Millennials, the Most Afflicted Generation: Suicide Trends Within Dallas County From 2019 to 2021.

ABSTRACT: In the wake of the SARS-CoV-2 (COVID-19) pandemic, mental health has become a pivotal topic of discussion nationwide.1,2 Recognition of mental health disorders, mitigation of psychological distress during times of uncertainty, and abating negative stigma have become a focus of many groups, both internal and external to the medical field. Still, one of the most devastating sequelae of mental health afflictions is suicide.A retrospective review of all cases classified as suicide from January 2019 through December 2021 was conducted using the laboratory information system database within the Southwestern Institute of Forensic Sciences, the county division that performs postmortem examinations of cases under the jurisdiction of Dallas County and some surrounding North Texas counties. A total of 846 cases were retrieved that occurred within Dallas County. This cohort consisted of 659 men and 187 women with an average age of 42.9 years (median, 40 years). This study highlights compelling trends of suicides within a localized portion of North Texas during a 3-year period in which the population endured momentous and unprecedented worldwide events.

Selective targeting of the αC and DFG-out pocket in p38 MAPK.

The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge-binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into back-pocket interactions that are not addressed in SR-318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.

Report of Increasing Overdose Deaths that include Acetyl Fentanyl in Multiple Counties of the Southwestern Region of the Commonwealth of Pennsylvania in 2015-2016.

Acetyl fentanyl is a Schedule I controlled synthetic opioid that is becoming an increasingly detected "designer drug." Routine drug screening procedures in local forensic toxicology laboratories identified a total of 41 overdose deaths associated with acetyl fentanyl within multiple counties of the southwestern region of the state of Pennsylvania. The range, median, mean, and standard deviation of blood acetyl fentanyl concentrations for these 41 cases were 0.13-2100 ng/mL, 11 ng/mL, 169.3 ng/mL, and 405.3 ng/mL, respectively. Thirty-six individuals (88%) had a confirmed history of substance abuse, and all but one case (96%) were ruled multiple drug toxicities. This report characterizes this localized trend of overdose deaths associated with acetyl fentanyl and provides further evidence supporting an alarmingly concentrated opiate and opioid epidemic of both traditional and novel drugs within this region of the United States.

Endoscopic ultrasound-guided FNA and ProCore biopsy in sampling pancreatic and intra-abdominal masses.

BACKGROUND: ProCore fine-needle biopsy (FNB) was introduced to improve the diagnostic yield of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) sampling. The aim of this study was to evaluate EUS-guided sampling of intra-abdominal masses and compare the diagnostic utility of conventional EUS-FNA and ProCore FNB. METHODS: EUS-guided biopsy samples (FNA and/or EchoTip ProCore FNB) were retrospectively retrieved over the course of 23 months. Clinical findings, pathology reports, and available histological materials were reviewed. All cell blocks were reviewed, and their cellularity was scored (range, 0-3). RESULTS: Fifty-six masses from 58 cases were acquired, and they included 40 pancreatic sites and 16 other intra-abdominal sites. Among the 31 FNB-only cases, 71% were satisfactory, 65% were positive for malignancy at the time of final diagnosis, and their cell blocks were moderately cellular. For the cases with both FNB and FNA performed, more FNB samples than FNA samples were satisfactory (83% vs 76%) and were positive for malignancy (65% vs 48%) at final diagnosis, and the former had more cellular cell blocks (mean score, 1.58 vs 1.29); however, the differences were not statistically significant. Significantly more FNB samples were used for immunostains (48% vs 10%; P = .005). CONCLUSIONS: These data show that a wide variety of intra-abdominal masses were amenable to sampling by ProCore FNB. In this subset of cases with prior/concurrent indeterminate FNAs, FNB showed slightly better diagnostic yield, and had more cellular tissue samples and more material for ancillary studies than matched FNAs.

The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells.

Microwave-assisted synthesis of the pyrazolyl ketone p38 MAPK inhibitor RO3201195 in 7 steps and 15% overall yield, and the comparison of its effect upon the proliferation of Werner Syndrome cells with a library of pyrazolyl ketones, strengthens the evidence that p38 MAPK inhibition plays a critical role in modulating premature cellular senescence in this progeroid syndrome and the reversal of accelerated ageing observed in vitro on treatment with SB203580.

Rates of motorcycle helmet use and reasons for non-use among adults and children in Luang Prabang, Lao People's Democratic Republic.

