Identification of a murder caused by brodifacoum poisoning based on clinical examinations and LC-MS/MS results.

Brodifacoum exerts its antagonistic effect against the metabolism of vitamin K, an essential component in the synthesis of blood coagulation factors. This effect ultimately hinders the blood's capacity to clot effectively, rendering it a commonly employed rodenticide. Instances of lethal poisonings are exceedingly rare owing to expeditious medical intervention and treatment. Within this report, we present a case of brodifacoum-induced homicide, wherein the patient exhibited distinct clinical examinations and symptoms. Moreover, the patient's blood sample exhibited a noteworthy brodifacoum concentration of 0.681 µg/mL even after a period of 43 days following the incident of poisoning. Although an autopsy was not conducted due to religious restrictions, we endeavor to reasonably deduce the cause of death and furnish corroborative evidence for clinical diagnosis, treatment, and forensic examination in instances involving brodifacoum poisoning.

Effect of intermittent pneumatic compression with different inflation pressures on the distal microvascular responses of the foot in people with type 2 diabetes mellitus.

Intermittent pneumatic compression (IPC) is commonly used to improve peripheral circulation of the lower extremity. However, its therapeutic dosage for people with type 2 diabetes mellitus (DM) at risk for ulcers is not well established. This study explored the effect of IPC with different inflation pressures on the distal microvascular responses of the foot in people with type 2 DM. Twenty-four subjects with and without DM were recruited. Three IPC protocols with inflation pressures of 60, 90, and 120 mmHg were applied to the foot. The foot skin blood flow (SBF) responses were measured by laser Doppler flowmetry during and after IPC interventions. Results show that all three IPC interventions significantly increased foot SBF of IPC stage in healthy subjects, but only 90 and 120 mmHg IPC significantly improved SBF in diabetic subjects. IPC with 90 and 120 mmHg showed a greater effect than 60 mmHg in both groups, but 120 mmHg IPC was more effective for diabetic subjects. This study demonstrates that 90 and 120 mmHg are effective dosages of IPC for improving blood flow in healthy people, and 120 mmHg IPC may be more suitable for people with type 2 DM.

Inferior vena cava injury during percutaneous vertebroplasty: a rare cause of fatal pulmonary thromboembolism.

Fatal pulmonary thromboembolism (PTE) following percutaneous vertebroplasty is rare in medical practice. Here, we report the case of a 70-year-old woman who suffered from lumbago with lower extremity pain and lameness and for whom lumbar osteoporotic vertebral compression fractures (L4, L5) were seen on MRI examination. Percutaneous vertebroplasty and posterior vertebral lamina fenestration discectomy were performed. One day later, her condition deteriorated after defecation, and she died suddenly. Pulmonary thromboembolus and deep venous thrombosis in the inferior vena cava were the major findings at forensic autopsy. Due to the rather uncommon components of the thromboembolus (chondrocytes, calcium deposits, and collagen fibers), the pulmonary thromboembolism was attributed to deep venous thrombosis in the inferior vena cava, which was injured during percutaneous vertebroplasty. The present study highlights the conclusion that pulmonary thromboembolism is a rare complication of percutaneous vertebroplasty that should attract the attention of clinical physicians and forensic pathologists.

The effects of different accumulated pressure-time integral stimuli on plantar blood flow in people with diabetes mellitus.

BACKGROUND: Exercise, especially weight-bearing exercise (e.g. walking), may affect plantar tissue viability due to prolonged repetitive high vertical and high shear pressure stimulus on the plantar tissue, and further induce development of diabetic foot ulcers (DFUs). This study aimed to investigate the effects of different accumulated pressure-time integral (APTI) stimuli induced by walking on plantar skin blood flow (SBF) responses in people with diabetes mellitus (DM). METHODS: A repeated measures design was used in this study. Two walking protocols (low APTI (73,000 kPa·s) and high APTI (73,000 × 1.5 kPa·s)) were randomly assigned to ten people with DM and twenty people without DM. The ratio of SBF measured by laser Doppler flowmetry after walking to that before (normalized SBF) was used to express the SBF responses. RESULTS: After low APTI, plantar SBF of people with DM showed a similar response to people without DM (P = 0.91). However, after high APTI, people with DM had a significantly lower plantar SBF compared to people without DM (P < 0.05). In people with DM, plantar SBF in the first 2 min after both APTI stimuli significantly decreased compared to plantar SBF before walking (P < 0.05). CONCLUSIONS: People with DM had a normal SBF response after low APTI walking but had an impaired SBF response after high APTI walking, which suggests that they should avoid weight-bearing physical activity with intensity more than 73,000 kPa·s and should rest for more than 2 min after weight-bearing physical activity to allow a full vasodilatory response to reduce risk of DFUs.

