Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Sudden Infant Death Syndrome: A Potential Model for Investigation.

Sudden infant death syndrome (SIDS) represents a significant cause of post-neonatal mortality, yet its underlying mechanisms remain unclear. The triple-risk model of SIDS proposes that intrinsic vulnerability, exogenous triggers, and a critical developmental period are required for SIDS to occur. Although case-control studies have identified potential risk factors, no in vivo model fully reflects the complexities observed in human studies. Pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved neuropeptide with diverse physiological functions, including metabolic and thermal regulation, cardiovascular adaptation, breathing control, stress responses, sleep-wake regulation and immunohomeostasis, has been subject to early animal studies, which revealed that the absence of PACAP or its specific receptor (PAC1 receptor: PAC1R) correlates with increased neonatal mortality similar to the susceptible period for SIDS in humans. Recent human investigations have further implicated PACAP and PAC1R genes as plausible contributors to the pathomechanism of SIDS. This mini-review comprehensively synthesizes all PACAP-related research from the perspective of SIDS and proposes that PACAP deficiency might offer a promising avenue for studying SIDS.

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10-6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10-13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10-43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10-22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10-12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10-4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10-7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10-29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Application of 3D printing in assessment and demonstration of stab injuries.

In stabbing related fatalities, the forensic pathologist has to assess the direction of wound track (thus, the direction of the stabbing) and the weapon's possible characteristics by examining the stab wound. The determination of these characteristics can be made only with a high level of uncertainty, and the precise direction of the stabbing is often difficult to assess if only soft tissues are injured. Previously reported techniques used for the assessment of these wound characteristics have substantial limitations. This manuscript presents a method using today's easily accessible three-dimensional (3D) printing technology for blade-wound comparison and wound track determination. Scanning and 3D printing of knives is a useful method to identify weapons and determine the precise stabbing direction in a stabbing incident without compromising the trace evidence or the autopsy results. Ballistic gel experiment, and dynamic stabbing test experiments prove the method can be applied in safety, without compromising the autopsy results. Identification of the exact knife is not possible with complete certainty but excluding certain knives will decrease the number of necessary DNA examinations, hence it can lower the burden on forensic genetic laboratories. The method addresses many of the shortcomings of previously used methods of probe insertion or post-mortem CT. Insertion of the printed knife into the wound gives a good visual demonstration of the stabbing direction, thus easing the forensic reconstruction of the stabbing incident. After combining the 3D printing with photogrammetry, the achieved 3D visualization is useful for courtroom demonstration and educational purposes.

Lexical Competition Without Phonology: Masked Orthographic Neighbor Priming With Deaf Readers.

Skilled reading is thought to rely on well-specified lexical representations that compete during visual word recognition. The establishment of these lexical representations is assumed to be driven by phonology. To test the role of phonology, we examined the prime lexicality effect (PLE), the index of lexical competition in signing deaf (N = 28) and hearing (N = 28) adult readers of Hungarian matched in age and education. We found no PLE for deaf readers even when reading skills were controlled for. Surprisingly, the hearing controls also showed reduced PLE; however, the effect was modulated by reading skill. More skilled hearing readers showed PLE, while more skilled deaf readers did not. These results suggest that phonology contributes to lexical competition; however, high-quality lexical representations are not necessarily built through phonology in deaf readers.

Orthographic-Phonological Mapping and the Emergence of Visual Expertise for Print: A Developmental Event-Related Potential Study.

The N1 effect is an electrophysiological marker of visual specialization for print. The phonological mapping hypothesis (Maurer & McCandliss, 2007) posits that the left-lateralized effect reflects grapheme-phoneme integration. In this event-related potential study, first (age = 7.06 years, N = 32) and third-grade readers (age = 9.29 years, N = 28) were presented with pairs of pseudowords and Armenian character strings in a novel implicit same-different paradigm. To test the phonological mapping hypothesis, stimuli were presented in visual-only and audiovisual conditions. The results demonstrated that tuning for print already emerges in first grade. Moreover, the parallel presentation of auditory stimuli enhanced the N1 effect suggesting a role of orthographic-phonological mapping in the development of specialization for print.

The Neuroprotective and Biomarker Potential of PACAP in Human Traumatic Brain Injury.