BACKGROUND: Motorcycles make up 81 % of the total vehicle population and 74 % of road traffic deaths in Lao PDR. Helmets reduce the risk and severity of injuries resulting from motorcycle accidents by 72 %. Although Lao law mandates motorcycle helmet use among drivers and passengers, the prevalence of helmet use in Luang Prabang, Lao PDR is unknown. This project aimed to measure the prevalence of motorcycle helmet use among riders (i.e., drivers and passengers) in Luang Prabang. METHODS: An observational survey in Luang Prabang was conducted in February 2015 to measure the prevalence of motorcycle helmet use among drivers and passengers. Additionally, non-helmet wearing riders were surveyed to identify the reasons for helmet non-use. RESULTS: Of 1632 motorcycle riders observed, only 16.2 % wore helmets. Approximately 29 % of adults wore helmets while less than 1 % of all children wore helmets. When surveyed about attitudes towards helmet use, the majority of adult drivers indicated that they did not like how adult helmets feel or made them look. Additionally, almost half of motorcyclists who did not own child helmets reported that their child was too young to wear a helmet. CONCLUSIONS: Our finding that children wear helmets at significantly lower rates compared to adults is consistent with findings from neighboring countries in Southeast Asia. Results of this study have implications for public health campaigns targeting helmet use, especially among children.

Microwave-Assisted Synthesis of a MK2 Inhibitor by Suzuki-Miyaura Coupling for Study in Werner Syndrome Cells.

Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells.

Microwave-assisted synthesis of 3-aminobenzo[b]thiophene scaffolds for the preparation of kinase inhibitors.

Microwave irradiation of 2-halobenzonitriles and methyl thioglycolate in the presence of triethylamine in DMSO at 130 °C provides rapid access to 3-aminobenzo[b]thiophenes in 58-96% yield. This transformation has been applied in the synthesis of the thieno[2,3-b]pyridine core motif of LIMK1 inhibitors, the benzo[4,5]thieno[3,2-e][1,4]diazepin-5(2H)-one scaffold of MK2 inhibitors and a benzo[4,5]thieno[3,2-d]pyrimidin-4-one inhibitor of the PIM kinases.

Low-grade fibromatosis-like spindle cell carcinoma of the breast.

Low-grade fibromatosis-like spindle cell carcinoma is a rare tumor in the breast, and represents a variant of the very heterogeneous group of metaplastic carcinomas of the breast. These tumors warrant distinction because of their resemblance to pure fibromatosis, their propensity for local recurrence, and their favorable prognosis among the metaplastic carcinomas of the breast. The diagnosis is potentially challenging, particularly on core needle biopsies, because of the morphologic overlap with other low-grade spindle cell lesions. Recognition of a proliferation of cytologically bland spindle cells with areas of epithelial differentiation in combination with immunohistochemistry using antibodies against cytokeratins and myoepithelial markers should aid in producing a definitive diagnosis. These tumors can be locally aggressive with an increased incidence of local recurrence, but the potential for lymph node or distant metastasis is low. Complete excision with adequate margins is considered curative in the majority of cases.

The effects of lesions to the postsubiculum or the anterior dorsal nucleus of the thalamus on spatial learning in rats.

To investigate the role of the head direction (HD) cell circuit in spatial navigation, rats with bilateral, neurotoxic lesions to the postsubiculum (PoS; Experiment 1) or the anterior dorsal nucleus of the thalamus (ADN; Experiment 2) were compared to sham controls on 2 tasks that could be solved using directional heading. Rats were first trained on a direction problem in a water T maze where they learned to travel either east or west from 2 locations in the experimental room. ADN lesioned rats were impaired relative to sham controls on the first block of 8 trials, but not on the total trials taken to reach criterion. This transient deficit was not observed in rats with lesions to the PoS. In the food-foraging task, rats were trained to leave a home cage at the periphery of a circular table, find food in the center of the table, and return to the home cage. Both PoS and ADN lesioned rats showed impairments on this task relative to sham rats, making more errors on the return component of the foraging trip. The spatial deficits produced by lesions to the PoS and the ADN, downstream structures in the HD cell circuit, are not as severe as those observed in earlier studies in rats with lesions to the dorsal tegmental nucleus.

The effects of bilateral lesions to the dorsal tegmental nucleus on spatial learning in rats.