A novel splicing mutation in Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is a connective tissue disease involving multiple organs and systems such as cardiovascular, skeletal, and ocular systems and is also an autosomal dominant inheritance disorder. METHOD: A 30-year-old woman was rushed into the hospital owing to sudden persistent pain in the abdomen and died suddenly 2 days later. To find the real cause of death, a forensic autopsy was conducted owing to suspected medical malpractice, and the diagnosis of MFS was made in accordance with the 2010 revised Ghent nosology. By sequencing the gene of Marfan, aneurysm, and related disorders, a novel splicing mutation in the fibrillin-1 gene (FBN1) was detected. For the clinical characteristic findings (wrist and thumb sign) of the daughter, we recommend genetic analysis for the family. To better understand the role of the variant in the disease, we also investigated functional validation of this mutation. RESULTS: According to the autopsy findings, the cause of death was acute cardiac tamponade caused by aortic rupture. DNA sequencing revealed a novel splicing mutation, c.5672-2delA, which was also detected in her daughter (II2). The functional validation of this mutation showed the base deletion at the same site in the PCR products using cDNA as a template. It is suggested that this mutation may cause abnormal spliceosome during transcription and may encode abnormal protein. CONCLUSION: A novel pathogenic splicing mutation (c.5672-2delA) was confirmed. Present work enriches the profile mutations in FBN1 associated with MFS and stresses the importance of postmortem genetic analysis in such cases.

The Warburg effect in human pancreatic cancer cells triggers cachexia in athymic mice carrying the cancer cells.

BACKGROUND: Cancer cachexia is a cancer-induced metabolic disorder and a major cause of cancer-induced death. The constituents of cancer cachexia include an increase in energy expenditure, hepatic gluconeogenesis, fat lipolysis, and skeletal-muscle proteolysis and a decrease in body weight. The aetiology of cancer cachexia is unclear and may involve cancer-cell metabolism and secretion. In this study, we investigated whether the high glycolysis in cancer cells (the Warburg effect) triggers cachexia in athymic mice carrying pancreatic cancer cells. METHODS: First, we examined five human pancreatic cancer cell lines for glycolysis and cachectic-cytokine secretion. Consequently, MiaPaCa2 and AsPC1 cells were selected for the present study, because the glycolysis in MiaPaCa2 cells was typically high and that in AsPC1 cells was exceptionally low. In addition, both MiaPaCa2 and AsPC1 cells were competent in the secretion of examined cytokines. Next, we transplanted MiaPaCa2 and AsPC1 cells subcutaneously in different athymic mice for 8 weeks, using intact athymic mice for control. In another experiment, we treated normal mice with the supernatants of MiaPaCa2 or AsPC1 cells for 7 days, using vehicle-treated mice for control. In both models, we measured food intake and body weight, assayed plasma glucose, triglycerides, and TNF-α and used Western blot to determine the proteins that regulated hepatic gluconeogenesis, fat lipolysis, and skeletal-muscle proteolysis in the corresponding tissues. We also studied the effect of MiaPaCa2-cell supernatants on the proteolysis of C2C12 skeletal-muscle cells in vitro. RESULTS: The athymic mice carrying high-glycolytic MiaPaCa2 cells had anorexia and also showed evidence for cachexia, including increased hepatic gluconeogenesis, fat lipolysis and skeletal-muscle proteolysis and decreased body weight. The athymic mice carrying low-glycolytic AsPC1 cells had anorexia but did not show the above-mentioned evidence for cachexia. When normal mice were treated with the supernatants of MiaPaCa2 or AsPC1 cells, their energy homeostasis was largely normal. Thus, the cachexia in the athymic mice carrying MiaPaCa2 cells may not result from humeral factors released by the cancer cells. In vitro, MiaPaCa2-cell supernatants did not induce proteolysis in C2C12 cells. CONCLUSION: The Warburg effect in pancreatic cancer cells is an independent aetiological factor for pancreatic cancer-induced cachexia.

