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Classifying bloodstains is an essential part of Bloodstain Pattern Analysis. Various experts have developed methods. Each method considers the same basic bloodstain pattern types. These use either terminology based on the observable characteristics or the mechanistic cause of the bloodstain patterns as part of the classification process. This review paper considers ten classification methods from fourteen sources, which are used to classify bloodstain patterns. There are fundamental differences in how the patterns are classified, how differentiated the classification is, and whether the classification process uses clear, unambiguous criteria, and is susceptible to contextual bias. Experts have also reported issues with classifying bloodstains that have indistinguishable features. These differences expose key limitations with current classification methods: mechanistic terminology is too heavily relied on, and the classification process is susceptible to contextual bias. The development of an unambiguous classification method, based on directly observable characteristics within bloodstain patterns is recommended for future work., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In a bloodletting incident, the area of origin (AO) of an impact bloodstain pattern is crucial when establishing the sequence of events. The use of laser scanners and other three-dimensional (3D) technologies to document and analyse bloodstains have been the subject of previous papers, especially where AO analysis is concerned. FARO Zone 3D (FZ3D) is a relatively new software programme that can be used for bloodstain AO analysis. FZ3D requires a greater understanding of inter-observer errors associated with AO. This study looked at the inter-observer variation between 21 examiners when repeatedly calculating the AO six times for a single impact pattern on a plain white wall. An impact rig which consisted of a spring tension arm was positioned and fixed 45 cm from the X wall (right wall), and 45 cm from the Y wall (left wall). This experimental design resembles an impact blow for a bloodletting event. The AO was unknown to all examiners, making it a blind study. The collected results were documented in a Microsoft Excel datasheet and later analysed. From previous literature, a 30 cm acceptable allowance was utilised for AO analysis; however, there is currently no accepted standard error for this type of analysis. The overall total 3D mean error for all examiners was 5.62 cm. The maximum error for any one impact analysis was 24.27 cm. The variation of the data, which was collected by all examiners, was documented as X = 1.14 cm, Y = 1.24 cm, Z = 1.68 cm, and the total 3D error = 2.28 cm. The total 3D error for any one examiner and the variance between examiners did not exceed the 30 cm acceptable allowance utilised in previous literature., (Copyright © 2021 The Chartered Society of Forensic Sciences. Published by Elsevier B.V. All rights reserved.)

To augment DNA profiling and body fluid identification techniques efforts are being made to increase the amount of information available from a crime scene stain, which includes efforts to identify externally visible characteristics through phenotypic analysis. A key question surrounding crime scene stains is the length of time between deposition of the stain and its subsequent recovery, in that is the stain recovered related to the incident in question or from a previously deposited stain number of weeks earlier? The inability to answer this fundamental question has a detrimental effect upon the successful completion of a criminal investigation. Once a body fluid leaves the body, the oxygen concentration in the environment changes; therefore, it may be that this change could cause a change in the expression of hypoxia-sensitive biomarkers. Here, a range of bloodstains, liquid saliva and liquid semen samples were collected at 0 days, 7 days, 14 days, 21 days and 28 days of degrading at room temperature (19-22 °C), before undergoing total RNA extraction and cDNA synthesis. Blood was recovered from filter paper with 3 mm 2 , with saliva and semen being left in their tubes and swabbed at the appropriate times. All samples then underwent quantitative PCR targeting Vascular Endothelial Growth Factor A (VEGFA) and Hypoxia-Inducible Factor 1 Alpha (HIF1A), with B-Actin (ACTB) as a reference gene. A range of linear and quadratic correlation values was obtained from the qPCR data and used to develop a predictive model with a mean absolute deviation (MAD) of 4.2, 2.1, and 5 days for blood, saliva, and semen respectively. Blind testing indicated that a stain age prediction model based upon VEGFA with ACTB as a reference gene could be used on samples up to four weeks old with a margin of error ranging from 2 days through to 5 days. While a sizeable potential time frame exists using this model; this represents a significant step towards the target of having an accurate stain age prediction model., (Copyright © 2020 The Chartered Society of Forensic Sciences. Published by Elsevier B.V. All rights reserved.)

