Sudden death after facial impacts: Is the brainstem involved?

Three deaths following facial impacts in the presence of witnesses and resulting in brain lesions that were visualized only on pathological examination were studied at the forensic medicine institute of Marseille. Craniofacial impacts, even of low intensity, received during brawls may be associated with brain lesions ranging from a simple knock-out to fatal injuries. In criminal cases that are brought to court, even by autopsy it is still difficult to establish a direct link between the violence of the impact and the injuries that resulted in death. During a facial impact, the head undergoes a movement of violent forced hyperextension. Death may thus be secondary to the transmission of forces to the brain, either by a mechanism involving nerve conduction that may be termed a reflex mechanism (for example by vagal hyperstimulation) or by injury to the central nervous system (axonal damage). In such situations, autopsy does not make it possible to determine the cause of death, but only to suspect it in a context of voluntary violence in the presence of witnesses, with or without violent injury observed on external examination or on superficial incisions to determine the extent of bruises or hematoma. Systemic and comprehensive investigation involving pathology and toxicology is essential in any medicolegal case for positive interpretation and discrimination of other causes of death.

Metal artifact reduction for intracranial projectiles on post mortem computed tomography.

PURPOSE: To compare the image quality of cranial post-mortem computed tomography (CT) obtained with and without projection-based single-energy metal artifact reduction (SEMAR) in cadavers with intracranial metallic ballistic projectiles. MATERIALS AND METHODS: From January 2017 to January 2018, cadavers with ballistic projectile head wounds with metal fragments and without massive head destruction were investigated using post-mortem CT. All subjects underwent CT using a conventional iterative reconstruction (IR) and SEMAR. To evaluate the impact of metallic artifacts, the total intracranial area (TA), non-interpretable zone (NIZ), disturbed interpretation zone (DZ), and artifact total surface (ATS) were delineated. Two independent readers identified extra-axial hemorrhage (EAH) and subarachnoid hemorrhage (SAH). Autopsy reports were used as the standard of reference. RESULTS: Eleven corpses (10 males, 1 female; mean age, 62.8±17.9 [SD] years) were evaluated. SEMAR showed a significant decrease in the ATS ratio with respect to conventional IR (72.1±26.1 [SD] % [range: 26.8-99.1] vs. 86.4±17.8 [SD] % [range: 37.2-100]; P<0.001) and NIZ/TA ratios (11.6±8.26% [range: 0.95-33.4] versus 42.5±30.5% [range: 3.86-100]; P<0.001). The interobserver reproducibility in diagnosing EAH and SAH was excellent with conventional IR (0.82) and good with SEMAR (0.75). SEMAR reduced uncertain diagnoses of EAH in 7 subjects for Reader 1 and in 6 for Reader 2, but did not influence the diagnosis of SAH for either reader. CONCLUSION: SEMAR reduces the influence of metallic artifacts and increases the confidence with which the diagnosis of EAH can be made on post-mortem CT.

[Forensic examination of sexual assault victims: Medical aspects and associations with the legal outcomes]. / Examen médicolégal des victimes d'agression sexuelle : caractéristiques et liens avec les suites judiciaires.

OBJECTIVES: To describe the medical and legal characteristics of sexual assault victims and to highlight which aspects of the medical examination may be associated with a conviction of the alleged offender. METHODS: This study included all women who consulted to the center for the victims of sexual assault in Nancy between 2008 and 2012 and who filed a complaint. Associations were evaluated with a logistic regression trying to explain the presence of a conviction at the end of the legal proceeding. RESULTS: Three hundred seventy-six victims were included. Following aspects were associated with a reduced probability of conviction: the use of psychoactive substances, the prescription of an antiretroviral therapy and the presence of more than one assailant. The prescription of pain killers were contrarily related to the conviction of an assailant. CONCLUSION: A detailed description, an interpretation of the physical injuries and the prescription of toxicological tests if needed are decisive in the outcome of the legal proceedings of victims of sexual assault. The education of populations at risk and the accompanying of the victims can reduce the delay of care and optimize the collection of evidence.