Chronic occupational N, N-dimethylformamide poisoning induced death: a case report.

N, N-dimethylformamide (DMF) is a toxic solvent that is widely used in many industries. Death directly attributed to DMF poisoning is rare. We report the case of a 40-year-old female who died of liver failure after occupational exposure to DMF poisoning over the course of 70 days, followed by 64 days treatment in hospital. Based on clinical procedures, autopsy findings, and environmental air quality assessment, the death in this case was confirmed to be the result of chronic DMF poisoning. This case gives further insight into occupational chronic poisoning-induced death, especially with negative toxicological analysis of rapid metabolism toxins poisoning.

Review of the lethal mechanism of insulin poisoning and the characteristic of forensic identification.

Insulin, as the only hypoglycemic hormone in the body, plays a key role in blood sugar control. However, excessive insulin intake can lead to insulin poisoning and even death, which often occurs in clinical and forensic work. At present, some researches on insulin poisoning have been carried out at home and abroad, however, it seems that the mechanism and forensic characteristics of insulin poisoning are not clear and complete. Therefore, in this paper, we reviewed the potential mechanism of insulin poisoning, the methods of insulin detection and the forensic identification of poisoning cases, aiming at providing services for the forensic identification of insulin poisoning.

Temporal profiles of axonal injury following impact acceleration traumatic brain injury in rats--a comparative study with diffusion tensor imaging and morphological analysis.

Traumatic axonal injury (TAI) plays a major role in the development of neurological impairments after traumatic brain injury (TBI), but it is commonly difficult to evaluate it precisely and early with conventional histological biomarkers, especially when the patients experience short-term survival after TBI. Diffusion tensor imaging (DTI) has shown some promise in detecting TAI, but longitudinal studies on the compromised white matter with DTI at early time points (≤72 h) following impact acceleration TBI are still absent. In the present study, rats were subjected to the Marmarou model and imaged with DTI at 3, 12, 24, and 72 h (n = 5 each) post-injury. Using a region-of-interest-based approach, the regions of interest including the corpus callosum, bilateral external capsule, internal capsule, and pyramidal tract were studied. Two DTI parameters, fraction anisotropy and axial diffusivity, were significantly reduced from 3 to 72 h in each region after trauma, corresponding to the gradient of axonal damage demonstrated by immunohistochemical staining of ß-amyloid precursor protein and neurofilament light chain. Remarkably, DTI changes predicted the approximate time in the acute phase following TBI. These results indicate that the temporal profiles of diffusion parameters in DTI may be able to provide a tool for early diagnosis of TAI following impact acceleration TBI.

TSA-PACT: a method for tissue clearing and immunofluorescence staining on zebrafish brain with improved sensitivity, specificity and stability.

For comprehensive studies of the brain structure and function, fluorescence imaging of the whole brain is essential. It requires large-scale volumetric imaging in cellular or molecular resolution, which could be quite challenging. Recent advances in tissue clearing technology (e.g. CLARITY, PACT) provide new solutions by homogenizing the refractive index of the samples to create transparency. However, it has been difficult to acquire high quality results through immunofluorescence (IF) staining on the cleared samples. To address this issue, we developed TSA-PACT, a method combining tyramide signal amplification (TSA) and PACT, to transform samples into hydrogel polymerization frameworks with covalent fluorescent biomarkers assembled. We show that TSA-PACT is able to reduce the opacity of the zebrafish brain by more than 90% with well-preserved structure. Compared to traditional method, TSA-PACT achieves approximately tenfold signal amplification and twofold improvement in signal-to-noise ratio (SNR). Moreover, both the structure and the fluorescent signal persist for at least 16 months with excellent signal retention ratio. Overall, this method improves immunofluorescence signal sensitivity, specificity and stability in the whole brain of juvenile and adult zebrafish, which is applicable for fine structural analysis, neural circuit mapping and three-dimensional cell counting.