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM., (© 2017 by The American Society of Hematology.)

Meditative techniques aim for and meditators report states of mental alertness and focus, concurrent with physical and emotional calm. We aimed to determine the electroencephalographic (EEG) correlates of five states of Buddhist concentrative meditation, particularly addressing a correlation with meditative level. We studied 12 meditators and 12 pair-matched meditation-naïve participants using high-resolution scalp-recorded EEG. To maximise reduction of EMG, data were pre-processed using independent component analysis and surface Laplacian transformed data. Two non-meditative and five meditative states were used: resting baseline, mind-wandering, absorptions 1, 2, 3, 4 and 5 (corresponding to four levels of absorption and an absorption with a different object of focus, otherwise equivalent to level 4; these five meditative states produce repeatable, distinctly different experiences for experienced meditators). The experimental protocol required participants to experience the states in the order listed above, followed immediately by the reverse. We then calculated EEG power in standard frequency bands from 1 to 80Hz. We observed decreases of central scalp beta (13-25Hz), and central low gamma (25-48Hz) power in meditators during deeper absorptions. In contrast, we identified increases in frontal midline and temporo-parietal theta power in meditators, again, during deeper absorptions. Alpha activity was increased over all meditative states, not depth-related. This study demonstrates that the subjective experiences of deepening meditation partially correspond to measures of EEG. Our results are in accord with prior studies on non-graded meditative states. These results are also consistent with increased theta correlating with tightness of focus, and reduced beta/gamma with the desynchronization associated with enhanced alertness., (Copyright © 2016. Published by Elsevier B.V.)

Although short tandem repeat profiling is extremely powerful in identifying individuals from crime scene stains, it is unable to differentiate between monozygotic (MZ) twins. Efforts to address this include mutation analysis through whole genome sequencing and through DNA methylation studies. Methylation of DNA is affected by environmental factors; thus, as MZ twins age, their DNA methylation patterns change. This can be characterized by bisulfite treatment followed by pyrosequencing. However, this can be time-consuming and expensive; thus, it is unlikely to be widely used by investigators. If the sequences are different, then in theory the melting temperature should be different. Thus, the aim of this study was to assess whether high-resolution melt curve analysis can be used to differentiate between MZ twins. Five sets of MZ twins provided buccal swabs that underwent extraction, quantification, bisulfite treatment, polymerase chain reaction amplification and high-resolution melting curve analysis targeting two markers, Alu-E2F3 and Alu-SP. Significant differences were observed between all MZ twins targeting Alu-E2F3 and in four of five MZ twins targeting Alu-SP (P<0.05). Thus, it has been demonstrated that bisulfite treatment followed by high-resolution melting curve analysis could be used to differentiate between MZ twins., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Forensic RNA analysis is gathering pace with reports of messenger RNA analysis being used in case work, and with microRNA being increasingly researched. Such techniques address a fundamental issue in body fluid identification, namely increased specificity over existing chemical tests, and the incorporation of additional body fluids such as vaginal material. The use of RNA analysis will be of particular value to sex offences, where there can be a mixture of multiple body fluids from different people. The aim of this study was to determine whether microRNA based body fluid identification tests can be applied to mixed body fluid samples. Blood and saliva were acquired from volunteers and underwent total RNA extraction. Mixed samples were prepared using a range of ratios from 1:1 to 10:1. Each mixed sample then underwent a blood-saliva differentiation test developed in-house, which includes stem-loop reverse transcription and real-time PCR analysis. Aliquots following mixture preparation also underwent standard STR analysis, utilising Quantiplex and Next Generation Multiplex kits. Data relating to the development of an in-house blood-saliva differentiation test is presented, in which it has been demonstrated that such a test has a lower limit of detection than the enzymatic equivalent. It has been shown that not only is it possible to determine the presence of more than one body fluid, it is also possible to determine the major body fluid contributor as well as the minor contributor., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The