Assassination of Elisabeth, Empress of Austria, Queen of Hungary, on 10 September 1898: further additions and minor annotations.

Very recently, a comprehensive re-evaluation of the medical facts and observations surrounding the death of Empress Elisabeth "Sisi" of Austria (1837-1898) was published. The Empress was assassinated in Geneva by the anarchist Luigi Luccheni or Lucheni (1873-1910). In parallel to this recent publication, our study group came across an almost unknown letter from Dr. Golay, who was one of the examining doctors of Empress Elisabeth. In this publication we add relevant additions based on this letter and provide further insights regarding the attempts at resuscitation.

Traumatic fractures in an early 19th century museum skeleton suggest the homicide of an old Munich character: the history of "Finessensepperl" (Finesse Joseph).

The well preserved skeleton of Joseph Huber, a very well-known historical character of the 19th century Munich, also nicknamed "Finessen-Sepperl", is the starting point of the reconstruction of life and death of this historical individual. He was known as a postilion d´amour (love's messenger) of the Royal Bavarian capital with numerous comments and anecdotes and a few biographical sketches that indicate he remained well until the last few years of his life where requests for his duties lessened. The skeleton shows a small-sized male individual with almost complete loss of teeth, but otherwise very well-mineralized bone, having suffered from three episodes of trauma - an old-healed incomplete femoral neck fracture leading to severe osteoarthrosis, a clavicle fracture of the medial third with a few weeks old callus formation, and fresh serial rib fractures along with severe skull trauma with fractures of the os temporale and petrosum, presumably leading to intracranial bleeding and finally death. The type and distribution of these latter two injuries are in agreement with a murderous attack - which was retrospectively reported several years after his death, while the old-healed femoral neck fracture may have caused reduction in Joseph´s walking activities but not reduced requests for his services. Paleopathology not only identifies the terminal decline, but also previous diseases of this Old Bavarian character and thereby completes his story.

Unilateral Facial Asymmetry in a 40 BCE Roman Carved Head.

ABSTRACT: We describe the peculiar facial morphology of a carved head dating to the end of the Roman Republican period (40 BCE) which displays evident unilateral asymmetry. A comprehensive discussion of the different etiologies is provided and a contextualization of this condition in the broader frame of Roman artistic verism is offered. This case study contributes to the knowledge of disease presentation in the ancient world, with a special focus on the anatomy of soft tissue pathology.

[The Iceman : Life scenarios and pathological findings from 30 years of research on the glacier mummy "Ötzi"]. / Der Mann aus dem Eis : Lebensszenario und Pathologische Befunde aus 30 Jahren Forschung an der Gletschermumie "Ötzi".

The comprehensive investigation of the excellently preserved mummy of Ötzi, the Iceman, and his equipment over the last 30 years has provided a wealth of information about the life and disease of this late Neolithic individual. This research has indicated that his origin was from a local southern Alpine population, that he grew up in the valleys of the Southern Alps, and that he had considerable local mobility. He had well-balanced nutrition with a mixed vegetable and animal diet. He was very mobile in the alpine terrain and of athletic constitution. The Iceman suffered from mild to moderate degenerative joint disease primarily of the right hip joint, slight spondylosis of the cervical and lumbar spine, a minor focal (premature) arteriosclerosis, lung anthracosis and possibly silicosis, previous pleuritic inflammation (possibly of post-specific origin), intestinal infections of the stomach by Helicobacter pylori and Trichuris trichiura worm infestation in the intestines, a mild osteomalacia of cancellous bone, and diverse pathologies of his teeth with dental caries and periodontitis, as well as hair anomalies. The presence of borreliosis is still under debate. As potential remedies, the Iceman carried some anthelmintic substances with him: a birch polypore and an anthelmintic fern. The numerous tattoos may also have had therapeutic effects. Finally, the last days of Ötzi could be reconstructed quite precisely: his gastrointestinal content indicates that the Iceman moved from Alpine heights to a lower location and then again up to the glacier region where he died. During this journey he encountered two attacks: the first, several days before his death, lead to a stabbing wound in his right hand; the second was an arrow hit that wounded the Iceman lethally at his left axilla by laceration of the subclavian artery.

Trichuris trichiura in a post-Colonial Brazilian mummy.