Sudden death due to cerebral leukemic hemorrhage occurring after acupuncture treatment for gingival bleeding.

A 45-year-old woman who experienced stomalgia and gingival bleeding for several days died unexpectedly after acupuncture treatment. At autopsy, trivial injuries on the liver and the stomach and mild hemoperitoneum due to improper acupuncture were found. Also,acute lymphoblastic leukemia and hyperleukocytosis were diagnosed by postmortem examinations. Intracranial hemorrhage due to undiagnosed acute lymphoblastic leukemia was identified as the cause of death.Moreover, the relationship between therapeutic misadventure and death was also determined. We suggest that undiagnosed leukemia should be considered as a differential diagnosis when sudden death occurs owing to intracranial hemorrhage. If therapeutic misadventure was involved,it is also of great importance to assess the relationship between that and death in forensic expertise.

[Magnetic resonance diffusion tensor imaging for diagnosis of pyramidal tract damage in rats].

OBJECTIVE: To explore the applicability of magnetic resonance diffusion tensor imaging (DTI) for diagnosis of pyramidal tract damage in rats. METHODS: Marmarou's model was set up, followed by DTI scanning at 3, 12, 24 and 72 h post trauma to acquire the dispersion parameter of bilateral pyramidal tracts. Moreover, axonal varicosities per square millimeter and the percentage of positive area of axons demonstrated by beta-amyloid precursor protein (beta-APP) immunostaining were obtained, as well as the mean density and sum density of neurofilament (NF) 68 immunostaining. RESULTS: Axial diffusivity (AD), fraction anisotropy (FA) and relative anisotropy (RA) in the pyramidal tract were significantly and continuously reduced and reached to the bottom at 72h post trauma (P < 0.05) in accord with the gradient of axonal damage verified by beta-APP and NF68 immunostaining. Furthermore, the changes of AD, FA and RA showed a significant negative correlation with the beta-APP immunohistochemical results. CONCLUSION: DTI has important value for early diagnosis in pyramidal tract damage.

The Biomechanics Effect of Hamstring Flexibility on the Risk of Osgood-Schlatter Disease.

Background: The relationship between hamstring flexibility and the risk of OSD continues to be a debate, and whether hamstring stretching exercises should be considered as one of the conservative treatments of OSD is still unclear. Objectives: To investigate the relationship between hamstring flexibility and the risk of OSD by assessing the changes of loading on the tibial tuberosity caused by the changes of hamstring optimal lengths. Methods: Experimental data of a young adult running at 4 m/s were used, which were collected by an eight-camera motion capture system together with an instrumented treadmill. Muscle forces were estimated in OpenSim when hamstring optimal lengths changed in the range of 70-130% of the control case in 5% increments. The force and accumulated force of quadriceps muscle were calculated to evaluate the impact of hamstring optimal lengths on the loading on tibial tuberosity. The changes in muscle forces throughout the gait cycle were compared by using statistical parametric mapping (SPM). The average peak force and accumulated force of five gait cycles were compared. Results: Although the maximum force of the quadriceps muscle was slightly affected by changes in hamstring optimal lengths, the accumulated force of quadriceps muscle increased by 21.97% with hamstring optimal lengths decreased by 30% of the control case. The increase of the muscle force mainly occurred in the early stance phase and terminal swing phase (P < 0.05). However, when hamstring optimal lengths were longer than the control, it had a little effect on accumulated force of quadriceps muscle. Conclusions: The results of this study indicate that a shorter hamstring optimal length, which means lack of flexibility, can cause a high accumulated force on tibial tuberosity, thus increasing the risk of OSD. Hamstring stretching exercise is only effective for people with lack of hamstring flexibility.

Relationship Between Plantar Tissue Hardness and Plantar Pressure Distributions in People With Diabetic Peripheral Neuropathy.