Poly(ethylene carbonate)s, part II: degradation mechanisms and parenteral delivery of bioactive agents.

The degradation and drug carrier properties of poly(ethylene carbonate) (PEC) were investigated in vitro and in rats and rabbits. PEC was found to be specifically degraded in vivo and in vitro by superoxide radical anions O2-*, which are, in vivo, mostly produced by inflammatory cells. No degradation of PEC was observed in the presence of hydrolases, serum or blood. PEC is biodegraded by surface erosion without significant change in the molecular weight of the residual polymer mass. The non-hydrolytic biodegradation by cells producing O2-* is unique among the polymers used as biodegradable drug carriers. The main degradation product of PEC in aqueous systems is ethylene glycol, formed presumably by hydrolysis of ethylene carbonate. The splitting off of a five-membered ring structure from the polymer chain indicates a chain reaction mechanism for the biodegradation. PEC is a suitable drug carrier, particularly for labile drugs. Using human interleukin-3 and octreotide as model drugs, surface erosion of the PEC formulations was indicated by a 1:1 correlation between drug release and polymer mass loss.

Assessment of the phototoxic potential of compounds and finished topical products using a human reconstructed epidermis.

The goal of this study was to design a model system for the assessment of phototoxic potential using a human reconstructed epidermis (HRE, SkinEthic Laboratories, Nice, France), by testing some representative phototoxic (P) and non-phototoxic (NP) compounds and finished topical products. The tissue response to 24-h application of 5-5000 microg/mL of the test agents in the presence and absence of UVA light was analyzed in terms of viability (Lactate Dehydrogenase release), pro-inflammatory activity (IL-8 release and mRNA expression) and morphology (histopathology). 8-Methoxypsoralen (P) and promethazin (P), but not sodium lauryl sulfate (NP) produced cytotoxicity concentration-response curves significantly different between irradiated and nonirradiated tissues. Only irradiated tissues showed morphological damage. Application of tetracyclin (P) in the culture medium, but not topically, induced similar signs of phototoxicity. 6-Methylcoumarine (weak P) was not cytotoxic, yet it increased IL-8 release and mRNA expression only following UVA irradiation. PUVA therapy creams containing 1% 8-Methoxy-psoralen (P) or coal tar (P) decreased viability and induced histologic damage in UVA-exposed tissues. In conclusion, the phototoxic potential of the tested agents was correctly predicted by using a tiered strategy that involves determining cytotoxicity, production of IL-8, and morphological damage following exposure of the HRE to the compounds and UVA light.

Use of human skin equivalent Apligraf for in vitro assessment of cumulative skin irritation potential of topical products.

The main goal of the present study was to investigate the response of the human skin equivalent Apligraf in vitro to the application of irritant substances and its predictivity as a screening tool for cumulative skin irritant potential in humans. Vaseline, calcipotriol, trans-retinoic acid, and sodium lauryl sulfate were applied to Apligraf in vitro for 24 h. Cell viability (lactate dehydrogenase leakage), release and mRNA expression of the proinflammatory cytokines IL-1alpha and IL-8, and morphological changes were assessed. The same products were applied to 30 healthy volunteers in a double-blind, randomized, vehicle-controlled within-subject study. The skin reactions after repeated 24-h applications over 3 weeks under Finn chamber patches were monitored by visual scoring and biophysical methods (trans-epidermal water loss, chromametry, and blood flow). Sodium lauryl sulfate was cytotoxic to Apligraf, and increased the release and expression of cytokines at low (0.2%, 0. 4%), but not at high (0.8%, 1%) concentrations. It induced severe irritancy in vivo. Trans-retinoic acid increased the expression and release of cytokines with no detectable cytotoxicity and showed moderate irritancy in humans. Although calcipotriol did neither affect cell viability nor the production of cytokines, it induced morphological signs of irritation and was mildly irritant for healthy volunteers. Vaseline was innocuous in vivo and induced no changes in Apligraf. In conclusion, the cumulative skin irritation potential of the tested products could be predicted with Apligraf in a sensitive and specific manner, by monitoring cytotoxicity, proinflammatory cytokines, and morphological changes.