Trichuris trichiura is a soil-transmitted helminth which is prevalent in warm, moist, tropical and subtropical regions of the world with poor sanitation. Heavy whipworm can result either in Trichuris dysenteric syndrome - especially in children - or in a chronic colitis. In heavy infections, worms can spread proximally and may cause ileitis. Here we provide first microscopic evidence for a T. trichiura adult worm embedded in the rectum of a post-Colonial Brazilian adult mummy. During Colonial and post-Colonial times, many European chroniclers described a parasitic disease named Maculo whose symptomatology coincides with heavy helminthiasis. Based on our findings and on comparison of ancient textual evidence with modern description of heavy whipworm, we feel confident in considering that the two syndromes are expressions of the same pathological condition.

Did Michelangelo paint a young adult woman with breast cancer in "The Flood" (Sistine Chapel, Rome)?

The Flood is the first pictorial scene that Michelangelo Buonarroti painted on the ceiling of the Sistine Chapel in the Vatican. On the right side of the fresco a woman with abnormal breast morphology is presented and the nature of her disease is considered using the Guidelines for Iconodiagnosis. A team of experts covering art history, art expertise, medicine, genetics, and pathology undertook the process and concluded that the pathology shown is probably breast cancer, most likely linked to the symbolic significance of an inevitable death as expressed in the Book of Genesis.

Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2.

In America and Western Europe, prostate cancer is the second leading cause of death in men. Emerging evidence suggests that chronic inflammation is a major risk factor for the development and metastatic progression of prostate cancer. We previously reported that the chemopreventive polyphenol curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. In this study, we analyze the effects of curcumin on prostate carcinoma growth, apoptosis and metastasis. We show that curcumin inhibits translocation of NFκB to the nucleus through the inhibition of the IκB-kinase (IKKß, leading to stabilization of the inhibitor of NFκB, IκBα, in PC-3 prostate carcinoma cells. Inhibition of NFκB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NFκB. The combination of curcumin with the synthetic IKKß inhibitor, SC-541, shows no additive or synergistic effects indicating that the two compounds share the target. Treatment of the cells with curcumin and siRNA-based knockdown of CXCL1 and -2 induce apoptosis, inhibit proliferation and downregulate several important metastasis-promoting factors like COX2, SPARC and EFEMP. In an orthotopic mouse model of hematogenous metastasis, treatment with curcumin inhibits statistically significantly formation of lung metastases. In conclusion, chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive proinflammatory and prometastatic feedback loop between NFκB and CXCL1/-2. Curcumin disrupts this feedback loop by the inhibition of NFκB signaling leading to reduced metastasis formation in vivo.

Influence of lumbar intervertebral disc degeneration on the outcome of total lumbar disc replacement: a prospective clinical, histological, X-ray and MRI investigation.

INTRODUCTION: The role of fusion of lumbar motion segments for the treatment of axial low back pain (LBP) from lumbar degenerative disc disease (DDD) without any true deformities or instabilities remains controversially debated. In an attempt to avoid previously published and fusion-related negative side effects, motion preserving technologies such as total lumbar disc replacement (TDR) have been introduced. The adequate extent of preoperative DDD for TDR remains unknown, the number of previously published studies is scarce and the limited data available reveal contradictory results. The goal of this current analysis was to perform a prospective histological, X-ray and MRI investigation of the index-segment's degree of DDD and to correlate these data with each patient's pre- and postoperative clinical outcome parameters from an ongoing prospective clinical trial with ProDisc II (Synthes, Paoli, U.S.A.). MATERIALS AND METHODS: Nucleus pulposus (NP) and annulus fibrosus (AF) changes were evaluated according to a previously validated quantitative histological degeneration score (HDS). X-ray evaluation included assessment of the mean, anterior and posterior disc space height (DSH). MRI investigation of DDD was performed on a 5-scale grading system. The prospective clinical outcome assessment included visual analogue scale (VAS), Oswestry Disability Index (ODI) scores as well as the patient's subjective satisfaction rates. RESULTS: Data from 51 patients with an average follow-up of 50.5 months (range 6.1-91.9 months) were included in the study. Postoperative VAS and ODI scores improved significantly in comparison to preoperative levels (p < 0.002). A significant correlation and interdependence was established between various parameters of DDD preoperatively (p < 0.05). Degenerative changes of NP tissue samples were significantly more pronounced in comparison to those of AF material (p < 0.001) with no significant correlation between each other (p > 0.05). Preoperatively, the extent of DDD was not significantly correlated with the patient's symptomatology (p > 0.05). No negative influence was associated with increasing stages of DDD on the postoperative clinical outcome parameters following TDR (p > 0.05). Increasing stages of DDD in terms of lower DSH scores were not associated with inferior clinical results as outlined by postoperative VAS or ODI scores or the patient's subjective outcome evaluation at the last FU examination (p > 0.05). Conversely, some potential positive effects on the postoperative outcome were observed in patients with advanced stages of preoperative DDD. Patients with more severe preoperative HDS scores of NP samples demonstrated significantly lower VAS scores during the early postoperative course (p = 0.02). CONCLUSION: Increasing stages of DDD did not negatively impact on the outcome following TDR in a highly selected patient population. In particular, no preoperative DDD threshold value was identified from which an inferior postoperative outcome could have been deduced. Conversely, some positive effects on the postoperative outcome were detected in patients with advanced stages of DDD. Combined advantageous effects of progressive morphological structural rigidity of the index segment and restabilizing effects from larger distraction in degenerated segments may compensate for increasing axial rotational instability, one of TDR's perceived disadvantages. Our data reveal a "therapeutic window" for TDR in a cohort of patients with various stages of DDD as long as preoperative facet joint complaints or degenerative facet arthropathies can be excluded and stringent preoperative decision making criteria are adhered to. Previously published absolute DSH values as contraindication against TDR should be reconsidered.

