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A 34-year-old heroin addict in the eighth month of pregnancy was found dead in her apartment. The head of a fetus was partly protruding from underneath the woman's slip. At the time of autopsy, the body was in a state of advanced putrefaction with greenish discoloration of almost the complete body surface showing pronounced marbling and, in addition, now not only the head but also the upper part of the chest of a dead fetus were extruding from the birth canal with head presentation. Autopsy showed no signs of external violence prior to death and, in particular, no indication of preceding manipulations in the region of the obstetrical canal and the uterus could be detected. The uterine cavity showed pronounced putrefactive alterations with the amniotic membranes being partially raised and bloated in a balloon-like fashion. Toxicological analyses revealed acute heroin intoxication of mother and child. The immature neonate showed no signs of live birth. Pathogenetically, the finding of not only the head but also the upper part of the chest of the fetus extruding from the birth canal at the time of autopsy (contrary to the observation made at the death scene that only part of the head of the fetus was protruding) is consistent with post-mortem fetal extrusion caused by putrefactive gas pressure against the pregnant uterus as reported in the earlier German forensic pathological literature.

A rare case of vehicle-assisted suicide in a 43-year-old man is presented. The man had tied a rope between a fence and his neck and, while seated on the driver's seat, accelerated the vehicle, which resulted in complete decapitation. Earlier that day, the man had tried to bleed himself to death by bottling his own blood in his flat, thus defining the case as secondary complex suicide.

Although glioblastomas are among the most common primary cerebral neoplasms, sudden death due to these tumors is an uncommon event. Due to the usual rapid increase in intracranial pressure, patients develop symptoms rather early, leading to medical attention in time. A search for cases of sudden unexpected death due to undiagnosed glioblastoma from a total of 14,482 cases from the archives of the Institute of Legal Medicine in Hamburg in the period of 1991-2003 revealed only one such case. Out of a total of 5,432 cases from the Institute of Neuropathology, Hamburg, during the same period, two further cases were found. A comprehensive literature review on cases of sudden death due to primary cerebral neoplasms published so far revealed a total of 83 cases with only ten cases of glioblastoma (12%), whereas 55 of these cases were due to histological benign tumors (66%).

Vater's ampulla is of great clinical relevance with regard to the influx of chyme, ascending inflammation, intubation during diagnostic and therapeutic endoscopic maneuvers, therapeutic papillotomy and, especially, the formation of malignancies. Little is known about the distribution of trefoil factor family (TFF) peptides in the ampulla. We have therefore examined TFF peptide distribution in the normal ampulla of Vater and compared it with that in duodenal mucosa and Brunner's glands. Expression and synthesis of TFF peptides in Vater's ampulla and duodenum was investigated by reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. The samples studied originated from 30 autopsy cases with short postmortem intervals. TFF3 was expressed in the ampulla of Vater. mRNA expression of TFF1 was detected in only approximately 25% of the investigated samples. Western blot revealed the production of TFF3 and immunohistochemistry showed that TFF3 was the product of goblet cells. TFF peptide composition of Vater's ampulla varied in comparison with that in the duodenum regarding TFF2 expression. The ampulla of Vater thus has a unique profile of TFF peptide production, supporting the hypothesis that the ampulla is an autonomous organ. The observed differences in the TFF peptide distribution between the duodenum and Vater's ampulla favour the investigation of TFF peptides as prognostic markers in the classification of ampullary carcinomas.

The assessment of individual wounds at autopsy may be complicated by the superimposition of a number of injuries or damage to tissues that occurred after death, either of which has the potential to distort the morphology of the initial injury. Additional factors that may change the shape of wounds are (1) the relationship of the wound to the so-called skin cleavage lines (Langer's lines) and (2) tension placed on the skin. Three autopsy cases are reported to demonstrate once more how wound morphology may be altered by such factors. In case 1, rectangular stab wounds to the base of the neck in a 53-year-old man, which suggested that a square or rectangular tool may have caused the injuries, were altered to more typical knife stab wounds once skin tension had been released at autopsy. The uppermost wounds, however, continued to gape due to the effects of skin cleavage lines. In case 2, slit-like wounds resembling stab wounds in the neck of a 54-year-old woman found in a river were shown to be circular once skin tension had been released. In case 3, the effects of either cleavage lines or skin tension could be demonstrated on excised wounds from a 43-year-old man whose body had also been found in a river; tensile forces easily changed circular into slit-like wounds. Tension and/or skin cleavage lines may transform round skin defects into slit-like wounds resembling knife stab wounds, round out genuine stab wounds and artefactually lengthen stab wounds. These factors must be taken into consideration carefully when wounds are assessed at the death scene prior to autopsy.

This autopsy-based study investigated the morphological correlates of pulmonary tissue destruction following fatal penetrating gunshot wounds to the lungs using morphometry, histology, immunohistochemistry, and scanning electron microscopy on whole human lungs fixed-expanded via formalin inflation. As the residue of temporary cavity formation, mantle-like hemorrhagic destruction zones were seen surrounding the missile track that showed an eccentric, conical extension enlarging toward subpleural lung segments. In addition, circumscribed, satellite-like bleeding zones at distances of up to 5.5 cm beyond the border of the permanent cavity were observed that corresponded to interstitial perivascular hemorrhages around larger and smaller pulmonary vessels on the micro-morphological level. These multifocal hemorrhages within macroscopically unaffected parts of pulmonary tissue at some distance from the actual missile track may represent unrecognized, life-threatening intrapulmonary bleeding sources in survivors, potentially leading to ventilation-perfusion mismatch and progressive lung failure. A further noticeable microscopic and ultrastructural finding was that of club-shaped distensions of ruptured alveolar septa strictly limited to the extent of the temporary cavity. These club-shaped distensions of ruptured alveolar septa seem to represent a special feature of alveolar architectural damage that can be explained by the dynamics of the temporary cavity formation: the radial acceleration and overdistension of tissue during temporary cavitation initiates stretch mechanisms of the displaced tissue, causing the alveolar septa to rupture with subsequent foreshortening and pursing of elastic alveolar fibers.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by mutations in the fumarate hydratase (FH) gene on chromosome 1q42.3-43. Massive macronodular adrenocortical disease (MMAD) is a heterogeneous condition associated with Cushing syndrome (CS) and bilateral hyperplasia of the adrenal glands. In MMAD, cortisol secretion is often mediated by ectopic, adrenocortical expression of receptors for a variety of substances; however, to date, no consistent genetic defects have been identified. In a patient with HLRCC caused by a germline-inactivating FH mutation, we diagnosed atypical (subclinical) CS due to bilateral, ACTH-independent adrenocortical hyperplasia. A clinical protocol for the detection of ectopic expression of various hormone receptors was employed. Histology was consistent with MMAD. The tumor tissue harbored the germline FH mutation and demonstrated allelic losses of the 1q42.3-43 FH locus. We then searched the National Institutes of Health (NIH) databases of patients with MMAD or HLRCC and found at least three other cases with MMAD that had a history of tumors that could be part of HLRCC; among patients with HLRCC, there were several with some adrenal nodularity noted on computed tomography but none with imaging findings consistent with MMAD. From two of the three MMAD patients, adrenocortical tumor DNA was available and sequenced for coding FH mutations; there were none. We conclude that in a patient with HLRCC, adrenal hyperplasia and CS were due to MMAD. The latter was likely due to the FH germline mutation because in tumor cells, only the mutant allele was retained. However, other patients with MMAD and HLRCC, or HLRCC patients with adrenal imaging findings consistent with MMAD, or MMAD patients with somatic FH mutations were not found among the NIH series. Although a fortuitous association cannot be excluded, HLRCC may be added to the short list of monogenic disorders that have been reported to be associated with the development of adrenal tumors; FH may be considered a candidate gene for MMAD.

