decreased trabecular bone volume, connectivity, number, and high bone turnover compared with sham-operated animals [p < 0.05 from sham-, hPTH(1-34)-, and bFGF-treated groups]. Treatment of OVX animals with bFGF and hPTH(1-34) both increased trabecular bone mass, but hPTH(1-34) increased trabecular thickness and bFGF increased trabecular number and connectivity. Histomorphometry revealed increased mineralizing surface and bone formation rate in both bFGF and hPTH(1-34) animals. However, osteoid volume was greater in bFGF-treated animals compared with both the hPTH(1-34) and OVX + vehicle animals (p < 0.05). Nanoindentation by atomic force microscope was performed on approximately 20 individual trabeculae per animal (three animals per group) and demonstrated that elastic modulus and hardness of the trabeculae in bFGF-treated animals were similar to that of the hPTH-treated and sham + vehicle-treated animals. CONCLUSION: Both hPTH(1-34) and bFGF are anabolic agents in the osteopenic female rat. However, hPTH(1-34) increases trabecular bone volume primarily by thickening existing trabeculae, whereas bFGF adds trabecular bone mass through increasing trabecular number and trabecular connectivity. These results suggest the possibility of sequential treatment paradigms for severe osteoporosis.