Adipositas and metabolic bone disorder in a 16th century Upper Austrian infant crypt mummy-An interdisciplinary palaeopathological insight into historical aristocratic life.

We describe here the results of a multidisciplinary study on an infant mummy from 16th century Upper Austria buried in the crypt of the family of the Counts of Starhemberg. The macroscopic-anthropological, radiological (whole-body CT scan), histological (skin tissue), and radiocarbon isotope investigations suggested a male infant of 10-18 months' age, most likely dying between 1550 and 1635 CE (probably Reichard Wilhelm, 1625-1626 CE), that presented with evidence of metabolic bone disease with significant bilateral flaring of costochondral joints resembling "rachitic rosary" of the ribs, along with straight long bones and lack of fractures or subperiosteal bleeding residues. Although incompletely developed, the osteopathology points toward rickets, without upper or lower extremities long bone deformation. The differential diagnosis is vitamin C deficiency (scurvy) (also with an incomplete presentation, although overlap between both disorders may be present). As additional pathology, there was significantly enlarged subcutaneous fat tissue (thickness more than 1 cm at the navel and thighs and longitudinal creases of the skin) along with a histologically enlarged subcutaneous fat layer consistent with infantile adipositas as a coincident disorder. Finally, remnants of lung tissue with pleural adhesion of the right lung indicate possibly lethal pneumonia, a disease with an increased prevalence in vitamin D deficient infants. Ultimately, the skull presented with extensive destruction of the bones of the base and dislocation of the bones of the skull squama. These changes, however, are most likely post-mortal pseudopathology, the result of a burial in a flat, narrow coffin because there were no bone fractures or residues of bleeding/tissue reaction that would have occurred whilst the patient was alive.

Trauma of bone and soft tissues in South American mummies-New cases provide further insight into violence and lethal outcome.

There exist numerous reports on violence in South American populations which shed a particular light on life and living conditions in those historic communities. Most studies have been performed on collections of isolated skulls. Whole-body investigations especially on well-preserved mummified human remains are rare. In the present study we investigated three South American mummies predating the Colonial Spanish period. The "Marburg" man lived between 996 and 1147 CE and was buried in typical burial bundle. The analysis of the textiles, ceramics and fishing tools associated with his naturally mummified body suggests that he most likely originated from the Arica region in Northern Chile and was possibly part of a fishing community. The "Delémont" natural mummies belong to an adult male and an adult female, respectively. The mummies, the textiles and grave goods were investigated. The ceramics suggest a provenance from the Arequipa region, supposing that all the artifacts were originally associated with the two mummies. The Delémont male mummy is 14C dated between 902 and 994 CE and the "Delémont" female mummy 14C dated between 1224 and 1282 CE. All mummies underwent Multidetector Computed Tomography which showed evidence of trauma, some of which were interpreted as evidence of interpersonal violence. An interdisciplinary approach was applied with the particular intention to identify trauma sequels and to evaluate their paleo-forensic potential. Evidence of violence was identified in the two male individuals. Our study provides evidence that the interdisciplinary investigation of well-preserved human remains may detect much more frequent traces of intentional trauma than previously thought. Particularly, trauma against the body may not be identified in studies on skulls alone, and trauma residues of internal organs/soft tissues will only be seen in mummies. We therefore add further evidence of two cases of (lethal) trauma in pre-colonial South-American male individuals.