Traumatic brain injury remains a growing public health concern and represents the greatest contributor to death and disability globally among all trauma-related injuries. There are limited clinical data regarding biomarkers in the diagnosis and outcome prediction of TBI. The lack of real effective treatment for recovery calls for research of TBI to be shifted into the area of prevention, treatment of secondary brain injury and neurorehabilitation. The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been reported to act as a hormone, a neuromodulator, a neurotransmitter and a trophic factor, and has been implicated in a variety of developmental and regenerative processes. The importance of PACAP in neuronal regeneration lies in the upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central nervous system injury. The aim of this minireview is to summarize both the therapeutic and biomarker potential of the neuropeptide PACAP, as a novel possible target molecule presently being investigated in several human conditions including TBI, and with encouraging results in animal models of TBI.

Adaptive specialization in position encoding while learning to read.

The present experiments focused on how orthographic processing develops during reading acquisition. Specifically, a large, cross-sectional sample of children from grade 2 to grade 4 was exposed to pairs of words, pseudowords, digit strings, and pseudo-letter (Armenian) strings while their sensitivity to transpositions (T) and substitutions (S) of internal characters was investigated in a perceptual matching task. The results showed that the development of identity and position decoding diverged between the four stimulus categories. Most importantly, sensitivity improved with longer exposure to formal education and higher reading level to both S and T pairs for digit strings, but only to S pairs for words and pseudowords. The results were successfully reproduced in two small independent samples. We propose a general framework, the Adaptive Specialization Hypothesis, to accommodate the results. According to this hypothesis, the transposed-letter effect is not a hard-wired feature of the orthographic processing system but an adaptive response of the developing orthographic system to the constraints of lexical access in several orthographies.

PCR-based identification of drowning: four case reports.

Proper diagnosis in drowning victims is often difficult due to the lack of signs specific to drowning. The diatom test is a widely used procedure for the diagnosis. Some types of water contain only minimal amounts of diatom cells which may provide false-negative results, while a negative diatom test result does not exclude drowning. In proving drowning, we used a polymerase chain reaction (PCR)-based biological method in addition to the conventional methods. DNA was extracted from postmortem spleen tissues and water of the drowning site. Samples were tested with algae (diatoms and small green algae)- and cyanobacteria (blue-green algae)-specific primers. We present here multiple drowning cases in which diatom tests of the postmortem tissue samples and the water were negative. In each case, the presence of phytoplanktonic DNA strengthened the autopsy diagnosis of drowning even in the absence of visible diatoms. In the future, the PCR method may be of consideration as a possible supplement of the diatom test in the examination of presumed drowning cases.

Investigation of PACAP38 and PAC1 Receptor Expression in Human Retinoblastoma and the Effect of PACAP38 Administration on Human Y-79 Retinoblastoma Cells.

Retinoblastoma represents the most prevalent malignant neoplasm affecting the eyes in childhood. The clear-cut origin of retinoblastoma has not yet been determined; however, based on experiments, it has been suggested that RB1 loss in cone photoreceptors causes retinoblastoma. Pituitary adenylate-cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide which has been shown to be affected in certain tumorous transformations, such as breast, lung, kidney, pancreatic, colon, and endocrine cancers. This study aimed to investigate potential changes in both PACAP38 and PAC1 receptor (PAC1R) expression in human retinoblastoma and the effect of PACAP38 administration on the survival of a human retinoblastoma cell line (Y-79). We analyzed human enucleation specimens removed because of retinoblastoma for PACAP38 and PAC1R immunostaining and the effect of PACAP38 on the survival of the Y-79 cell line. We described for the first time that human retinoblastoma cells from patients showed only perinuclear, dot-like immunopositivity for both PACAP38 and PAC1R, irrespective of laterality, genetic background, or histopathological features. Nanomolar (100 nM and 500 nM) PACAP38 concentrations had no effect on the viability of Y-79 cells, while micromolar (2 µM and 6 µM) PACAP38 significantly decreased tumor cell viability. These findings, along with general observations from animal studies showing that PACAP38 has strong anti-apoptotic, anti-inflammatory, and antioxidant effects on ocular tissues, together suggest that PACAP38 and its analogs are promising candidates in retinoblastoma therapy.

Predictors of developmental dyslexia in European orthographies with varying complexity.