Background: The survival of children and adolescents with advanced (unresectable or metastatic) nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) is poor. In order to clarify the role of combining chemotherapy with aggressive local control using surgery and/or radiation, we reviewed our institutional experience with the treatment of advanced pediatric NRSTS., Procedure: We reviewed the charts of all patients less than 21 years treated for an advanced NRSTS at the National Cancer Institute (NCI) between 1983 and 2003. Tumor pathology was confirmed and demographic, disease, and treatment data were abstracted. Survival was calculated using standard methods., Results: Of the 25 patients who were treated over the study period, 15 had metastatic disease and 10 had unresectable or incompletely resected disease at presentation. Twenty-one patients received chemotherapy consisting of the combination of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, and the remaining 4 received regimens that included doxorubicin. Twenty patients (80%) had a complete (5/25) or partial (15/25) response after chemotherapy alone. After the combination of chemotherapy and local control, 14 patients (56%) had a complete response (CR). The estimated 5-year overall and event-free survival (EFS) for all patients was 0.50 (standard error = 0.11) and 0.34 (standard error = 0.10), respectively., Conclusions: The combination of chemotherapy with aggressive local control in this cohort of pediatric patients with advanced NRSTS yielded results comparable to those observed in patients with advanced sarcomas that are chemotherapy responsive. Prospective randomized trials are needed to quantify the contribution of chemotherapy and to determine the ideal regimen., (Published 2004 Wiley-Liss, Inc.)

Black oesophagus is a rare pathological condition of unknown aetiology characterised by a full length, circumferential black discolouration of the entire oesophageal mucosa. The disease is sporadically encountered during upper gastrointestinal endoscopy. We used conventional histology, enzyme histochemistry and immunohistology to examine five autopsy cases (four males, one female; age range 43-86 years) of black oesophagus. On microscopical examination, the esophageal mucosa was entirely necrotic with demarcation by a leukocytic infiltrate in the upper submucosa. This infiltrate was dominated by neutrophilic granulocytes and scattered macrophages lacking haemosiderin deposits, placing the noxious mucosal injury in a time frame of approximately 24-72 h prior to death. Black oesophagus was established as the immediate cause of death in one case due to desanguination from the oesophagus and significantly contributed to the fatal outcome in a second case. Apart from a history of chronic alcohol consumption in four cases, no other pre-existing pathological or debilitating conditions could be established. The remarkably consistent pathomorphological picture of the disease seems to be the result of impaired microcirculation of the oesophageal mucosa due to prolonged hypotension of variable aetiology. The diagnosis of black oesophagus requires exclusion of other causes such as ingestion of caustic materials and should be based on histological examination.

Peliosis is a pathological entity characterized by the gross appearance of multiple cyst-like, blood-filled cavities within parenchymatous organs. Peliosis has been related to several underlying debilitating illnesses such as tuberculosis, hematological malignancies, the acquired immunodeficiency syndrome (AIDS), and post-transplant immunodeficiency, as well as intravenous drug abuse, chronic alcoholism, and in conjunction with the intake of oral contraceptives or steroids. The classical pathoanatomical concept is based upon the opinion that peliosis exclusively develops in organs belonging to the mononuclear phagocytic system (liver, spleen, bone marrow, and lymph nodes). However, a paucity of studies indicates that other organs such as lungs, parathyroid glands, and kidneys may be affected too. Concerning the underlying pathogenetic mechanisms of onset and maintenance of peliosis, the morphological data obtained by different investigators suggest that there is more than one path of formal pathogenesis (e.g., congenital malformation of vessels manifesting under altered local intravascular pressure conditions, acquired vascular disorder triggered by toxic noxae, active proliferation of vessels corresponding to the benign end on the spectrum of neoplastic vascular lesions). In the liver, at gross inspection, the peliotic lesions give the cut sections a "swiss cheese" appearance. Microscopically, two different types of peliosis can be distinguished in the liver: (1) "parenchymal peliosis" consisting of irregular cavities that are neither lined by sinusoidal cells nor by fibrous tissue, and (2) "phlebectatic peliosis" characterized by regular, spherical cavities lined by endothelium and/or fibrosis. One of the differential diagnoses that most closely resembles peliosis hepatis is secondary hepatic congestion due to veno-occlusive disease or the Budd-Chiari syndrome. In the spleen, the peliotic lesions may be arranged sporadically, disseminated, or in clusters in an uneven distribution pattern. Histologically, the cavities show frequently well-demarcated margins that may appear focally lined by sinusoidal endothelium, or totally lack a clear cell lining. Differential diagnoses are hemangiomas and involvement of the spleen in hairy-cell leukaemia. Since the disease may culminate in spontaneous rupture of the affected organ and thus may mimic a violent death at autopsy, peliosis is far more than just another morphological curiosity. Awareness of peliosis at autopsy as well as an appreciation for the histopathological changes in less characteristic or advanced cases may become an important issue for both the forensic and clinical pathologist.

Little is known of the molecular events underlying the genesis of pancreatoblastoma tumors in the pediatric population. Such studies have been limited by the rare nature of the disease, infrequent reports detailing cytogenetic alterations, and the lack of availability of cell lines for biologic studies. We present the isolation of a cell line from a 14-year-old boy with malignant pancreatoblastoma, and its cytogenetic characterization using spectral karyotyping and comparative genomic hybridization (CGH). The cytogenetic analysis revealed an exceedingly complex cytogenetic karyotype, with 33 aberrant chromosomes. CGH revealed multiple regions of chromosomal loss and gain, including a region on 8q gained in adult pancreatic cancers, one that frequently contains the MYC oncogene.

Splenic artery aneurysms are an uncommon form of vascular disease that have a significant potential for rupture, resulting in life-threatening intraperitoneal hemorrhage. We describe the case of a 33-year-old man who died suddenly and unexpectedly due to the rupture of a splenic artery aneurysm. At medicolegal autopsy, 3000 mL of fluid blood were recovered from the peritoneal cavity. The source of bleeding was a sack-like aneurysm of the splenic artery, measuring 2 cm in diameter. Histologic examination of the splenic artery aneurysm revealed fibromuscular dysplasia. No atherosclerotic lesions or any inflammatory changes were apparent within the wall of the splenic artery. Portal hypertension and pancreatitis, previously described as important factors promoting splenic artery aneurysm formation, were excluded by autopsy and histology. From the forensic pathologist's viewpoint, this rare case underlines the importance of splenic artery aneurysm rupture as a relevant differential diagnosis of intraperitoneal hemorrhage and sudden death, respectively, since such cases may be misinterpreted as a result of blunt-force trauma.