Human MMP28 expression is unresponsive to inflammatory stimuli and does not correlate to the grade of intervertebral disc degeneration.

BACKGROUND: MMP28 (epilysin) is a recently discovered member of the MMP (matrix metalloproteinase) family that is, amongst others, expressed in osteoarthritic cartilage and intervertebral disc (IVD) tissue. In this study the hypothesis that increased expression of MMP28 correlates with higher grades of degeneration and is stimulated by the presence of proinflammatory molecules was tested. Gene expression levels of MMP28 were investigated in traumatic and degenerative human IVD tissue and correlated to the type of disease and the degree of degeneration (Thompson grade). Quantification of MMP28 gene expression in human IVD tissue or in isolated cells after stimulation with the inflammatory mediators lipopolysaccharide (LPS), interleukin (IL)-1ß, tumor necrosis factor (TNF)-α or the histondeacetylase inhibitor trichostatin A was performed by real-time RT PCR. RESULTS: While MMP28 expression was increased in individual cases with trauma or disc degeneration, there was no significant correlation between the grade of disease and MMP28 expression. Stimulation with LPS, IL-1ß, TNF-α or trichostatin A did not alter MMP28 gene expression at any investigated time point or any concentration. CONCLUSIONS: Our results demonstrate that gene expression of MMP28 in the IVD is not regulated by inflammatory mechanisms, is donor-dependent and cannot be positively or negatively linked to the grade of degeneration and only weakly to the occurrence of trauma. New hypotheses and future studies are needed to find the role of MMP28 in the intervertebral disc.

Unique paleopathology in a pre-Columbian mummy remnant from Southern Peru--severe cervical rotation trauma with subluxation of the axis as cause of death.

We describe the multidisciplinary findings in a pre-Columbian mummy head from Southern Peru (Cahuachi, Nazca civilisation, radiocarbon dating between 120 and 750 AD) of a mature male individual (40-60 years) with the first two vertebrae attached in pathological position. Accordingly, the atlanto-axial transition (C1/C2) was significantly rotated and dislocated at 38° angle associated with a bulging brownish mass that considerably reduced the spinal canal by circa 60%. Using surface microscopy, endoscopy, high-resolution multi-slice computer tomography, paleohistology and immunohistochemistry, we identified an extensive epidural hematoma of the upper cervical spinal canal-extending into the skull cavity-obviously due to a rupture of the left vertebral artery at its transition between atlas and skull base. There were no signs of fractures of the skull or vertebrae. Histological and immunohistochemical examinations clearly identified dura, brain residues and densely packed corpuscular elements that proved to represent fresh epidural hematoma. Subsequent biochemical analysis provided no evidence for pre-mortal cocaine consumption. Stable isotope analysis, however, revealed significant and repeated changes in the nutrition during his last 9 months, suggesting high mobility. Finally, the significant narrowing of the rotational atlanto-axial dislocation and the epidural hematoma probably caused compression of the spinal cord and the medulla oblongata with subsequent respiratory arrest. In conclusion, we suggest that the man died within a short period of time (probably few minutes) in an upright position with the head rotated rapidly to the right side. In paleopathologic literature, trauma to the upper cervical spine has as yet only very rarely been described, and dislocation of the vertebral bodies has not been presented.

Chronic active non-lethal human-type tuberculosis in a high royal Bavarian officer of Napoleonic times-a mummy study.

In paleopathology, morphological and molecular evidence for infection by mycobacteria of the M. tuberculosis complex (MTC) is frequently associated with early death. In the present report, we describe a multidisciplinary study of a well-preserved mummy from Napoleonic times with a long-standing tuberculous infection by M. tuberculosis senso stricto who died at the age of 88 years of focal and non-MTB related bronchopneumonia. The well-preserved natural mummy of the Royal Bavarian General, Count Heinrich LII Reuss-Köstritz (1763-1851 CE), was extensively investigated by macro- and histomorphology, whole body CT scans and organ radiography, various molecular tissue analyses, including stable isotope analysis and molecular genetic tests. We identified signs for a long-standing, but terminally inactive pulmonary tuberculosis, tuberculous destruction of the second lumbar vertebral body, and a large tuberculous abscess in the right (retroperitoneal) psoas region (a cold abscess). This cold abscess harboured an active tuberculous infection as evidenced by histological and molecular tests. Radiological and histological analysis further revealed extensive arteriosclerosis with (non-obliterating) coronary and significant carotid arteriosclerosis, healthy bone tissue without evidence of age-related osteopenia, evidence for diffuse idiopathic skeletal hyperostosis and mild osteoarthrosis of few joints. This suggests excellent living conditions correlating well with his diet indicated by stable isotope results and literary evidence. Despite the clear evidence of a tuberculous cold abscess with bacterioscopic and molecular proof for a persisting MTC infection of a human-type M. tuberculosis strain, we can exclude the chronic MTC infection as cause of death. The detection of MTC in historic individuals should therefore be interpreted with great caution and include further data, such as their nutritional status.

XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells.

Deficiency in X-linked inhibitor of apoptosis protein (XIAP) is the cause for X-linked lymphoproliferative syndrome 2 (XLP2). About one-third of these patients suffer from severe and therapy-refractory inflammatory bowel disease (IBD), but the exact cause of this pathogenesis remains undefined. Here, we used XIAP-deficient mice to characterize the mechanisms underlying intestinal inflammation. In Xiap−/− mice, we observed spontaneous terminal ileitis and microbial dysbiosis characterized by a reduction of Clostridia species. We showed that in inflamed mice, both TNF receptor 1 and 2 (TNFR1/2) cooperated in promoting ileitis by targeting TLR5-expressing Paneth cells (PCs) or dendritic cells (DCs). Using intestinal organoids and in vivo modeling, we demonstrated that TLR5 signaling triggered TNF production, which induced PC dysfunction mediated by TNFR1. TNFR2 acted upon lamina propria immune cells. scRNA-seq identified a DC population expressing TLR5, in which Tnfr2 expression was also elevated. Thus, the combined activity of TLR5 and TNFR2 signaling may be responsible for DC loss in lamina propria of Xiap−/− mice. Consequently, both Tnfr1−/−Xiap−/− and Tnfr2−/−Xiap−/− mice were rescued from dysbiosis and intestinal inflammation. Furthermore, RNA-seq of ileal crypts revealed that in inflamed Xiap−/− mice, TLR5 signaling was abrogated, linking aberrant TNF responses with the development of a dysbiosis. Evidence for TNFR2 signaling driving intestinal inflammation was detected in XLP2 patient samples. Together, these data point toward a key role of XIAP in mediating resilience of TLR5-expressing PCs and intestinal DCs, allowing them to maintain tissue integrity and microbiota homeostasis.

Immunohistochemical identification of notochordal markers in cells in the aging human lumbar intervertebral disc.

The fate of notochord cells during disc development and aging is still a subject of debate. Cells with the typical notochordal morphology disappear from the disc within the first decade of life. However, the pure morphologic differentiation of notochordal from non-notochordal disc cells can be difficult, prompting the use of cellular markers. Previous reports on these notochordal cell markers only explored the occurrence in young age groups without considering changes during disc degeneration. The aim of this study, therefore, was to investigate presence, localization, and abundance of cells expressing notochordal cell markers in human lumbar discs during disc development and degeneration. Based on pilot studies, cytokeratins CK-8, -18 and -19 as well as Galectin-3 were chosen from a broad panel of potential notochordal cell markers and used for immunohistochemical staining of 30 human lumbar autopsy samples (0-86 years) and 38 human surgical disc samples (26-69 years). In the autopsy group, 80% of fetal to adolescent discs (0-17 years) and 100% of young adult discs (18-30 years) contained many cells with positive labeling. These cells were strongly clustered and nearly exclusively located in areas with granular changes (or other matrix defects), showing predominantly a chondrocytic morphology as well as (in a much lesser extent) a fibrocytic phenotype. In mature discs (31-60 years) and elderly discs (≥ 60 years) only 25 and 22-33%, respectively, contained few stained nuclear cells, mostly associated with matrix defects. In the surgical group, only 16% of samples from young adults (≤ 47 years) exhibited positively labeled cells whereas mature to old surgical discs (>47 years) contained no labeled cells. This is the first study describing the presence and temporo-spatial localization of cells expressing notochordal cell markers in human lumbar intervertebral discs of all ages and variable degree of disc degeneration. Our findings indicate that cells with a (immunohistochemically) notochord-like phenotype are present in a considerable fraction of adult lumbar intervertebral discs. The presence of these cells is associated with distinct features of (early) age-related disc degeneration, particularly with granular matrix changes.