The head-direction (HD) signal is believed to originate in the dorsal tegmental nucleus (DTN) and lesions to this structure have been shown to disrupt HD cell firing in other areas along the HD cell circuit. To investigate the role of the DTN in spatial navigation, rats with bilateral, electrolytic (Experiment 1), or neurotoxic (Experiment 2) lesions to the DTN were compared with sham controls on two tasks that differed in difficulty and could be solved using directional heading. Rats were first trained on a direction problem in a water T maze where they learned to travel either east or west from two locations in the experimental room. DTN-lesioned rats were impaired relative to sham controls, both early in training, on the first block of eight trials, and on the total trials taken to reach criterion. In the food-foraging task, rats were trained to leave a home cage at the periphery of a circular table, find food in the center of the table and return to the home cage. Again, DTN-lesioned rats were impaired relative to sham rats, making more errors on the return component of the foraging trip. These data extend previous cell-recording studies and behavioral tests in which rats with electrolytic DTN lesions were used, and they demonstrate the importance of the direction system to spatial learning.

Investigation of the reductive cleavage of BINAP and application to the rapid synthesis of phospholes.

A rapid and easy entry into λ(3)-phospholes and λ(4)-phosphole oxides derived from BINAP is reported herein featuring a variety of C and Si substituents and functional groups, as well the investigative work on the mechanistic pathway. DFT calculations using B3LYP functionals have been carried out to rationalize the mechanism. The observed experimental (31)P resonance shifts were compared with the calculated shifts of the proposed intermediates after calibration of the shielding tensors. The calculations included the use of polarizable continuum models to take into account solvent effects and were found to be in excellent agreement, providing further evidence for the proposed mechanism.

Ketoacidosis and trace amounts of isopropanol in a chronic alcoholic patient.

BACKGROUND: Alcohol ketoacidosis is a frequently missed diagnosis, but is well described in the literature. We present a case of ketoacidosis, likely alcohol ketoacidosis, in a 40 y-old chronic alcoholic patient. The detection of trace serum isopropanol prompted a discussion of alcohol ketoacidosis versus toxic isopropanol ingestion or a combination of both, including comparisons with citations in current literature. METHODS: The automated instruments used to analyze the patient's urine, blood, and serum samples are described. RESULTS: The initial impression was severe metabolic acidosis with an increased anion gap and normal serum glucose and whole blood lactate. Testing for potential toxic ingestions detected only increased serum acetone and trace serum isopropanol. A urinalysis positive for ketones and an increased serum ß-hydroxybutyrate concentration clenched the diagnosis of ketoacidosis. CONCLUSION: Ketoacidosis with an increased anion gap in the absence of hyperglycemia or glycosuria in a chronic alcoholic patient should prompt the evaluation for alcohol ketoacidosis. Trace serum isopropanol may be worrisome for a toxic ingestion, but this finding in severe ketoacidosis may be explained by the reversible action of the enzyme alcohol dehydrogenase. Markedly increased serum isopropanol with a low serum acetone:isopropanol ratio would be more indicative of a toxic isopropanol ingestion.

Age-dependent alterations in spermatogenesis in itchy mice.

Spermatogenesis is an intricate process in which spermatogonial stem cells divide and differentiate to produce mature sperm. This process strongly depends on protein turnover both in the developing germ cells and the supportive Sertoli cells, and recent evidence has demonstrated the role of the ubiquitin-proteasome system in this protein turnover in the testis. Itch, an E3 ligase important in the immune system, has been implicated in regulating the blood testis barrier. Although the specific role of Itch during spermatogenesis is not yet well understood, its ubiquitous expression and wide array of functional targets suggest multiple and tissue-specific roles. Here the testes of mice that lack Itch protein are evaluated at two developmental time points: peri-pubertal postnatal day (PND) 28 and adult PND 56. Itchy mice demonstrate an increased germ cell apoptotic index compared with wild type C57BL/6J mice at both PND 28 and PND 56. A corresponding 27% reduction in the total number of spermatid heads produced in PND 56 itchy mice was also evident. A histological evaluation of itchy mice revealed a delay in spermatogenesis at PND 28 and disorganization of late stage spermatids at PND 56. An analysis of several apoptotic markers revealed an age-dependent change in cleaved caspase 9, an intrinsic apoptosis mediator. The breeding success of the itchy mice was also significantly decreased, possibly due to a developmental defect. Taken together, these findings indicate that Itch is required for functional spermatogenesis, and that it may play differing cellular roles during development.