We prospectively monitored the postmortem course of interleukin-1beta (IL-1beta), soluble interleukin-2 receptor (sIL-2R) and lipopolysaccharide binding protein (LBP) in septic and non-septic fatalities to evaluate their potential as biochemical postmortem markers of sepsis. Serum concentrations were determined by chemiluminescent immunometric assays. In both the sepsis group and the control group a postmortem increase of IL-1beta levels with the progression of time after death was observed, in both groups mainly starting from the reference concentration of healthy individuals (5 pg/ml) and with no significant differences at later time points postmortem. SIL-2R (reference limit 1,000 U/ml) was highly elevated in all individuals included in the sepsis group at all time points postmortem with statistically significant differences between the sepsis and control groups (p<0.01). An excessive postmortem decrease of sIL-2R serum levels associated with progression of time after death was observed in all cases included in the sepsis group in contrast to just 1 out of 16 control cases. LBP (reference limit <10 g/ml) was elevated in all sepsis cases whereas in the control group LBP levels were below 10 microg/ml in 88%. The postmortem time course of LBP serum concentrations showed a continuous increase in both the sepsis and control groups. We conclude that sIL-2R and LBP seem to represent appropriate diagnostic tools for the postmortem diagnosis of sepsis in forensic autopsy practice. sIL-2R serum levels above 1,000 U/ml and LBP serum levels above 10 microg/ml in peripheral venous blood obtained in the early postmortem interval can be regarded as diagnostic hints for an underlying septic condition in a deceased person.

The diagnosis of death caused by hypothermia can often only be made by exclusion. In this article, we discuss the significance of rectal temperature determination at the death scene for establishing the diagnosis of fatal hypothermia. Six cases of fatal hypothermia subjected to medico-legal autopsy at the Institute of Legal Medicine, Hamburg, Germany, were reviewed. Findings at external examination, autopsy findings with special regard to characteristics hypothermia-related changes, histological findings, and toxicology results were analyzed. In all cases investigated, a discrepancy between a low rectal temperature and other parameters for estimation of the time since death such as still displaceable postmortem lividity and electrical excitability of skeletal muscles was present, leading to the prompt suspicion of fatal hypothermia at the medico-legal death scene investigation. An early death scene investigation by a forensic specialist is of striking importance for establishing the correct diagnosis, because this discrepancy can only be observed in the early postmortem interval.

Although a plethora of reports on life-threatening complications of salt emesis has been published since the early 1960s, salt is still used to induce emesis in cases of intoxication in the clinical as well as in the domestic setting. We report three cases of fatal hypernatremia after salt was used as an emetic. All fatalities were subjected to medico-legal autopsy at the Institute of Legal Medicine in Hamburg, Germany. In all cases, symptoms of cerebral damage such as seizures, fever and somnolence developed within hours after salt ingestion. All individuals were admitted to hospital before their deaths. Here, severe hypernatremia (up to 245 mmol/l) was detected, and all patients died under the clinical picture of cerebral edema despite intensive medical treatment. At autopsy, unspecific signs of a central regulatory failure were present. Histology revealed crenated red blood cells and few venous microthrombi in internal organs. Neuropathological investigations yielded no specific results but confirmed fatal cerebral edema and excluded other cerebral causes of death. Viewing the results of clinical and post-mortem investigations together, death could clearly be attributed to excessive salt intake in all cases.

A fatal case of influenza A infection with Staphylococcus aureus superinfection in a previously healthy 49-year-old woman presenting as sudden, unexpected death is reported. Autopsy revealed severe necrotizing tracheobronchitis and hemorrhagic pneumonia. Microscopic examination of the trachea and bronchi showed mucosal necrosis and a dense lympho-monocytic infiltration of all layers. The lungs showed focal hemorrhagic pneumonia. No pathological changes were detectable in the myocardium. Influenza A virus was detected in bronchi and lung samples obtained during autopsy by the polymerase chain reaction (PCR) and bacterial superinfection with Staphylococcus aureus was shown by culturing from tracheal, bronchial and pulmonary swabs obtained during autopsy. PCR assays for the detection of Panton-Valentine leukocidin performed from all samples were negative. This case demonstrates the need for an interdisciplinary approach towards an organism-specific diagnosis of potentially infection-related deaths undergoing a medico-legal autopsy. With improved diagnostic possibilities such as PCR and DNA sequencing, forensic pathologists can, in close association with the field of microbiology, make a significant contribution to the detection of highly infectious agents which must be notified to the authorities. This will increase particularly the knowledge about the influence of these agents on sudden, unexpected deaths in outpatients.

Differential diagnosis of injuries caused by accidental slipping of the hand onto the blade of a knife includes self-inflicted injuries (e.g. to simulate an offense) as well as active and passive defense injuries indicative of the involvement of another party. The injury pattern on the hands of five perpetrators who suffered accidental cuts during knife attacks, as seen by the authors during the clinical forensic examination, is presented. The injuries were localized on the ulnar aspect of the thumb facing the index finger, the radial aspect of the index finger facing the thumb and variable sites on the flexor or extensor side of the middle and ring fingers. Especially in those cases in which the injuries of the victim (e.g. involvement of bony structures) and the dominant hand of the perpetrator are known, additional information for the reconstruction of the course of events may be derived from the cut wounds occurring during the knife attack as the hand slipped onto the blade.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces selective apoptosis in a variety of tumors, including most cell lines derived from Ewing's sarcoma family of tumors, an aggressive sarcoma that afflicts children and young adults. To determine the in vivo efficacy of TRAIL receptor agonists in Ewing's sarcoma family of tumors, mice with orthotopic xenografts were treated with anti-TRAIL-R2 monoclonal antibody or TRAIL/Apo2L in a model that can identify effects on both primary tumors and metastases. Administration of either agonist slowed tumor growth in 60% of animals and induced durable remissions in 11 to 19% but did not alter the incidence of metastatic disease. Response rates were not improved by concurrent doxorubicin treatment. Cells recovered from both TRAIL receptor agonist-treated and nontreated tumors were found to be resistant to TRAIL-induced death in vitro unless pretreated with interferon (IFN) gamma. This resistance coincided with a selective down-regulation of TRAIL receptor expression on tumor cells. In vivo treatment with IFNgamma increased tumor expression of TRAIL receptors and caspase 8, but did not increase the antitumor effect of TRAIL receptor agonists on primary tumors. However, IFNgamma treatment alone or in combination with a TRAIL receptor agonist significantly decreased the incidence of metastatic disease and the combination of TRAIL receptor agonist therapy with IFNgamma-mediated impressive effects on both primary tumors and metastatic disease. These data demonstrate that in vivo growth favors TRAIL resistance but that TRAIL receptor agonists are active in Ewing's sarcoma family of tumors and that the combination of TRAIL receptor agonists with IFNgamma is a potent regimen in this disease capable of controlling both primary and metastatic tumors.

In contrast to other causes of herpetic lymphadenitis, the histological features associated with human herpesvirus-6 (HHV-6) infection have remained elusive since its discovery in 1986. We describe the histologic and phenotypic changes associated with acute HHV-6 lymphadenitis in two immunocompetent adults who presented with fever, fatigue, generalized lymphadenopathy, and elevated liver enzymes. Serologic tests for human immunodeficiency virus, acute Epstein-Barr virus, and cytomegalovirus infection were negative. Lymph node biopsies were consistent with viral lymphadenitis. Intranuclear and cytoplasmic inclusions were identified in CD4-positive T lymphocytes in expanded paracortical areas. Immunohistochemical staining with monoclonal antibody to the HHV-6 gp60/110 kDa envelope glycoprotein showed that the inclusions were positive for viral antigen. Electron microscopy demonstrated numerous viral particles in the cytoplasm and nucleus, characteristic of Herpesviridae family. Clustering of viral particles was observed, which has previously been reported only in infected tissue culture cells. PCR followed by sequencing of DNA extracted from the lymph nodes identified the virus as HHV-6, type B. This is the first report that documents distinctive histologic features of HHV-6 lymphadenitis and demonstrates that the cells harboring the virus in vivo are CD4-positive T lymphocytes.