BACKGROUND: The relationship between phoneme awareness, rapid automatized naming (RAN), verbal short-term/working memory (ST/WM) and diagnostic category is investigated in control and dyslexic children, and the extent to which this depends on orthographic complexity. METHODS: General cognitive, phonological and literacy skills were tested in 1,138 control and 1,114 dyslexic children speaking six different languages spanning a large range of orthographic complexity (Finnish, Hungarian, German, Dutch, French, English). RESULTS: Phoneme deletion and RAN were strong concurrent predictors of developmental dyslexia, while verbal ST/WM and general verbal abilities played a comparatively minor role. In logistic regression models, more participants were classified correctly when orthography was more complex. The impact of phoneme deletion and RAN-digits was stronger in complex than in less complex orthographies. CONCLUSIONS: Findings are largely consistent with the literature on predictors of dyslexia and literacy skills, while uniquely demonstrating how orthographic complexity exacerbates some symptoms of dyslexia.

Role of endocrine PACAP in age-related diseases.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a conserved neuropeptide, which confers diverse anti-aging endocrine and paracrine/autocrine effects, including anti-apoptotic, anti-inflammatory and antioxidant action. The results of the in vivo and in vitro experiments show that increasing emphasis is being placed on the diagnostic/prognostic biomarker potential of this neuropeptide in a wide array of age-related diseases. After the initial findings regarding the presence and alteration of PACAP in different body fluids in physiological processes, an increasing number of studies have focused on the changes of its levels in various pathological conditions associated with advanced aging. Until 2016 - when the results of previous human studies were reviewed - a vast majority of the studies had dealt with age-related neurological diseases, like cerebrovascular and neurodegenerative diseases, multiple sclerosis, as well as some other common diseases in elderly such as migraine, traumatic brain injury and post-traumatic stress disorder, chronic hepatitis and nephrotic syndrome. The aim of this review is to summarize the old and the new results and highlight those 'classical' and emerging clinical fields in which PACAP may become subject to further investigation as a diagnostic and/or prognostic biomarker in age-related diseases.

[The use of lot numbers of surgically implanted devices for forensic identification]. / Mutéti implantátumok tételszáma alapján történo igazságügyi célú személyazonosítás.

The present study aims to discuss two successful identification cases of the search warrants on unknown bodies by the Baranya County Police Department. In both cases, identification was only possible by using lot numbers of the traumatological metal implants removed during exhumation, several years after the bodies had been discovered and the post-mortem investigation was completed. We hope that the cases provided will highlight the importance of secondary identifiers, specifically the lot numbers of medical implants, in forensic identification practice. We would also like to draw attention to the fact that the only way to identify the majority of the over a thousand unknown corpses in Hungary (742 of them have been under warrant for more than ten years) is to re-examine the corpses using recent years' results in technical and technological improvements. The presented cases highlight the importance of documenting the identification numbers of implanted surgical devices during autopsies. Orv Hetil. 2023; 164(23): 911-918.

Beyond Henssge's Formula: Using Regression Trees and a Support Vector Machine for Time of Death Estimation in Forensic Medicine.

Henssge's nomogram is a commonly used method to estimate the time of death. However, uncertainties arising from the graphical solution of the original mathematical formula affect the accuracy of the resulting time interval. Using existing machine learning techniques/tools such as support vector machines (SVMs) and decision trees, we present a more accurate and adaptive method for estimating the time of death compared to Henssge's nomogram. Using the Python programming language, we built a synthetic data-driven model in which the majority of the selected tools can estimate the time of death with low error rates even despite having only 3000 training cases. An SVM with a radial basis function (RBF) kernel and AdaBoost+SVR provided the best results in estimating the time of death with the lowest error with an estimated time of death accuracy of approximately ±20 min or ±9.6 min, respectively, depending on the SVM parameters. The error in the predicted time (tp[h]) was tp±0.7 h with a 94.45% confidence interval. Because training requires only a small quantity of data, our model can be easily customized to specific populations with varied anthropometric parameters or living in different climatic zones. The errors produced by the proposed method are a magnitude smaller than any previous result.

Simultaneous fatal poisoning of two victims with 4F-MDMB-BINACA and ethanol.