use of mRNA for the identification of body fluids is of particular interest in forensic science, and increasing support has been demonstrated for the use of microRNA (miRNA) analysis. MiRNA is more stable than mRNA and has been shown to be differentially expressed in body fluids. No studies involving miRNA analysis from previously extracted DNA samples have yet been reported. The aim of this experiment was to determine if it was possible to conduct miRNA analysis on samples that were previously extracted using standard DNA extraction. Blood and saliva samples were extracted using DNA and RNA kits, followed by cDNA synthesis, and then underwent quantitative PCR analysis. A direct comparison of ΔCt values shows a larger abundance of miRNA following DNA extraction as opposed to total RNA extraction for both blood- and saliva-specific markers. By carrying out a comparison between the amounts of said markers, it could be seen that the expression of the blood-specific marker was higher in blood than in saliva, and vice versa for the saliva-specific marker. The results obtained could have a profound impact on cases for which the sample has already undergone DNA extraction, such as in cold cases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Osteogenesis imperfecta (OI or brittle bone disease) is a disorder of connective tissues caused by mutations in the collagen genes. We previously showed that intrauterine transplantation of human blood fetal stem/stromal cells in OI mice (oim) resulted in a significant reduction of bone fracture. This work examines the cellular mechanisms and mechanical bone modifications underlying these therapeutic effects, particularly examining the direct effects of donor collagen expression on bone material properties. In this study, we found an 84% reduction in femoral fractures in transplanted oim mice. Fetal blood stem/stromal cells engrafted in bones, differentiated into mature osteoblasts, expressed osteocalcin, and produced COL1a2 protein, which is absent in oim mice. The presence of normal collagen decreased hydroxyproline content in bones, altered the apatite crystal structure, increased the bone matrix stiffness, and reduced bone brittleness. In conclusion, expression of normal collagen from mature osteoblast of donor origin significantly decreased bone brittleness by improving the mechanical integrity of the bone at the molecular, tissue, and whole bone levels.

Background: Nicotine improves cognition in humans and animal models of neuropsychiatric disorders. Here, we sought to establish whether selective stimulation of the neuronal nicotinic α7 receptor could improve spatial working memory in nonhuman primates., Methods: Beginning with an estimated dose range from rodent studies, the dose of the α7 agonist AZD0328 was titrated for a significant impact on working memory in rhesus macaques after acute administration. After training to stability on the spatial delayed response task, subjects were administered AZD0328 (1.6 ng/kg-.48 mg/kg; intramuscular) or vehicle 30 min before cognitive testing. AZD0328 (1 ng/kg-1.0 μg/kg; intramuscular) was then administered in a repeated, intermittent ascending dose regimen where each dose was given in two bouts for 4 days with a 1-week washout in between bouts, followed by 2-week washout., Results: Acute AZD0328 improved cognitive performance when the dose was titrated down to .0016 and .00048 mg/kg from a cognitively impairing dose of .48 mg/kg. In a subgroup, sustained enhancement of working memory was evident for 1 month or more after acute treatment. Immediate and sustained cognitive enhancement was also found during and after repeated administration of AZD0328 at .001 mg/kg., Conclusions: These findings demonstrate that extremely low doses of a nicotinic α7 agonist can have profound acute and long-lasting beneficial consequences for cognition, dependent upon the integrity of dorsolateral prefrontal cortex. Thus, the α7 receptor might have a fundamental role in the neural circuitry of working memory and in the synaptic plasticity upon which it might depend., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The hypothalamic-pituitary-thyroid axis plays a key role in skeletal development, acquisition of peak bone mass and regulation of adult bone turnover. Euthyroid status is essential for maintenance of optimal bone mineralization and strength. In population studies, hypothyroidism and hyperthyroidism have both been associated with an increased risk of fracture. Furthermore, recent studies in healthy euthyroid post-menopausal women indicate that thyroid status in the upper normal range is also associated with low bone mineral density and an increased risk of non-vertebral fracture. Studies in mutant mice have demonstrated that thyroid hormone receptor α is the major mediator of T3 action in bone and that thyroid hormones exert anabolic actions during growth but