Deaths due to falls from height are common in urban settings. At the time the body is found, it is often unclear whether the mode of death is accident, suicide, or homicide. To assess the injury pattern in fatal falls from height with special regard to criteria that might be helpful in discrimination between accident, suicide, and homicide, respectively, we reviewed 68 medicolegal autopsy cases (22 females, 46 males, age range 13-89 years) of fatal falls from height regarding demographic data, findings at the death scene, results of the postmortem examination, psychiatric history, and toxicologic findings. Among the 68 cases, there were 34 suicides, 23 accidents, and 11 unclarified cases, in 3 of which homicide was suspected. In general, suicides were from greater heights than accidents (mean height 22.7 m for suicides and 10.8 m for accidents, respectively; 79% of suicides from more than 16 m). Strikingly, severe head injuries predominantly occurred in falls from heights below 10 m (84%) and above 25 m (90%), whereas in the group of falls from 10 to 25 m, these lesions were seen less frequently (28%). Neck injuries like muscle bleeds and fractures of the hyoid bone were found in 33% of falls from more than 10 m and did not occur from less than 10 m. Our data stress that the evaluation of pathologic features alone is not sufficient to assess the mode of death in fatal falls from height. Instead, postmortem findings have to be considered within the framework of the subject's social, medical, and psychiatric history in conjunction with findings at the death scene and toxicology results to obtain the clearest possible picture of the circumstances of death.

Isolated peliosis of the spleen, characterized by the gross appearance of multiple cystlike, blood-filled cavities on cut surfaces of the organ, is a very rare pathologic entity that has been reported in 33 cases to date. We present 2 additional cases of isolated peliosis of the spleen observed at autopsy and confirmed by histology. In both cases investigated, cirrhosis of the liver was present. We hypothesize that local microcirculatory disturbances manifesting under altered local intravascular pressure conditions in the spleen may, at least to a certain degree, be responsible for the peliosis-associated vascular lesions. For the forensic pathologist, isolated peliosis of the spleen represents more than just another morphologic curiosity. The significance of peliosis lienalis lies in the potential of (1) overlooking the correct diagnosis as the cause of a spontaneous splenic rupture with intraabdominal hemorrhage, thus leading to the false conclusion of a violent death; and (2) misinterpreting the macromorphological appearance of this rare disease, also in the absence of splenic rupture, as a result of blunt force trauma.

Fatal monointoxications with benzodiazepines, for instance with a suicidal intention, are exceptional findings. We report the autopsy case of an 82-year-old woman who died due to a suicidal monointoxication with Rohypnol 1 mg film tablets (therapeutical agent: flunitrazepam). 0.065 mg/L flunitrazepam and 0.34 mg/L 7-aminoflunitrazepam were detected in a postmortem heart blood sample and toxicological analysis revealed the metabolite 7-aminoflunitrazepam in gastric contents, too. At external examination, a bluish-turquoise coloration was seen around the woman's right nostril and within the oral cavity. At autopsy, similar coloration phenomena were seen on the mucosa of the distal esophagus and the stomach. Formerly, bluish stains on mouth and nostrils were considered indicative of intoxications with organophosphates such as parathion (E 605). More recently, case reports accumulate where an intoxication with Rohypnol 1 film tablets (containing the coloring agent indigocarmine in its core) have to be considered as a potential differential diagnosis of such coloration phenomena.

Carney complex (CNC) is a familial multiple endocrine neoplasia syndrome associated with GH-producing pituitary tumours and transmitted as an autosomal dominant trait. Mutations of the PRKAR1A gene are responsible for approximately half the known CNC cases but have never found in sporadic pituitary tumours. Pituitary tissue was obtained from an acromegalic CNC patient heterozygote for a common (PRKARIA)i-inactivating mutation. Both immunohistochemistry and electron microscopy showed a highly pleiomorphic pituitary adenoma. The cell culture population appeared morphologically heterogeneous and remained so after more than 30 passages. The mixture was comprised of cells strongly immunostained for GH, spindle-shaped myofibroblast-like cells, and cuboid cells with large axonal projections (negative for GH). The population appeared to have both epithelial and mesenchymal cells. Both at baseline and at passage 30, cytogenetic analysis indicated the presence of normal 46, XY diploid karyotype, whereas losses of the PRKARIA(i) locus were demonstrated in more than 98% of the cells by fluorescent in situ hybridisation, supporting this gene's involvement in pituitary tumorigenesis. Allelic loss may have occurred in a single precursor cell type that differentiated and clonally expanded into several phenotypes. Epithelial-to-mesenchymal transition may also occur in CNC-associated pleiomorphic pituitary adenomas.

Background: Falls from height are contributing widely to population morbidity and mortality, especially in urban settings. The presence of blunt cardiac injuries can increase morbidity among these patients, leading even to death. Some clinical studies and case reports have been published on the subject, but a systematic autopsy-based approach to the subject is missing in the literature of recent decades., Methods: This study reviewed 61 cases of fatal fall from height that were subjected to a full autopsy at the Institute of Legal Medicine, Hamburg, Germany, from 1998 to 2002. The autopsy protocols and available clinical information were evaluated for assessment of the cardiac injury pattern., Results: Cardiac injuries were found in 33 cases (54%), all of which involved falls from heights exceeding 6 m. In 16 cases, the cardiac injuries were the cause of death or contributed to the fatal outcome. In five of these cases, the individuals possibly could have recovered from their trauma if their heart injury had been sufficiently diagnosed and adequately treated in time. The most frequent finding was pericardial tearing (45%). Tears caused by stretching of the epicardium in the area wherein the inferior vena cava leads into the right atrium and epicardial hematoma were present in 11 cases (33%). Endocardial tears of the atria were found in six cases (18%), and did not occur during falls from heights lower than 11 m. Transmural tears to the right atrium were present in 10 cases (39%), and to the left atrium in 6 cases (18%). These tears occurred with increasing frequency in relation to greater heights. When the heights were lower than 15 m, these tears were smaller than 1 cm in diameter, but when the heights exceeded 15 m, extensive irregular tears were observed. Sternal fractures were seen in 76% of all cases involving heart injuries. In 16% of these cases, the fractures were multiple. Only 18% of the cases without cardiac injuries had sternal fractures, and none of these was multiple. Thus, the presence of severe sternal fractures can be used as an indicator of possible cardiac trauma., Conclusions: A thorough cardiologic diagnosis should always be performed for patients who survive a fall from height. These patients should be transported to a unit capable of performing cardiopulmonary bypass, and explorative thoracotomy should be considered.

Vascular endothelial growth factor (VEGF) has been shown to play an important role during endochondral bone formation in hypertrophic cartilage remodeling, ossification, and angiogenesis, but it is not expressed in normal adult articular cartilage. Thyroid cartilage undergoes only partial ossification beginning at the age of about 20. Because it never completely ossifies, we investigated a possible role of VEGF and its receptors (VEGFRs) as well as the angiogenetic inhibitor endostatin in this permanent cartilage. In analysis of cartilage samples from all specimens evaluated, VEGF121 and VEGF165 were identified as the only VEGF splice forms expressed. In addition to VEGF, VEGFR-2 (kinase domain region/fetal liver kinase 1), but not VEGFR-1 (fms-like tyrosine kinase 1), was detectable by RT-PCR in cartilage. However, VEGFR-2 expression was only detectable up to the age of 19 years. Deposition of VEGF and VEGFR was confirmed by immunohistochemistry. VEGF concentrations measured by ELISA in thyroid cartilage increased with age in males but decreased in females. Endostatin concentrations measured by ELISA in thyroid cartilage were three times lower than in articular cartilage and showed no change with age, either in females or males. VEGF was immunostained within the intra- and pericellular matrices of some but not all chondrocytes. Thus, apart from its production in hypertrophic chondrocytes of growth plates, VEGF is also produced in single chondrocytes of thyroid cartilage. The data allow us to speculate that thyroid cartilage persists in an embryological state until it has reached its final size. After reaching its final size at the end of the second decade, VEGFR-2 is downregulated and ossification starts in the posterior part of the thyroid cartilage, proceeding ventrally. Both proteins, VEGF121 and VEGF165, should contribute to this process. VEGF concentration is high and changes in an age-related and sex-specific manner. Therefore, we postulate that VEGF is at least one of the key factors that is important for the lifelong ossification in thyroid cartilage.