Predictivity of an in vitro model for acute and chronic skin irritation (SkinEthic) applied to the testing of topical vehicles.

An in vitro human reconstructed epidermis model (SkinEthic) used for screening acute and chronic skin irritation potential was validated against in vivo data from skin tolerability studies. The irritation potential of sodium lauryl sulfate (SLS), calcipotriol and trans-retinoic acid was investigated. The in vitro epidermis-like model consists of cultures of keratinocytes from human foreskin on a polycarbonate filter. The modulation of cell viability, the release and gene expression of proinflammatory cytokines, interleukins 1alpha and 8, and morphological changes were evaluated during 3 days as endpoints representative for an inflammatory reaction. The cumulative irritation potential of the topical products was evaluated in a human clinical study by visual scoring and biophysical measurement of inflammatory skin reaction after repeated 24 h applications over 3 weeks under Finn chamber patches. All topical products that were nonirritating in the human study were noncytotoxic and did not induce cytokine expression in the in vitro acute model (day 1 exposure). All irritating controls exhibited specific cell viability and cytokine patterns, which were predictive of the in vivo human data. The ranking of mild to moderate skin irritation potential was based on the lack of cytotoxicity and the presence of cytokine patterns including gene expression specific for each irritant, using the chronic in vitro model (up to 3 days exposure). The human reconstructed epidermis model SkinEthic was shown to be a reliable preclinical tool predicting the irritation potential of topical products. Moreover, it is a useful model in a two-step tiered strategy for screening acute and chronic irritation potential for the selection of vehicles for new topical drugs.

Blood glucose control on Sunday in IDDM patients: intensified conventional insulin therapy versus continuous subcutaneous insulin infusion.

We have assessed the capacity of continuous subcutaneous insulin infusion (CSII) to maintain good blood glucose metabolic control on Sundays, when waking is delayed, with reference to intensified conventional insulin therapy by multiple daily injections (MDI). The study lasted 3 weeks, including 3 week-ends. A total of 20 IDDM patients were selected for metabolic control: ten were treated by CSII and ten by MDI. Blood glucose was determined at least three times a day (fasting on waking, pre-lunch and pre-dinner). The times of blood glucose determinations and their values were recorded in a memory reflectance meter. Waking, the first blood glucose measurement and the first insulin injection (MDI) or bolus (CSII) were about 1 h later on Sundays than on a weekday (44 +/- 4 min in MDI group, P < 0.04; and 59 +/- 7 min in CSII group, P < 0.02). The times of the pre-lunch and pre-dinner blood glucose determinations were not significantly different. The mean waking and pre-lunch blood glucose values of the MDI group were higher on Sundays (11.5 +/- 3.8 and 9.7 +/- 4.5 mmol/l) than on weekdays (8.7 +/- 2.3 and 7.1 +/- 2.5 mmol/1)(P < 0.01). The pre-prandial blood glucose levels of the CSII group on Sundays and weekdays were not statistically different at any time. Changes in the waking time and the subsequent delay in the first insulin bolus on Sunday may alter blood glucose control in patients on MDI, but CSII allows such changes without any glycemic side effects.

In vitro tolerability of human nasal mucosa: histopathological and scanning electron-microscopic evaluation of nasal forms containing Sandostatin.