Objective: People with diabetic peripheral neuropathy (DPN) are usually accompanied with increased plantar pressure. Such high plantar loading during daily activities may cause changes in the biomechanical properties of plantar soft tissue, whose viability is critical to the development of foot ulcers. This study aimed to investigate the relationship between plantar tissue hardness and plantar pressure in people with and without DPN, and preliminarily explore the influence of plantar loading patterns on the plantar pressure and tissue hardness. Methods: The study was conducted on 14 people with DPN and 14 diabetic people without DPN. The Shore durometer and MatScan System were used to measure the plantar tissue hardness and plantar pressure, respectively. The plantar loading level was evaluated by the duration of daily weight-bearing activity and was used to group diabetic participants with and without DPN into two subgroups (lower loading group and higher loading group). Results: The plantar tissue hardness was significantly correlated with static peak plantar pressure (PPP, p < 0.05) and dynamic pressure-time integral (PTI, p < 0.05) in the forefoot region in people with DPN. Results of variance analysis showed a significant interaction effect between peripheral neuropathy and plantar loading on tissue hardness (p < 0.05), but not plantar pressure. For people with DPN, significant differences in tissue hardness between the higher loading group and lower loading group were observed in the forefoot, midfoot and hindfoot regions. In the higher loading group, people with DPN had significantly greater tissue hardness than that in people without DPN in the toes, forefoot, midfoot and hindfoot regions (p < 0.05). Conclusions: There is a significant correlation between tissue hardness and PPP, and between tissue hardness and PTI in people with DPN. Plantar loading associated with daily activities plays a significant role on the plantar tissue hardness in people with DPN. The findings of this study contribute to further understand the relationship between increased plantar tissue hardness and high plantar pressure in people with diabetic peripheral neuropathy.

[Advance in animal models of traumatic brain injury].

Traumatic brain injury (TBI) is a highly complex multi-factorial disorder. Animal models of TBI are used to elucidate primary and secondary injury mechanisms and pathophysiological changes and to provide the diagnostic and therapeutical basis for TBI. The choices of animal models depend upon the research objectives. However, various animal models have limitations. The models only can duplicate the pivotal injury mechanisms or a certain important pathophysiological course. The characteristics of human TBI can not fully be reflected by using these models. In the review, animal models of traumatic brain injury are classified as dynamic direct brain injury, indirect dynamic brain injury and combined neuro-traumatic models. Several common models are described for consideration.

Sudden death due to a novel nonsense mutation in Marfan syndrome.

BACKGROUND: Marfan syndrome is a hereditary connective tissue disease accompanied by autosomal dominant inheritance; that mainly arises from a mutation in the fibrillin-1 gene (FBN1). Aortic dissection and rupture are the common and lethal complications of MFS and may cause sudden unexpected death. METHOD: A man aged 34 was admitted to the hospital due to persistent pain in his abdomen 12 h post-drinking and suddenly died 10 h later. A forensic autopsy was performed to identify the underlying mechanism of death. Due to the high suspected of MFS, Sanger sequencing was performed, and a novel mutation was detected in the deceased. To clarify the underlying mechanism of this mutation, real-time quantitative polymerase chain reaction was conducted and Western blot analysis was performed in vitro. RESULTS: A novel PTC mutation c.933C > A in FBN1 was found. Through family history inspection and Sanger sequencing, other MFS patients in the present family were confirmed. The pathologic changes in the aorta in the present case showed media cystic degeneration, disordered arrangement of elastic fibers and a significant reduction in fibrillin 1 compared with the control. The mutation led to significant reduction inFBN1 mRNA and fibrillin-1 in cells in vitro, and overexpression of phospho-Smad2 was observed. CONCLUSION: We confirmed a novel pathogenic PTC mutation in the FBN1gene through Sanger sequencing, and the pathological changes and underlying mechanisms were also identified. The present work not only extends the pathogenic mutation spectrum of MFS, but also stresses the role of forensic autopsy, genetic analysis and functional validation of novel mutations in cases of sudden death associated with congenital diseases.