Ectopic adrenal cortical neoplasms are extremely rare, and only a few have involved the CNS. We report the first case of an intramedullary oncocytic adrenal cortical neoplasm of the spinal cord with immunohistochemical (IMHC) confirmation. A 27-year-old man presented with progressive lower extremity weakness, spastic paraparesis, decreased reflexes, and hypoesthesia below T10. A spinal myelogram showed cauda equina blockade and obliteration of sacral nerve roots. This prompted emergent surgical intervention. A well-circumscribed, approximately 3 x 2 cm, light brown to tan, intramedullary tumor was identified at the level of the conus medullaris. Histologically, the tumor showed sheets and nests of plump, cytologically bland polygonal cells with abundant eosinophilic cytoplasm. A single mitosis, but no necrosis, was identified. By IMHC, the cells were positive for inhibin, melan-A, and synaptophysin, and negative for GFAP, EMA, cytokeratins, S-100, HMB-45, and chromogranin. Electron microscopy study performed from paraffin-embedded tissues demonstrated abundant mitochondria, and lipid vacuoles. This case confirms the occurrence of adrenal cortical neoplasms in the CNS and is the first report of an intradural, intramedullary adrenal cortical adenoma of the spinal cord, and the first to occur in a male. This tumor should be considered in the differential diagnosis of tumors of the CNS.

Cushing syndrome is uncommon in childhood and rare in infancy. We report the case of a 3-yr-old child who presented with symptoms of Cushing syndrome beginning shortly after birth. Her hypercortisolemia was cyclical, causing relapsing and remitting symptoms, which eventually led to suspicions of possible Munchausen syndrome by proxy. Investigation at the National Institutes of Health excluded exogenous administration of glucocorticoids and indicated ACTH-independent Cushing syndrome. Paradoxical response to dexamethasone stimulation (Liddle's test) suggested a diagnosis of primary pigmented nodular adrenocortical disease (PPNAD). After bilateral adrenalectomy, both glands showed micronodular adrenocortical hyperplasia, but histology was not consistent with typical PPNAD. DNA analysis of the coding sequences of the PRKAR1A gene (associated with PPNAD and Carney complex) and the GNAS gene (associated with McCune-Albright syndrome) showed no mutations. We conclude that hypercortisolemia in infancy may be caused by micronodular adrenocortical hyperplasia, which can be cyclical and confused with exogenous Cushing syndrome. A paradoxical rise of glucocorticoid excretion during Liddle's test may delineate these patients. Infantile micronodular disease has some features of PPNAD and may represent its early form; however, at least in the case of the patient reported here, micronodular hyperplasia was not caused by coding mutations of the PRKAR1A or GNAS genes or associated with typical histology or any other features of Carney complex or McCune-Albright syndrome and may represent a distinct entity.

Background: The most common site of rupture of the posterior tibial tendon is the retromalleolar region where the tendon changes its direction of pull. The aim of this study was to characterize the tissue of the gliding zone of the tibialis posterior tendon to gain further knowledge about possible structural causes for spontaneous tendon rupture., Methods: Light microscopy, transmission electron microscopy and immunohistochemical methods were used to describe the structure of the human tibialis posterior tendon., Results: In the region where the tendon wraps around the medial malleolus, the structure of the tissue changes from the typical structure of a traction tendon. The superficial zone which was directed towards the pulley tissue had the structure of fibrocartilage with a specific three-dimensional collagen fibril texture. Transmission electron microscopy showed chondrocytes with a felt-like pericellular matrix that increased in size towards the gliding surface. The extracellular matrix of the fibrocartilage was rich in acid glycosaminoglycans and stained intensively with alcian blue at pH 1. Immunohistochemical staining of cartilage-specific extracellular matrix components such as type II collagen, chondroitin-4-sulphate, chondroitin-6-sulphate, keratan sulphate and aggrecan was positive., Conclusion: The location of the fibrocartilage corresponds to the region where the tibialis posterior tendon wraps around the medial malleolus, which serves as a pulley. According to the theory of 'causal histogenesis', the stimulus for the development of fibrocartilage within dense connective tissue is intermittent compressive and shear stress. The fibrocartilaginous region is the region where most spontaneous ruptures of the tibialis posterior tendon occur. Due to its structure, the fibrocartilaginous region may be more vulnerable to repetitive tensile microtrauma; degeneration may occur due to the poor repair response of the avascular fibrocartilaginous tissue.

Four cases of complete decapitation connected to homicidal acts are presented. In 3 cases, decapitation was inflicted postmortem after killing the victim. The motives for decapitation were considered defensive, aggressive, and a possible combination of the 2 in one case each. In one case, decapitation was a vital injury and accounted for death. In this case, an offensive motive for mutilation was suspected. The combination of death scene findings and autopsy results will in most cases distinguish between homicidal and other modes of death.

Evidence suggests neovascularization is involved in the etiology of spontaneous Achilles tendon rupture. Therefore we investigated expression of the receptors of one of the most important angiogenic factors, the vascular endothelial growth factor in normal and pathologic human Achilles tendons by immunohistochemical and molecular biology methods. Light microscopy showed degenerative changes in all spontaneously ruptured tendons with a higher vascular density compared with controls of healthy tendons from a cadaver. The vascular endothelial growth factor receptors-1 and 2 could be immunostained in endothelial cells of ruptured and fetal tendons, but not in normal tendons. Reverse transcription-polymerase chain reaction showed messenger ribonucleic acid of both receptors are expressed in ruptured and fetal tendons but not in normal tendons. These results prove the reexpression of the major receptors for the angiogenic peptide vascular endothelial growth factor, the vascular endothelial growth factor receptor-1, and the vascular endothelial growth factor receptor-2 in ruptured and fetal tendons and support our theory that high vascular density is associated with the pathogenesis of tendon degenerations. Inhibiting angiogenesis could be a new approach in the therapy of degenerative Achilles tendon disease.

Despite high suicide rates all over the world, complete decapitation as a consequence of violent suicide methods is exceptionally rare and there is always a potential for confusion with homicide as well as with body dismemberment or mutilation. We analyzed the phenomenology and morphology of 10 cases (six male, four female; individual age 18-60 years) of suicidal complete decapitation that were subjected to medico-legal autopsies at the Institute of Legal Medicine, University of Hamburg, Germany, between 1995 and 2002. All decapitations occurred while the person was alive as proven by signs of vitality. Blood alcohol levels were positive in five cases and ranged between 28 and 202 mg/dl. The applied methods of suicide were running over by a train in eight cases and hanging in two cases. In suicidal hanging resulting in complete decapitation the wound margins were clear-cut with an adjacent sharply demarcated circumferential band-like abrasion zone showing a homogenous width, the latter determined by the thickness of the rope. In decapitations due to railway interference a broad spectrum of pathologic alterations such as the co-existence of irregular, ragged and sharp-edged wound margins, vascular and nervous pathways forming bridges in the depth of the wound and bruising could be observed. In such cases skin abrasion zones were generally not circumferential and showed a heterogenous width. Concerning hanging-related complete decapitations, our findings are well in line with those of other authors, namely that heavy body weight of the suicidal, fall from a great height and in some cases inelastic and/or thin rope material used for the noose are the determining factors decisive for complete decapitation.