An in vitro human nasal model was developed as a tool to study the local tolerability of nasal powder forms using excised nasal mucosa in a diffusion chamber. The suitability of this model was tested using Sandostatin (SMS) an octapeptide analog of somatostatin, as a reference drug enhanced by Avicel (microcrystalline cellulose) or lactose (100 mesh). The standard nasal spray vehicle was taken as a harmless control and 1% chenodeoxycholate (CDC) as a harmful control in terms of local tolerability. The extent of peptide permeation was determined by measuring SMS concentration in the receiving chamber. The labeling of SMS was detected by immunoperoxidase staining on cross sections. The local tolerability for all tested forms was assessed by histopathological examination and scanning electron microscopy. The apparent permeation coefficient allowed us to rank the absorption of the tested drug forms as Avicel > spray = lactose > 1%CDC. For all formulations, SMS was detected in the epithelium. No changes of the nasal mucosa could be observed with Avicel, lactose or nasal spray vehicle in the presence or absence of SMS. 1%CDC with or without drug showed an immediate destruction of the nasal epithelium. The validation of this in vitro model using human nasal mucosa will be further discussed as a tool for assessing the local tolerability of intranasally applied test substances.

Respiratory symptoms and airway responsiveness in apparently healthy workers exposed to flour dust.

Our aim was to measure the levels of exposure to wheat flour dust in a modern industrial bakery, and to assess the relationship between respiratory symptoms, sensitization to wheat flour antigens and airway responsiveness in the workforce. Forty four flour-exposed male workers and 164 unexposed controls were examined. Inspirable dust concentrations were measured using personal samplers. Respiratory symptoms were assessed by questionnaire, sensitization to wheat flour antigens by skin-prick tests, and methacholine airway challenge (MAC) test using an abbreviated method. Subjects were labelled MAC+ if forced expiratory volume in one second (FEV1) fell by 20% or more. The linear dose-response slope (DRS) was calculated as the percentage fall in FEV1 at last dose divided by the total dose administered. Inspirable dust concentrations were within acceptable limits in all working areas but one. The proportion of subjects with one or more symptoms and with airway hyperresponsiveness was significantly greater among flour-exposed workers than among controls. Using logistic or linear regression analysis, airway responsiveness was found to be strongly related to working at the bakery and to the baseline level of lung function. A positive skin-prick test was found in only 11% of flour-exposed workers and 6% of controls. In conclusion, our data show that despite exposure to relatively low concentration levels of inspirable flour dust, subjects working in the baking industry are at risk of developing both respiratory symptoms and airway hyperresponsiveness.

Self-monitoring of blood glucose and insulin dose alteration in type 1 diabetes mellitus.

The purpose of this study was to evaluate the relationship between proper use of self-monitoring of blood glucose (SMBG) including knowledge and application of specific algorithms and metabolic control in a group of randomly selected insulin-dependent diabetic patients. We studied 80 patients responding to the following criteria: intensive conventional insulin therapy and SMBG for at least 6 months using a reflectance meter, and previous 5-day hospital education period. The practical knowledge of the guidelines was evaluated by a questionnaire simulating 8 metabolic situations. A computer analysis of the SMBG data for the 3 months preceding the study allowed us to evaluate patient compliance with SMBG (number of blood glucose determinations) and patients' application of the guidelines (percentage of insulin doses modified according to the guidelines). Fifty-nine patients (79%) were compliant with SMBG and had better metabolic control than the non-compliers (HbA1c: 6.7 +/- 1.1% vs. 7.5 +/- 1.9, P < 0.05). Twenty-eight out of the 59 compliant subjects had good knowledge of the guidelines but without patent improvement of glycemic control. Seventeen of these 28 correctly used the algorithms to modify insulin dosage; their HbA1c levels were lower than those of the 11 patients who did not use the algorithms (6.1 +/- 0.9 vs. 7.1 +/- 0.9%, P < 0.05). The percentage of insulin dose modification consistent with the guidelines and the level of HbA1c was negatively correlated in the good-knowledge group. The conclusion is that good metabolic control is linked not only with the degree of knowledge but also with the application of this knowledge.