have catabolic effects on the adult skeleton. Nevertheless, TSH has also been proposed to be a direct negative regulator of bone turnover, although the relative importance of T3 and TSH actions in the skeleton has yet to be clarified., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Neuroplasticity is a key factor in restoration of brain function following neuropathology associated with disease or drug exposure. Here we examined the potential for chronic treatment with the selective D1 receptor antagonist SCH39166 to reverse the profound and enduring cognitive impairment associated with amphetamine (AMPH) sensitization in the nonhuman primate and to stimulate re-growth of atrophied pyramidal dendrites in the dorsolateral prefrontal cortex of these animals. Four rhesus monkeys with sustained cognitive impairment (>1year following AMPH sensitization) were treated for up to 8months with SCH39166. Cognitive testing was performed before, during, and for up to 1(1/2) year following treatment. Significant improvement in working memory performance was observed only after cessation of the D1 antagonist treatment but then was sustained for the duration of the post-treatment testing period. Postmortem quantitative assessment of Golgi-impregnated pyramidal neurons in BA9 showed that apical dendritic length and trunk spine density were increased in D1 antagonist treated monkeys relative to AMPH-sensitized and AMPH-naïve monkeys. These findings, which suggest that the deleterious consequences of AMPH sensitization can be reversed by modulation of D1 receptor signaling, have implications for treating the underlying neural basis of cognitive deficits in both schizophrenia and substance abuse., (Copyright 2010. Published by Elsevier Inc.)

Background: Ketamine has been used to model cognitive and behavioral symptoms of schizophrenia. Current hypotheses state that inadequate glutamatergic transmission in schizophrenia leads to a deficiency in gamma-aminobutyric acid (GABA)ergic inhibitory mechanisms and treatment with a GABA type A receptor subunits alpha2/alpha3 (GABA(Aalpha2/3)) modulator improved working memory performance in a preliminary study in patients. Here, we used ketamine to impair spatial working memory and disrupt behavior to examine the capacity for the GABA(Aalpha2/3) agonist 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) to reverse these symptoms., Methods: Rhesus monkeys received TPA023 (.7, 2.0, and 5 mg/kg; by mouth) or vehicle 45 minutes before ketamine (1.0-1.7 mg/kg; intramuscular) or saline in a semirandomized Latin square design. Behavioral observations were acquired at approximately 5 minutes, and spatial delayed response performance was tested at 15 minutes postinjection., Results: Ketamine produced a profound impairment in spatial working memory in association with the emergence of hallucinatory-like behaviors. TPA023 at all doses blocked ketamine's cognitive-impairing ability but did not influence the behavioral symptoms., Conclusions: Acute GABA(Aalpha2/3) agonist administration reverses the working memory deficits induced by ketamine in primates. This finding indicates that the consequences of N-methyl-D-aspartate deficiency on the function of prefrontal circuits involved in working memory can be completely overcome by acute enhancement of GABA signaling., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The inherited skeletal dysplasia osteogenesis imperfecta (OI) results in multiple fractures and is currently treated empirically. We transplanted human first-trimester fetal blood mesenchymal stem cells (MSCs) into homozygous oim mice in utero. This resulted in a two-thirds reduction in long bone fractures (P < .01), with fewer fractures per mouse (median 1, range 0-2 in mice that received transplants vs median 3, range 1-5 in mice that did not receive transplants by 12 weeks, P < .01). Nearly all mice that did not receive transplants had fractures (47 [97.9%] of 48), in contrast to 17 (58.6%) of 29 4- to 12-week-old mice that received transplants (P < .01). Transplantation was associated with increased bone strength (P < .01), thickness (P < .01), and length (P < .01), and normalization/reduction of growth plate height in 4- to 12-week-old oim was reduced in mice that underwent transplantion (P < .001). More donor cells were found in bone tissues compared with other organs (P < .001), with cells clustered in areas of active bone formation and remodeling, and at sites of fracture healing. Donor cells found in the bone expressed osteoblast lineage genes, and produced the extracellular bone structural protein osteopontin. Finally, MSC transplantation decreased bone hydroxyproline content. In conclusion, intrauterine transplantation of fetal MSCs markedly reduced fracture rates and skeletal abnormalities in a mouse model of the intermediate severity type III OI, suggesting a scientific basis for MSC treatment of affected human fetuses.