Two cases of planned complex suicide are presented. In both cases, the suicidal persons shot themselves after making sure that in the sequel their bodies would be burnt. In the first case, a 65-year-old man had shot himself in the mouth and consequently fell into a fire he had lighted before. In the second case, a 43-year-old man set fire to his flat and shot himself directly afterwards. On the basis of the reported cases, a short literature review on planned complex suicides is given.

Carney complex (CNC) is a familial multiple neoplasia syndrome with features overlapping those of McCune-Albright syndrome (MAS) and multiple endocrine neoplasia (MEN) type 1 (MEN 1). Like MAS and MEN 1 patients, patients with CNC develop growth hormone (GH)-producing pituitary tumors. Occasionally, these tumors are also prolactin-producing, but there are no isolated prolactinomas or other types of pituitary tumors. In at least some patients with CNC, the pituitary gland is characterized by hyperplastic areas; hyperplasia appears to involve somatomammotrophs only. Hyperplasia most likely precedes the formation of GH-producing adenomas in CNC, as has been suggested in MAS-related somatotropinomas, but has never been seen in MEN 1 patients. In at least one case of a patient with CNC and advanced acromegaly, a GH-producing macroadenoma showed extensive genetic changes at the chromosomal level. So far, half of the patients with CNC have germline inactivating mutations in the PRKAR1A gene; in their pituitary tumors, the normal allele of the PRKAR1A gene is lost. Loss-of-hererozygosity suggests that PRKAR1A, which codes for the regulatory subunit type 1alpha of the cAMP-dependent protein kinase A (PKA) may act as a tumor-suppressor gene in CNC somatomammotrophs. These data provide evidence for a PRKAR1A-induced somatomammotroph hyperpasia in the pituitary tissue of CNC patients; hyperplasia, in turn may lead to additional genetic changes at the somatic level, which then cause the formation of adenomas in some, but not all, patients.

Context: Decubitus ulcers constitute a serious medical problem, often encountered in association with hospitalization or institutionalization in senior citizens' or nursing homes. Potentially life-threatening sepsis has been reported to originate not only from soft tissue infection, but also from osteomyelitis as a complication of involvement of bone tissue in decubitus ulcers., Objective: To assess the histopathology of osseous structures involved in grade IV decubitus ulcers., Design: Autopsy-based histopathologic assessment of the presence and extent of osteomyelitis on os sacrum specimens from 28 deceased individuals with grade IV sacral decubitus ulcers using an undecalcified preparation following plastic embedding (staining with Goldner, Kossa modification, toluidine blue, and Giemsa)., Results: The histologic findings were classified in 4 types of pathomorphologic changes: type 1, decubitus ulcer confined to soft tissue, no inflammation (n = 7); type 2, decubitus ulcer involving bone, no inflammation (n = 7); type 3, decubitus ulcer involving bone, inflammation of soft tissue, no osteomyelitis (n = 1); and type 4, decubitus ulcer involving bone, presence of osteomyelitis (n = 13). Type 4 changes are further described as follows: type 4a, chronic osteomyelitis alone (n = 6); and type 4b, chronic and acute osteomyelitic changes (n = 7). More than half of the cases (n = 15) showed no inflammatory reaction within the medullary cavity (types 1-3). In all cases with osteomyelitis, inflammation was exclusively confined to the superficial parts of the os sacrum. Chronic osteomyelitis was seen in all cases in which osteomyelitis was present. In addition, mild acute osteomyelitic changes were observed in 7 cases. Severe liquefying osteomyelitis affecting deeper layers of the os sacrum was not found. Sepsis was present in 2 cases; in one of these cases, the decubitus ulcer was considered a possible source of infection., Conclusions: Our results provide evidence that in cases of grade IV decubitus ulcers, the macroscopic aspect and clinical imaging techniques may lead to an overestimation of the extent of osseous involvement. We suggest that the investigation of bone biopsies is not necessary in a considerable proportion of cases of grade IV decubitus ulcers in patients without sepsis, as the minor osseous alterations are of little consequence when establishing a therapeutic approach.

Two brothers with a leukodystrophy, progressive spastic diplegia, and peripheral neuropathy were found to have proteinaceous aggregates in the peripheral nerve myelin sheath. The patients' mother had only subclinical peripheral neuropathy, but the maternal grandmother had adult-onset leukodystrophy. Sequencing of the proteolipid protein (PLP) gene showed a point mutation IVS4 + 1 G-->A within the donor splice site of intron 4. We identified one transcript with a deletion of exon 4 (Deltaex4, 169bp) encoding for PLP and DM20 proteins and lacking two transmembrane domains, and a second transcript with exon 4 + 10bp encoding three transmembrane domains. Immunohistochemistry showed abnormal aggregation in the myelin sheath of MBP and P0. Myelin-associated glycoprotein was present in the Schmidt-Lanterman clefts but significantly reduced in the periaxonal region. Using immunogold electron microscopy, we demonstrated the presence of mutated PLP/DM20 and the absence of the intact protein in the patient peripheral myelin sheath. We conclude that insertion of mutant PLP/DM20 with resulting aberrant distribution of other myelin proteins in peripheral nerve may constitute an important mechanism of dysmyelination in disorders associated with PLP mutations.

Childhood osteogenic sarcoma (OS) is a rare bone cancer occurring primarily in adolescents. The North American pediatric cooperative groups have performed a series of clinical treatment trials in this disease over the past several decades, and biology studies of tumor tissue have been an important study component. A meeting was held in Bethesda, Maryland on November 29-30, 2001, sponsored by the NIH Office of Rare Diseases, the Children's Oncology Group, and the National Cancer Institute-Cancer Therapy Evaluation Program with the general objectives: (a) to review the current state of knowledge regarding OS biology; (b) to identify, prioritize, and support the development of biology studies of potential clinical relevance in OS; and (c) to discuss the available tissue resources and the appropriate methods for analysis of OS samples for the conduct of biology studies. This report summarizes the information presented and discussed by the meeting participants.

Antigen-specific lymphocytes are involved in synovial proliferation within inflamed joints. Activated lymphocytes and synoviocytes from patients with rheumatoid arthritis express receptors that can bind TNF-related apoptosis-inducing ligand (TRAIL). A new study demonstrates that DCs pulsed with collagen and transduced with an adenovirus-based vector able to express TRAIL limit the incidence of arthritis in a model of collagen-induced arthritis and joint inflammation. These results suggest that gene-modified cell therapy represents a therapeutic option for systemic rheumatic diseases.

Inflammatory myofibroblastic tumor (IMT) is a rare childhood neoplasm. The natural history of this disease is poorly understood. Recently chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene have been implicated in this tumor. We have studied a case of ALK-positive soft tissue IMT showing clinical and morphologic features of malignancy. Interphase fluorescence in situ hybridization demonstrated ALK rearrangements in both primary and metastatic lesions. Rapid amplification of cDNA ends (5'RACE) identified cysteinyl-tRNA synthetase (CARS) gene fused to ALK, which predicts an in-frame chimeric protein with the preserved functional catalytic domain of ALK at the C terminus. Amplification and sequencing of tumor DNA confirmed the breakpoint at the genomic level. Restriction analysis of DNA from primary soft tissue and recurrent lung tumors showed identical patterns, indicating the same clonal origin of both lesions. Western blot analysis with C-terminus ALK antibody showed expression of an aberrantly sized chimeric protein of approximately 130 kd in tumor tissue. This is the second case of IMT demonstrating CARS as the ALK fusion partner, which confirms the recurring involvement of ALK in IMT by a common genetic mechanism. Moreover, identical clonality of separate lesions involving different sites supports metastasis in IMT.

