Immune Checkpoint Inhibitor-induced Bilateral Vestibulopathy.

Checkpoint inhibitors (CPI), such as anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4antibodies cause serious, rarely fatal immune-related adverse events (irAE) potentially in all organ systems. Neurological immune-related adverse events occur in 1%-5% of patients on CPI therapy and may present with dramatic clinical symptoms of the sensory organs. After exclusion of other causes, a high-dose treatment with corticosteroids is crucial for clinical outcome with lower risk of sequelae. We present a severe case of CPI-related ongoing and most likely irreversible bilateral vestibular affection. A 59-year-old male melanoma patient with brain metastasis undergoing immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies developed severe debilitating rotatory vertigo. Bilateral vestibulopathy was diagnosed as a result of the CPI therapy after a thorough analysis including magnetic resonance imaging, laboratory tests of blood and cerebrospinal fluid as well as neurological and otorhinolaryngology examinations. The vertigo improved slightly during a 10-day course of steroid therapy and intensive balance training but did not resolve completely.

Analysis of the tonal sound generation during phonation with and without glottis closure.

The human phonation is characterized by periodical oscillations of the vocal folds with a complete glottis closure. In contrast, a glottal insufficiency (GI) represents an oscillation without glottis closure resulting in a breathy and weak voice. In this study, flow-induced oscillations of silicone vocal folds were modeled with and without glottis closure. The measurements comprised the flow pressure in the model, the generated sound, and the high-speed footage of the vocal fold motion. The analysis revealed that the sound signal for vocal fold oscillations without closure exhibits a lower number of harmonic tones with smaller amplitudes compared to the case with complete closure. The time series of the pressure signals showed small and periodical oscillations occurring less frequently and with smaller amplitude for the GI case. Accordingly, the pressure spectra include fewer harmonics similar to the sound. The analysis of the high-speed videos indicates that the strength of the pressure oscillations correlates with the divergence angle of the glottal duct during the closing motion. Physiologically, large divergence angles typically occur for a pronounced mucosal wave motion with glottis closure. Thus, the results indicate a correlation between the intensity of the mucosal wave and the development of harmonic tones.

CHARGE and Kabuki syndromes: a phenotypic and molecular link.

CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding gene CHD7. Kabuki syndrome, another developmental disorder, is characterized by typical facial features in combination with developmental delay, short stature, prominent digit pads and visceral abnormalities. Mutations in the KMT2D gene, which encodes a H3K4 histone methyltransferase, are the major cause of Kabuki syndrome. Here, we report a patient, who was initially diagnosed with CHARGE syndrome based on the spectrum of inner organ malformations like choanal hypoplasia, heart defect, anal atresia, vision problems and conductive hearing impairment. While sequencing and MLPA analysis of all coding exons of CHD7 revealed no pathogenic mutation, sequence analysis of the KMT2D gene identified the heterozygous de novo nonsense mutation c.5263C > T (p.Gln1755*). Thus, our patient was diagnosed with Kabuki syndrome. By using co-immunoprecipitation, immunohistochemistry and direct yeast two hybrid assays, we could show that, like KMT2D, CHD7 interacts with members of the WAR complex, namely WDR5, ASH2L and RbBP5. We therefore propose that CHD7 and KMT2D function in the same chromatin modification machinery, thus pointing out a mechanistic connection, and presenting a probable explanation for the phenotypic overlap between Kabuki and CHARGE syndromes.

CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance.