Overview of quantitative methods in toxicologic pathology.

Today's stringent requirements for new drugs make it necessary to prove their safety by the use of ever more refined techniques, in particular methods to quantify morphologic findings to determine accurately, for example, the highest non-toxic dose in animal studies or to correlate morphological effects with other parameters. Increased cell proliferation due to subtle cytotoxicity can lead to epigenetic tumorigenicity, which can be recognized early by cytokinetic investigations using bromodeoxyuridine (BrdU) incorporation and/or proliferating cell nuclear antigen (PCNA) expression, or by malignancy-associated nuclear texture changes. Morphometric criteria are also used to increase diagnostic accuracy in experimental animal pathology. The various applications of morphometry in toxicopathology are reviewed, and examples illustrating these applications are presented, most of them unpublished.

In situ analysis of adenohypophysis proliferative activity in beagle dogs. Preliminary results.

In order to establish control data on adenohypophysis cell cycle in beagle dogs, two different approaches were used. In the first approach, the adenohypophysis mitotic index (percentage of cells in mitosis: MI) was determined using pituitary glands from 50 control beagle dogs, 10 to 25 months old, from retrospective regulatory safety assessment studies. We found that the MI in males was 0.024 +/- 0.007% and in females 0.068 +/- 0.019%. The second approach involved the determination of the adenohypophysis cell fraction in S phase by means of bromodeoxyuridine (BrdU) anti-BrdU method in 16 control beagle dogs, 8 to 20 months old, from ongoing safety assessment studies. We found that the BrdU labeling index (percentage of BrdU-positive cells per total number of cells: BrdU LI) was 0.053 +/- 0.009% in males and 0.059 +/- 0.015% in females. Analysis of our data indicated that the results obtained from the BrdU LI were more reliable (coefficient of variation [CV] less than 0.07) compared to those obtained from the MI (CV greater than 1.4). No clear difference was found between male and female beagle dogs, regarding adenohypophysis cell proliferation. In both studies, adenohypophysis cell proliferation was found to be age-dependent, with the highest value in immature dogs. No correlation between estrus cycle in females and adenohypophysis cell proliferation was noted.

[Psychological aspects of remission induced by intensive insulin therapy in type I diabetes. A retrospective study of 44 patients]. / Aspects psychologiques de la rémission induite par une insulinothérapie intensive dans le diabète de type 1. Etude rétrospective de 44 patients.

The psychological consequences of induced remission of type 1 diabetes, have not yet been investigated thoroughly. We studied the psychological status of 44 patients (16 women, 28 men), age 21 years +/- 8 months (mean +/- SD), whose remission lasted 12 +/- 9 months. Patients' psychological reactions were analyzed retrospectively, using a 20 items standardized questionnaire, investigating 3 successive periods: 1) initial intensive insulin therapy; 2) remission; 3) permanent insulin therapy. 8% of the subjects only considered the remission phase useless, whereas 49% expressed a positive appraisal. Hope was predominant feeling, 25% of the patients believing in a completed recovery of diabetes. Perceived therapeutic constraints were, in decreasing order: regimen, way of life's regularity, self monitoring of blood glucose. When starting permanent insulin therapy, opposite answers were given: 49% negative feelings, 33% positive feelings and 18% ambivalent feelings. During this period, insulin injections represented the major therapeutic constraint, followed by self monitoring of blood glucose. To summarize, induced remission does not appear to be psychologically harmful and is considered useful by a large majority of patients. Effective psychological support has to be offered to help those patients to cope with their irrational hopes of healing and to dampen their deception at the end of the remission period.

A brief review of modern toxicologic pathology in regulatory and explanatory toxicity studies of chemicals.