PURPOSE: Methyl-2-(1-(4-fluorobutyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (4F-MDMB-BINACA) is a newly emerging synthetic cannabinoid receptor agonists (SCRA) first described in 2018 in both Europe and the United States. Two fatal cases are reported caused by simultaneous consumption of 4F-MDMB-BINACA and ethanol. METHODS: The victims were brothers who were both found deceased after consuming 4F-MDMB-BINACA and ethanol. Post-mortem toxicological analyses of blood and urine were carried out by supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) and headspace gas chromatography with flame ionization detection (HS-GC-FID). RESULTS: The concentration of 4F-MDMB-BINACA in the postmortem blood was 2.50 and 2.34 ng/mL, and blood alcohol concentration was 2.11 and 2.49 g/L, respectively. CONCLUSION: According to the reported cases and reviews of the scientific literature, concurrent ethanol consumption should amplify the toxicity of SCRAs. The threshold SCRA concentration for fatal overdose can be estimated ng/mL level (0.37-4.1 ng/mL according to the reported cases) in cases in which 1.5-2.5 g/L of ethanol is present in the blood.

Fatal Overdose with the Cannabinoid Receptor Agonists MDMB-4en-PINACA and 4F-ABUTINACA: A Case Report and Review of the Literature.

A case of a 26-year-old male who died from consuming synthetic cannabinoid receptor agonists MDMB-4en-PINACA and 4F-ABUTINACA is reported. MDMB-4en-PINACA and 4F-ABUTINACA are potent synthetic cannabinoid receptor agonists (SCRAs). This is the first detailed reporting of MDMB-4-en-PINACA and 4F-ABUTINACA associated fatality, which can help the routine forensic work. The scientific literature on the symptoms associated with these substances are evaluated, along with the pharmacological properties and possible mechanism of death. A forensic autopsy was performed according to Recommendation No. R (99)3 of the Council of Europe on medico-legal autopsies. Histological samples were stained with hematoxylin and eosin (HE). Complement component C9 immunohistochemistry was applied to all heart samples. Toxicological analyses were carried out by supercritical fluid chromatography coupled with tandem mass spectrometry (SFC-MS/MS) and headspace gas chromatography with a flame ionization detector (HS-GC-FID). The literature was reviewed to identify reported cases of MDMB-4en-PINACA and 4F-ABUTINACA use. Autopsy findings included brain edema, internal congestion, petechial bleeding, pleural ecchymoses, and blood fluidity. Toxicological analyses determined 7.2 ng/mL of MDMB-4en-PINACA and 9.1 ng/mL of 4F-ABUTINACA in the peripheral blood. MDMB-4en-PINACA and 4F-ABUTINACA are strong, potentially lethal SCRA, and their exact effects and outcome are unpredictable.

Forensic assessment of a life-threatening penetrating abdominal air gun injury.

Air guns are considered mostly harmless by the public opinion, but projectiles shot from common air guns can penetrate skin and thus able to cause severe, even life-threatening injury. The prevalence of air gun injuries is constantly high, but severe injuries occur rarely. Forensic evaluation of air gun injuries can be challenging since the shot wound characteristics produced by combustion in case of firearm injuries are missing. Despite these difficulties, the topic of air gun injuries is mostly overlooked in forensic literature, and there are no guidelines available which can help the assessment of specific cases. A case of an air gun injury is reported, where the projectile penetrated the abdominal wall and created multiple bowel injury. The complex assessment of all available information (macroscopic and microscopic appearance of entrance wound, types of injuries, CT findings, and crime scene reconstruction) helped to uncover the truth about the circumstances of the injury.

Piercing the surface: A mechanical analysis of stabbing with household tools.

Estimating the applied power during a stabbing incident, or estimating the minimal force necessary to penetrate the body with a certain weapon is a challenging task in forensic practice. A thorough forensic evaluation of stabbing forces needs objective numerical experimental data. Stabbing tests of 12 different weapons - including knives, a pair of scissors, a fork, screwdrivers, a rasp, a corkscrew, and a utility knife blade - were performed with a Mecmesin MultiTest-dV material tester on pork loin and ballistic gel to estimate the stabbing forces and dynamics. Penetration force (Fp ) and maximal force (Fmax ) were recorded, and the registered force curves were analyzed. Fmax was 159.8-212.07 Newton (N), 30.56-30.58 N, 168.9-185.48 N for various knives; 171.39-190.43 N for the pair of scissors, 233.6 N for the fork; 532.65-562.65 N, 370.31-367.19 N and 314.51-432.89 N for various screwdrivers, 44.14-56.62 N for utility knife during pork loin stabbing. The butter knife, corkscrew and rasp were not able to penetrate the pork loin, and the curved fork bent during stabbing. The results prove that weapon characteristics greatly influence the force necessary for penetration. Maximal stabbing force depends mostly on tip sharpness, and the force sharply decreases after penetration occurs, which indicates that edge sharpness is not as important as tip characteristics during stabbing perpendicular to skin surface. The penetration force during stabbing with a pair of scissors is comparable to the penetration force of knives. Stabbing with screwdrivers generally needs larger force than average knives but depends greatly on screwdriver size.