The objective of this autopsy-based study was to investigate the pathology of human blast lung injury using histology, Fat Red 7B staining, immunohistochemistry, and scanning electron microscopy on lung specimens from eight medicolegal autopsy cases of fatal close-range detonations of chemical explosives. The micromorphologic equivalents of human blast lung injury can be summarized as follows: diffuse alveolar overdistension, circumscribed interstitial hemorrhages showing a cufflike pattern around pulmonary vessels, venous air embolism, bone marrow embolism, and pulmonary fat embolism. Hemorrhages within the lung parenchyma that were present in this study in blast victims without coexisting blunt or penetrating chest trauma must be regarded as potentially life-threatening intrapulmonary bleeding sites in survivors. In addition, the potential clinical importance of the presence of massive pulmonary fat embolism, which has, to the best of our knowledge, not been described previously in human blast lung injury, must be emphasized because pulmonary fat embolism may be a leading cause of the rapid respiratory deterioration with progressive hypoxia and development of acute respiratory distress syndrome in blast victims who survive. Furthermore, this study provides evidence that air embolism presenting in blast victims is not a mere ventilation-induced artifact.

Avascular zones of tendons are predisposed for degenerative changes and spontaneous rupture. Therefore, we analyzed the expression of the endogenous angiogenesis inhibiting factor endostatin in human fetal and adult tendons by immunohistochemical and biochemical methods. Moreover, to elucidate factors involved in the regulation of vascularity, we exposed primary cultures of rat tendon cells to intermittent hydrostatic pressure (0.2 MPa, 0.1 Hz for 24 h), and measured the endostatin content by ELISA and the effect of the conditioned medium to the proliferation of human umbilical vein endothelial cells (HUVEC). In fetal tendons high endostatin levels could be quantified by ELISA whereas low levels were found in adult tissue. In fetal tendons endostatin could also be immunostained in endothelial cells but mainly in fibroblasts. In adult Achilles tendons endostatin immunostaining was restricted to endothelial cells. In the tibialis posterior tendon--as an example for "wrap around"--endostatin immunostaining remained positive in the fibrocartilage adjacent to the medial malleolus. Fibrochondrocytes of the type II collagen positive fibrocartilage were intensively stained with the endostatin antibody. Factor VIII immunostaining showed that this region was largely avascular. Monolayer cultures of tendon cells released measurable amounts of endostatin into their culture supernatants. Application of intermittent hydrostatic pressure increased endostatin expression significantly. The conditioned media of tendon fibroblasts cultivated under intermittent hydrostatic pressure inhibited the proliferation of HUVEC in a dose dependent way. The spatial expression of endostatin in adult gliding tendons suggests that mechanical factors are involved in the regulation of this anti-angiogenic factor. In accordance, tendon cells exposed to intermittent hydrostatic pressure inhibit endothelial cell proliferation via humoral factors and produce endostatin. These findings support the view that the development and maintenance of avascular zones in tendons might be caused by a mechanically induced upregulation of anti-angiogenic factors.

Lathosterol 5-desaturase catalyzes the conversion of lathosterol to 7-dehydrocholesterol in the next to last step of cholesterol synthesis. Inborn errors of cholesterol synthesis underlie a group of human malformation syndromes including Smith-Lemli-Opitz syndrome, desmosterolosis, CHILD syndrome, CDPX2 and lathosterolosis. We disrupted the lathosterol 5-desaturase gene (Sc5d ) in order to further our understanding of the pathophysiological processes underlying these disorders and to gain insight into the corresponding human disorder. Sc5d (-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol levels, had craniofacial defects including cleft palate and micrognathia, and limb patterning defects. Many of the malformations found in Sc5d (-/-) mice are consistent with impaired hedgehog signaling, and appear to be a result of decreased cholesterol rather than increased lathosterol. A patient initially described as atypical SLOS with mucolipidosis was shown to have lathosterolosis by biochemical and molecular analysis. We identified a homozygous mutation of SC5D (137A>C, Y46S) in this patient. An unique aspect of the lathosterolosis phenotype is the combination of a malformation syndrome with an intracellular storage defect.

This review addresses our present-day knowledge on the role of different cellular adhesion molecules, cytokines and glycoproteins for the detection of sepsis-induced injury in the microvasculature of the human lung using immunohistochemistry. Through the induction and modulation of endothelial cell adhesion molecules, such as E-selectin (CD 62E), the vascular endothelium controls leukocyte extravasation into tissue. E-Selectin, not expressed by unstimulated endothelium, is activated by cytokines and initiates neutrophil recruitment in sepsis-induced lung injury. Since E-selectin is strongly expressed in the pulmonary microvasculature in sepsis-associated fatalities, the immunohistochemical detection of an intense expression of E-selectin in lung tissue is a valuable diagnostic tool in the forensic postmortem elucidation of death due to sepsis. VLA-4 (CD49d/CD29) is strongly expressed on intravascular, interstitial and intra-alveolar leukocytes in sepsis-associated fatalities, whereas in non-septic fatalities an irregular weak immunoreactivity can be observed on interstitial leukocytes and no positive immunohistochemical expression can be observed on intravascular or intra-alveolar leukocytes. ICAM-1 (CD54) is strongly expressed on endothelial cells of the pulmonary microvasculature and on pulmonary macrophages and lymphocytes in sepsis-associated fatalities. In contrast, an infrequent weak immunohistochemical reaction for ICAM-1 is found on pulmonary endothelium and on perivascular leukocytes in non-septic fatalities. The up-regulation of both cellular adhesion molecules can be considered as an useful immunohistochemical postmortem marker of sepsis. Lactoferrin (LF) is an iron-binding glycoprotein located in specific (secondary) granules of leukocytes and plays a central role in the host response to infectious stimuli in providing both bacteriostatic and bactericidal protection. There is a statistically significant association between an enhanced expression of LF on pulmonary leukocytes in sepsis-related fatalities in contrast to non-septic controls. The immunohistochemical detection of an enhanced expression of LF can contribute to the postmortem discrimination between sepsis and non-septic fatalities. Application of carbohydrate-specific lectins (ConA, UEA, GSA I, GSA II, MPA, PNA, Jac, WGA, MAA, LPA, SNA) on deparaffinated lung tissue sections from sepsis-associated fatalities and control cases results to some extent in different staining patterns of alveolar epithelial cells and subepithelial seromucous glands of the bronchi. Apart from differences in binding sites for alpha-mannose, N-acetyl-neuraminic acid and alpha-(2-6)-galactose (as detected by different expression for ConA, MAA and SNA), the main finding is that no binding sites for alpha-N-acetyl-galactosamine (as investigated by MPA immunoreactivity) can be detected on alveolar epithelial cells and mucous parts of subepithelial seromucous glands in sepsis cases in contrast to the presence of such binding sites in controls. Since most intracellular pathogens persist in macrophages and epithelial cells during infection, it is likely that these pathogens contribute to a continual deprivation or consumption, respectively, of glycoproteins physiologically secreted by alveolar epithelial and glandular cells at different time points and stages of infection and may, among other mechanisms, by reducing pathogen clearance amplify the inflammatory response. Vascular endothelial growth factor (VEGF), an angiogenic and chemotactic peptide, is abundantly expressed in normal lung tissue, especially in alveolar and bronchial epithelium, glandular cells of the bronchi, and activated alveolar macrophages. Pulmonary VEGF immunostaining differs in sepsis when compared to healthy individuals. In the latter a preponderant strong VEGF immunoreaction can be found on alveolar epithelium (predominately type II pneumocytes), bronchial epithelium and glandular cells of the bronchi and bronchioli, and activated alveolar macrophages. In contrast, in sepsis no VEGF immunopositivity can beivity can be observed on bronchial epithelium or glandular cells of the bronchi and bronchioli, and no or relatively sparse VEGF immunoreactivity is found on alveolar epithelial cells. The precise mechanisms of the decreased pulmonary VEGF expression in septic patients under conditions of intensive care medicine are not clear at present. During the complex cascade of excessive pro-inflammatory and anti-inflammatory mediator release involved in the host's systemic inflammatory response in the development of sepsis-induced lung injury, VEGF expression may be suppressed in sepsis by a hitherto not identified agent or the interaction of different mediators of cellular inflammation. For the detection of sepsis-induced lung injury the aforementioned markers can be used sufficiently, e.g. to give immunohistochemical evidence of a previously undiagnosed sepsis and to confirm or rule out a presumed diagnosis of a sepsis-associated fatality. The employment of the presented immunohistochemical methods will be particularly helpful when macroscopical and routine histological autopsy findings in cases of suspected fatal sepsis are unspecific or unconvincing, respectively, and clinical data on the patient's previous history are not available. Referring to the forensic argumentation regarding causality on the subject of possibly fatal septic complications, e.g. in the sequel of diagnostic or therapeutic iatrogenic injection procedures or being relevant to pressure sore-associated fatalities, aetiopathogenetic conclusions can be optimized on the basis of the described micromorphological investigations.