Heterozygous loss of function mutations in CHD7 (chromodomain helicase DNA-binding protein 7) lead to CHARGE syndrome, a complex developmental disorder affecting craniofacial structures, cranial nerves and several organ systems. Recently, it was demonstrated that CHD7 is essential for the formation of multipotent migratory neural crest cells, which migrate from the neural tube to many regions of the embryo, where they differentiate into various tissues including craniofacial and heart structures. So far, only few CHD7 target genes involved in neural crest cell development have been identified and the role of CHD7 in neural crest cell guidance and the regulation of mesenchymal-epithelial transition are unknown. Therefore, we undertook a genome-wide microarray expression analysis on wild-type and CHD7 deficient (Chd7 (Whi/+) and Chd7 (Whi/Whi)) mouse embryos at day 9.5, a time point of neural crest cell migration. We identified 98 differentially expressed genes between wild-type and Chd7 (Whi/Whi) embryos. Interestingly, many misregulated genes are involved in neural crest cell and axon guidance such as semaphorins and ephrin receptors. By performing knockdown experiments for Chd7 in Xenopus laevis embryos, we found abnormalities in the expression pattern of Sema3a, a protein involved in the pathogenesis of Kallmann syndrome, in vivo. In addition, we detected non-synonymous SEMA3A variations in 3 out of 45 CHD7-negative CHARGE patients. In summary, we discovered for the first time that Chd7 regulates genes involved in neural crest cell guidance, demonstrating a new aspect in the pathogenesis of CHARGE syndrome. Furthermore, we showed for Sema3a a conserved regulatory mechanism across different species, highlighting its significance during development. Although we postulated that the non-synonymous SEMA3A variants which we found in CHD7-negative CHARGE patients alone are not sufficient to produce the phenotype, we suggest an important modifier role for SEMA3A in the pathogenesis of this multiple malformation syndrome.

Identification and characterization of FAM124B as a novel component of a CHD7 and CHD8 containing complex.

BACKGROUND: Mutations in the chromodomain helicase DNA binding protein 7 gene (CHD7) lead to CHARGE syndrome, an autosomal dominant multiple malformation disorder. Proteins involved in chromatin remodeling typically act in multiprotein complexes. We previously demonstrated that a part of human CHD7 interacts with a part of human CHD8, another chromodomain helicase DNA binding protein presumably being involved in the pathogenesis of neurodevelopmental (NDD) and autism spectrum disorders (ASD). Because identification of novel CHD7 and CHD8 interacting partners will provide further insights into the pathogenesis of CHARGE syndrome and ASD/NDD, we searched for additional associated polypeptides using the method of stable isotope labeling by amino acids in cell culture (SILAC) in combination with mass spectrometry. PRINCIPLE FINDINGS: The hitherto uncharacterized FAM124B (Family with sequence similarity 124B) was identified as a potential interaction partner of both CHD7 and CHD8. We confirmed the result by co-immunoprecipitation studies and showed a direct binding to the CHD8 part by direct yeast two hybrid experiments. Furthermore, we characterized FAM124B as a mainly nuclear localized protein with a widespread expression in embryonic and adult mouse tissues. CONCLUSION: Our results demonstrate that FAM124B is a potential interacting partner of a CHD7 and CHD8 containing complex. From the overlapping expression pattern between Chd7 and Fam124B at murine embryonic day E12.5 and the high expression of Fam124B in the developing mouse brain, we conclude that Fam124B is a novel protein possibly involved in the pathogenesis of CHARGE syndrome and neurodevelopmental disorders.

[Aquatic fatalities--a systematic retrospective analysis]. / Ertrinkungstod--eine systematische retrospektive Untersuchung.

In a retrospective analysis of the autopsy material (n = 5,767) of the Institute of Legal Medicine of the Hanover Medical School covering the period of 1998-2007, all aquatic fatalities were evaluated, categorized and systematically compared under epidemiological and forensic criteria. The total of 156 cases of death by drowning (2.7 % of all autopsies) included 38 bathtub drownings and 28 deaths in the water for which no pathological anatomical cause of death could be reliably demonstrated. A control group (n = 221) was investigated for the presence of aqueous liquid in the sphenoid sinuses and compared with the findings of the drowning cases without signs of putrefaction. About 16 % of the control cases had fluid in the sphenoid sinuses compared with 57.6 % in the drowning group. Most of the drowning victims were men (60.9 %), whereas in the group of bathtub drownings the majority were women. More than half of the drowning cases (n = 89) could be classified as accidents. The individual groups showed a different incidence of findings associated with drowning.

Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) in human serum by liquid chromatography-tandem mass spectrometry.

The current paper describes a validated method for the detection and quantification of naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018), an ingredient of a herbal mixture called "Spice", by means of HPLC-ESI-MS-MS in serum. Lower limit of detection and lower limit of quantification were 0.07 and 0.21 ng/ml, respectively. In 2 subjects who consumed ca. 50 µg/kg of JWH-018 by smoking, the active ingredient was detected by means of the described method. Thereby, the serum concentrations reached values of approx. 10 ng/ml and dropped within 3 h very fast (<10% of the measured maximum concentrations).

[Analysis of clinical forensic examination reports on sexually abused children]. / Analyse der Untersuchungsergebnisse bei sexuellem Kindesmissbrauch.

Clinical forensic examinations of children suspected of having been sexually abused are increasingly part of the routine of medicolegal institutes. The findings collected from 2005 until 2007 at the Institute of Legal Medicine of the Hanover Medical School were analysed retrospectively. Altogether, 91 children (74 females, 17 males, mean age 8.7 years) were examined. In 87.9% of the cases, the examination had been ordered by the police. In 73.6%, the victim knew the suspected perpetrator well or he was a family member. 40.7% of the children were seen within 72 hours after the alleged abuse. 12.1% of the children had extragenital lesions. In 27% of the victims, marked anogenital injuries were found, which were characteristic of sexual abuse in 9%. In 18 cases (20.2%), swabs were taken for spermatozoa detection. 3 of 17 vaginal smears showed positive test results for sperm up to 21 hours after the incident. No spermatozoa could be detected in 4 anal and 2 oral swabs as well as in one swab taken from the skin of the victim's thigh. In summary, the evaluation shows that early clinical forensic examination of children suspected of having been sexually abused is crucial to document evidence that is highly significant for the investigation and court proceedings. Often suspected sexual child abuse cannot be proved by medical findings alone. Of course, the absence of anogenital injuries does nor rule out sexual abuse.

Analysis of clinical forensic examination reports on sexual assault.

Medical-forensic examination of sexual assault victims and alleged offenders is a common task of many forensic institutes. In the current study, the results from samples taken at the Institute of Legal Medicine, Hanover Medical School, during a period from 2005 to 2007 were retrospectively evaluated. In total, 292 victims (283 females and nine males) and 88 suspects were examined. At the time of the assault, 41.8% of the victims and 43.2% of the alleged perpetrators were under the influence of alcohol. Injuries were found in 84.9% of the victims and 39.8% of the suspects. Thirty victims (10.3%) reported having been choked or strangled. Cytology was performed in 218 victims. In 81 cases (38.0%), sperm could be detected in vaginal swabs up to 3 days post-assault. In seven (18.9%) out of 37 anal samples, evidence of sperm could be found 24 h post-assault. None of 22 oral samples was positive for sperm. Out of 301 sexual assault cases, 171 could be proved by means of medical-forensic examination. In summary, our evaluation shows that an early medical-forensic examination of both victim and suspect can secure numerous medical findings. Furthermore, persons intoxicated by alcohol, handicapped persons and persons with psychiatric disorders are more vulnerable to become a sexual assault victim.

[Clinical forensic examination findings in assault cases among adolescents]. / Untersuchungsergebnisse bei Gewaltdelikten unter Jugendlichen.

Child and youth criminality has risen markedly over the past 25 years and causes increasing concern to the general public. The clinical forensic examination cases of youth violence victims examined at the Institute of Legal Medicine of the Hanover Medical School and its Oldenburg Branch between 1999 and 2008 were retrospectively analyzed. In all, 55 adolescents (37 females, 18 males; median age 15.5 years) were examined. In most cases the suspect was a close (40.0%) or passing (23.6%) acquaintance. 16 assaults were committed by two or more adolescents jointly. Most of the juveniles were victims of sexual assaults (56.4%). In 15 victims of sexual offences (51.7%) diagnostic findings were obtained on the basis of anogenital injuries and/or the presence of sperm. In summary, the analysis shows that adolescents frequently become victims of sexual assault. In addition, youth violence is often committed in a group.