Biomechanical study on the effect of atherosclerosis on the vulnerability of thoracic aorta, and it's role in the development of traumatic aorta injury.

Traumatic aorta injury (TAI) is the second most common traumatic cause of death preceded only by head injuries, being responsible for 5% to 30% of all mortalities in high-speed deceleration injuries. Multiple external factors might play a role such as impact speed, impact direction, occupant location, and presence or lack of restraining safety mechanism. Apart from these external factors, also human biological factors can influence its development. Based on the data of scientific literature, age clearly plays a role in suffering TAI, but the role of atherosclerosis-as a disease affecting the structure of the aorta-is unknown. Biomechanical properties of tissue samples of 104 aorta specimens removed during the autopsy from the posterior (Group 'A') and lateral wall (Group 'B') of descending aorta were analyzed. Specimens were examined by a Zwick/Roell Z5.0 biaxial tester. The Young's modulus (E (MPa)) was calculated using a linear regression procedure where the base of the elongation was the parallel length of the sample, the achieved maximal force (Fmax (N)), the elongation at the time of Fmax (Lmax (mm)), the force at the beginning of rupture (Fbreak (N)), the elongation at the time of Fbreak (Lbreak (mm)) were registered. Specimens were categorized based on macroscopic and microscopic appearance. In the posterior (A) samples the difference between Lbreak (p<0.001) and Lmax (p<0.001) was significant between the macroscopic group. Lbreak (p = 0.009) and Lmax (p = 0.003) showed similar pattern in the lateral (B) samples. Comparing the histological groups by the measured parameters (Fmax, Lmax, Fbreak, Lbreak) showed a significant difference in the means (p<0.001, p = 0.003, p<0.001 respectively). The study demonstrated that atherosclerosis decreases the resistance of the aorta. The rupture occurs at lower force (Fmax and Fbreak), and at shorter elongation (Lmax and Lbreak) in case of the presence of atherosclerosis. This effect is most substantial if calcification is present: the resistance of aorta affected by calcification is only two-thirds on average compared to aorta affected by the early phase of atherosclerosis. This phenomenon can be clearly explained by the weakening structure of the tunica intima.

Lethal case of myocardial ischemia following overdose of the synthetic cannabinoid ADB-FUBINACA.

The serious adverse effects of synthetic cannabinoids (SCB), the lack of human pharmacological data on SCBs, and the increasing number of SCBs with diverse structures are growing public health concerns. A fatal case of myocardial ischemia after ADB-FUBINACA overdose is reported. A 41-year-old male died after consuming a brown, powder-like drug. Autopsy revealed pallor in the left ventricle of the subendocardial two-third of the myocardium, and histological examination revealed early signs of myocardial ischemia: few wavy myocardial fibers, contraction band necrosis in the subendocardial region, and patchy subendocardial complement component 9 (C9) positivity. Toxicological analysis detected a high concentration of the indazole carboxamide derivative SCB ADB-FUBINACA (peripheral blood: 105 ng/mL) and a low concentration of the synthetic cathinone (SC) derivative stimulant N-ethylpentylone (NEP). The literature concerning ADB-FUBINCA overdoses is reviewed, and the possible mechanism of death and the cardiac effects of SCBs are discussed. Effects of SCBs are unpredictable, but they are potentially cardiotoxic, capable causing arrhythmias, cardiac hypertrophies, and myocardial ischemia. The cardiotoxicity of SCBs can be attributed to vasospasms, decreased myocardial contractility, and increased cardiac workload and oxygen demand. Based on the autopsy, histology, and toxicology, it could be reasonably suggested, that ADB-FUBINACA have been a significant contributor to the myocardial ischemia seen in histology. The mechanism of death was likely fatal arrhythmia induced by the patchy myocardial ischemia. Due to the low concentration of NEP, it's role in the fatal outcome is improbable.