Combined Analysis of RNA Sequence and Microarray Data Reveals a Competing Endogenous RNA Network as Novel Prognostic Markers in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with short survival time. Unbalanced competing endogenous RNAs (ceRNAs) have been shown to participate in the tumor pathogenesis and served as biomarkers for the clinical prognosis. However, the comprehensive analyses of the ceRNA network in the prognosis of MPM are still rarely reported. In this study, we obtained the transcriptome data of the MPM and the normal samples from TCGA, EGA, and GEO databases and identified the differentially expressed (DE) mRNAs, lncRNAs, and miRNAs. The functions of the prognostic genes and the overlapped DEmRNAs were further annotated by the multiple enrichment analyses. Then, the targeting relationships among lncRNA-miRNA and miRNA-mRNA were predicted and calculated, and a prognostic ceRNA regulatory network was established. We included the prognostic 73 mRNAs and 13 miRNAs and 26 lncRNAs into the ceRNA network. Moreover, 33 mRNAs, three miRNAs, and seven lncRNAs were finally associated with prognosis, and a model including seven mRNAs, two lincRNAs, and some clinical factors was finally established and validated by two independent cohorts, where CDK6 and SGMS1-AS1 were significant to be independent prognostic factors. In addition, the identified co-expressed modules associated with the prognosis were overrepresented in the ceRNA network. Multiple enrichment analyses showed the important roles of the extracellular matrix components and cell division dysfunction in the invasion of MPM potentially. In summary, the prognostic ceRNA network of MPM was established and analyzed for the first time and these findings shed light on the function of ceRNAs and revealed the potential prognostic and therapeutic biomarkers of MPM.

Bibliometric Insights in Genetic Factors of Substance-Related Disorders: Intellectual Developments, Turning Points, and Emerging Trends.

Substance-related disorders are a group of medical conditions that affect a person's brain and behavior and lead to an inability to control the use of legal or illegal drug(s) or medication. Substance-related disorder is a serious public health and society problem worldwide. Genetic factors have been proven to have an important role. Researchers have carried out a lot of work in this field, and a large number of research results have been published in academic journals around the world. However, there are few overviews of research progress, presentation, and development trends in this field. In this study, a total of 636 articles related to genetic factors of substance-related disorders were retrieved from the Web of Science (WoS) database from 1997 to 2018, and the scientific literatures were analyzed by bibliometrics. The study found that the United States (US) has maintained a leading position in the field of research, with many core institutions and plenty of high-quality research results. Alcohol use disorder is still the most concerning issue in this field. Over the past 20 years, new techniques such as genome-wide association study (GWAS) based on high-throughput sequencing technology have replaced family studies, twin studies, and retrospective studies in this field. We believe that it is urgent to study the genetic factors of substance-related disorders, which can greatly deepen the understanding of the pathogenesis of substance-related disorders and may provide potential targets for precise treatment of such diseases.

Effect of Exercise Volume on Plantar Microcirculation and Tissue Hardness in People With Type 2 Diabetes.

Objective: Exercise has been reported to be beneficial for people with type 2 diabetes (T2DM), but exercise, especially weight-bearing exercise, may increase the risk of diabetic foot ulcers (DFUs). This study aimed to explore the associations between different volumes of weight-bearing physical activities and plantar microcirculation and tissue hardness in people with T2DM. Methods: 130 elderly people with T2DM were enrolled for this cross-sectional study. They were classified into the high exercise volume group and the low exercise volume group based on their weekly energy expenditure (metabolic equivalents per week) in the past year. Weekly energy expenditure was calculated using the International Physical Activity Questionnaire and the Compendium of Physical Activities. The plantar oxygen saturation (SO2) and soft tissue hardness of each participant's right foot were measured. Results: A total of 80 participants completed the trial. The average exercise energy expenditure of the high exercise volume group and the low exercise volume group were significantly different (p < 0.05). The results showed that the SO2 of the high exercise volume group (67.25 ± 6.12%) was significantly higher than the low exercise volume group (63.75 ± 8.02%, p < 0.05). The plantar tissue hardness of the high exercise volume group was lower than the low exercise volume group in the big toe, midfoot and hindfoot regions (p < 0.05). Conclusion: This study demonstrates that higher volumes of exercise are associated with better plantar microcirculation and lower plantar tissue hardness in people with T2DM. The findings of this study indicate that weight-bearing exercise may not increase risk of developing diabetic foot ulcers.