[Practicability of the mobile one-finger scanner Cross Match MV5 in fingerprinting of corpses: are mobile fingerprinting scanners suitable for use in mass disasters?]. / Praktikabilität des mobilen Einzelfingerscanners Cross Match MV5 in der Leichendaktyloskopie: Sind die mobilen Einzelfingerscanner für den Einsatz bei Massenkatastrophen geeignet?

Dactyloscopy is a special field in the police records department and a suitable means for identifying unknown dead persons as well as solving crimes by taking fingerprints from living persons. Apart from the conventional methods of dactyloscopy, mobile and more compact instruments are to facilitate taking prints of fingertips and palms also at the scene of mass disasters. In the presented study, living persons and corpses were examined to find out the possible uses and limits of mobile one-finger scanners. The concrete issue of the investigation was whether the mobile one-finger scanner Cross Match MV5 is suitable for application in mass disasters. The device was used in 12 corpses aged 5 weeks to 76 years (mean postmortem interval 5.5 days) and in 28 living persons aged 6 weeks to 87 years. In summary, the scanner produced qualitatively good prints in all age groups of the living individuals. In the corpses, the prints were only partly evaluable. In particular, fingers and fingertips with soot blackening and livid discoloration were difficult to analyse. Postmortem rigidity also complicated the handling of the scanner. In fresh corpses, the scanner can be recommended without reservation. Even if the epidermis was detached, the scanner was able to produce evaluable prints of the dermis of the hypothenar.

[Postmortem dismemberment/mutilation--medicolegal and criminalistic evaluation of the autopsies performed by the Institute of Legal Medicine at the Hanover Medical School]. / Leichenzerstückelungen/-verstümmelungen --differenzierte rechtsmedizinische und kriminalistische Aufarbeitung des Sektionsgutes des Institutes für Rechtsmedizin der Medizinischen Hochschule Hannover.

Among all the autopsies performed by the Institute of Legal Medicine at the Hanover Medical School between 1978 and 1998. 16 cases of postmortem dismemberment/mutilation were evaluable under criminalistic and medicolegal aspects. In the present study, particular attention was paid to the psychosocial circumstances of the perpetrator's and victim's lives and also to the classification of the different types of postmortem dismemberment/mutilation illustrated by case reports. Apart from an unfavourable personal life situation at the time of the offence, essential predisposing factors were: poor integration in society and family, occupational problems, drug abuse and mental diseases. As the interactions between these factors differ in every single case and may be combined with other factors, the analysis of such homicides should always be based on the assessment of the individual case.

The lingual tonsillar hyperplasia in relation to unanticipated difficult intubation: is there any relationship between lingual tonsillar hyperplasia and tonsillectomy?

The lingual tonsillar hyperplasia (LTH) is a rare and dangerous condition of the upper airway because it is one of several risks during intubation which can cause serious complications like cardiac arrest, cerebral anoxia, and death. The LTH is rarely detectable during a routine oropharyngeal examination. The lingual tonsil is of particular interest to forensic medicine to assess cases with malpractice in connection with intubation difficulties. Our study looked at how often autopsy specimens had enlarged lingual tonsils and whether any relationship existed between LTH and tonsillectomies. In total, 497 corpses were examined. Only in 16 cases (3.2%), an enlarged lingual tonsil was detected. Of the 16 cases, 10 (62.5%) had normal palatine tonsils; the other 6 cases (37.5%) had no palatine tonsils or were scarred, atrophied, or only remnants remained. Statistically, it was not possible to prove any relationship between enlarged lingual tonsils and tonsillectomies. From the forensic point of view, a description of the lingual tonsil should appear in special cases in autopsy reports. When reviewing malpractice cases, special anatomic features should be described.