Macroscopic and histologic evaluation of animal studies for general toxicity and carcinogenicity are cornerstones of the risk assessment of new chemical entities. Standard toxicopathologic evaluation is mainly based on the study of paraffin sections stained with hematoxylin and eosin. There are, however, a number of new approaches and techniques which have improved the objectivity of evaluation and the accuracy of cell identification, and provided deeper insight into the molecular biological mechanisms of toxicity and carcinogenicity. Such approaches include the standardization of the nomenclature, the creation of data banks for morphological alterations, the use of computers to register pathological findings in toxicity studies and to statistically evaluate incidences, and the use of morphometry. Other modern techniques are immunohistochemistry, in situ hybridization, and the assessment of cell kinetics.

Morphologic and immunohistochemical characterization of Leydig cell tumor variants in Wistar rats.

During a routine long-term drug safety study, lasting approximately 2 1/2 yr, male Wistar rats, treated with a prolactin-inhibiting compound, developed an excess of Leydig cell tumors (LCTs). Most tumors were typical for the rat but a small number showed an unusual variation and some appeared malignant. The variation consisted of glandular and/or tubular structures within the tumor mass which occasionally anastomosed and contained an eosinophilic periodic-acid Schiff (PAS) positive material. In a few of these variants, malignant features such as cellular atypia, capsular, and lymphatic invasion and necrosis were seen. No metastases were detected. Detailed morphological and immunohistochemical investigations were conducted in order to establish the cell of origin of these variants. Glandular/tubular structures were found to stain with varying intensity for vimentin and cytokeratin, but were always negative for beta-tubulin. The results indicated that the cell of origin of these LCT variants was indeed the Leydig cell and that glandular and/or tubular structures within LCTs represented a form of Leydig cell metaplasia.

Reliability of self-monitoring of blood glucose by CSII-treated patients with type I diabetes.

The reliability of patient-generated data from self-monitoring of blood glucose (SMBG) was studied in 14 patients with type I (insulin-dependent) diabetes mellitus treated by continuous subcutaneous insulin infusion (CSII) (7 women, 7 men). The reflectance meters (Glucometer I, Ames, Elkhart, IN) used by the patients were replaced for a period of 21 days by memory-reflectance meters; patients were unaware of the memory capacity of the new meters and were instructed to continue their practice of recording the meter readings in their logbook. This study compares the data recorded in the memory-reflectance meters with those reported in the logbook. The number of SMBG measurements was different in 11 patients (differences ranging from 2 to 66). Mean glycemia was similar (8.23 +/- 0.36 mM in logbook vs. 8.49 +/- 0.48 mM in memory-reflectance meters), but both the M value and mean amplitude of glycemic excursions (MAGE) index were lower when calculated from logbook data (38 +/- 5 vs. 48 +/- 7 mM, P less than .05 and 6.91 +/- 0.43 vs. 7.72 +/- 0.52 mM, respectively; P less than .05). Overreporting (addition of phantom values in logbook) and underreporting (omission of SMBG measurements from logbook) indexes were 19 +/- 7 and 12 +/- 3%, respectively. Precision (percent of identical values in logbook and in memory-reflectance meters at the corresponding time) was 77 +/- 6.8%. The number of SMBG measurements recorded in the memory-reflectance meter was negatively correlated with glycosylated hemoglobin [HbA1c; (r = -.85, P less than .001)], whereas overreporting was positively correlated with HbA1c (r = .76, P less than .01).

[Impotence in the diabetic]. / L'impuissance chez le diabétique.

Two-hundred-and-two impotent diabetic patients gave their consent to be investigated. Impotence is linked to diabetes mellitus in 58.9% of patients so all the other etiologies have to be systematically eliminated. Neuropathy or arteriopathy, when isolated, are found with the same frequency, but these 2 etiologies are often associated (47 patients). No statistical difference between IDDM and NIDDM was found. Mercury strain gauge plethysmography and venous occlusion coupled to ECG allows detection of arterial lesions in diabetic impotence. Patients agreed to submit to all of the various therapeutic possibilities. Combination of alpha-blockade and good glycemic control induced the best results.