Under forensic differential diagnostic aspects postmortem findings of adhesive tape in the face suggest either suicide, an autoerotic accident or homicide, in which case the adhesive tape could have been used for sealing the mouth or as a means to commit the homicide itself. 9 autopsy cases are described as examples with this constellation and discussed under criminological aspects.

Chronic decubital lesions have a limited potential to heal. Evidence suggests that a lack of local revascularization is involved in this aetiology. The present study investigated the expression of one of the most important angiogenic factors, the vascular endothelial growth factor (VEGF), in different regions of sacral chronic decubital lesions and in normal skin by immunohistochemical, biochemical, molecular, and cell biology methods. To elucidate some of the factors responsible for the induction of VEGF in chronic skin ulcers, cultured fibroblasts were exposed to hypoxia and/or growth factors. In the central part (zone I) of chronic ulcers and in normal skin, immunostaining for VEGF remained largely negative. However, VEGF could be immunostained in cells in the granulation tissue adjacent to central necrosis (zone II). VEGF receptor 2 (VEGFR-2; KDR) could also be identified in microvessels. High VEGF levels were present in homogenates from granulation tissue by enzyme-linked immunosorbent assay (ELISA) and western blot experiments: low concentrations were found in areas of central necrosis and negligible amounts were present in normal skin. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that only the splice variants VEGF(121) and VEGF(165) were expressed. In cultured fibroblasts, hypoxia or platelet-derived growth factor (PDGF) raised VEGF production. The angiogenic peptide VEGF is present in all zones of chronic decubital ulcers. Its strong expression within the adjacent granulation tissue supports the view that there is no deficiency of VEGF. VEGF may be involved in the healing process of chronic skin lesions, but it seems that loss of another factor may be responsible for the poor healing response., (Copyright 2003 John Wiley & Sons, Ltd.)

The Ewing's sarcoma family of tumors (ESFT) contain a translocation, t(11;22), which results in the novel oncogenic fusion protein EWS/FLI1. Platelet-derived growth factors (PDGF) and their receptors (PDGFR) are involved in the induction and proliferation of numerous solid tumors and are the potential candidates for novel targeted antitumor therapy. Since a relation was reported between PDGF-C and EWS/FLI1, we sought to characterize the PDGF signaling pathway in ESFT. Eight out of nine ESFT cell lines were found to express significant levels of beta-PDGFR. Interestingly, none of the tested cell lines expressed alpha-PDGFR, which is the receptor isotype required for PDGF-C binding. By immunohistochemical staining 47 of 52 (90.4%) archival tumor samples from patients with ESFT were positive for beta-PDGFR. ESFT cell lines were treated with PDGF-AA or PDGF-BB ligands to evaluate downstream signaling. Autophosphorylation of beta-PDGFR and tyrosine phosphorylation of PLC-gamma, PI3Kp85 and Shc were detected only in PDGF-BB-stimulated cells that express beta-PDGFR. Receptor function was further evaluated using chemotaxis assays that showed TC-32 cell migration towards PDGF-BB. A specific PDGFR kinase inhibitor AG1295 blocked beta-PDGFR activation, downstream signaling, growth in cell culture and chemotaxis of TC-32 cells. AG1295 also delayed tumor formation and prolonged survival in an ESFT animal model. We conclude that ESFT express beta-PDGFR and that this is a functional and potentially crucial signaling pathway. Therefore, beta-PDGFRs may provide a novel therapeutic target in ESFT that can be utilized to design better treatment modalities.

Context: Vascular endothelial growth factor (VEGF), an angiogenic and chemotactic peptide, is abundantly expressed in normal lung tissue, especially in alveolar and bronchial epithelium, glandular cells of the bronchi, and activated alveolar macrophages., Objective: To investigate the role of VEGF in progressively impaired lung function as the major complication and cause of death in septic patients., Materials and Methods: We evaluated pulmonary VEGF expression in lung autopsy material from septic patients who had been cared for by intensive care medicine using enzyme-linked immunosorbent assay (ELISA), reverse transcriptase-polymerase chain reaction (RT-PCR), and immunohistochemical methods., Results: Compared with expression in nonseptic control individuals (n = 10), pulmonary VEGF expression as determined by ELISA was significantly (P <.001) decreased in septic patients (n = 8). As monitored by RT-PCR, mRNA for the 2 splice variants, VEGF(121) and VEGF(165), and for VEGFR-2/KDR were expressed in both groups, the yields being lower in the sepsis group. Samples from septic patients lacked or showed only sparse immunoreaction on bronchial and alveolar epithelium, whereas this reaction was strong in all control samples. However, alveolar macrophages were similarly immunopositive in both groups., Conclusions: The precise underlying mechanisms for the distinctly different expression of pulmonary VEGF in septic patients and nonseptic control individuals are not clear at present. Particularly the role of VEGF in the development of sepsis-induced lung injury and acute respiratory distress syndrome in mechanically ventilated patients suffering from severe sepsis remains to be clarified.

A fatal case of Waterhouse-Friderichsen syndrome resulting from infection in a previously healthy 74-year-old woman is reported. The patient died suddenly within 14 hours after presentation. The diagnosis of Waterhouse-Friderichsen syndrome as the cause of death was established post mortem based on autopsy findings, microscopic examination, measurement of serum procalcitonin concentration (113 ng/ml), and outcome of postmortem bacteriologic cultures that grew in heart and spleen blood samples. Since the introduction of as a new group in the family in 1983, more recent case studies have established its clinical significance and pathogenic potential to cause severe, life-threatening bacteremia and sepsis. is a rare pathogen that should be added to the list of unusual bacteria causing Waterhouse-Friderichsen syndrome.