Megaesophagus and possible mechanisms of sudden death.

Achalasia is a neurodegenerative condition characterized by esophageal dysmotility and megaesophagus. Two cases are reported that demonstrate unexpected deaths associated with previously unsuspected achalasia. Case 1: A 66-year-old woman was found dead at her home. At autopsy significant stenosing coronary artery atherosclerosis was found with cardiac failure. In addition, a striking finding was narrowing of the distal esophagus with marked proximal dilatation. The esophagus was completely filled with a large amount of soft masticated food and was bulging anteriorly, compressing the left atrium. Death was attributed to ischemic heart disease complicated by previously unsuspected achalasia. Case 2: An 84-year-old man collapsed and suffered a respiratory arrest while eating. Internal examination revealed narrowing of the cardioesophageal junction with marked proximal dilatation of the esophagus that contained approximately 50 mL of soft semi-fluid masticated yellow food paste. Fragments of yellow masticated food remnants were present in upper and lower airways but not within the stomach. There was a history of dementia with symmetrical cerebral ventricular dilatation found at autopsy. Death was attributed to food asphyxia complicating previously unsuspected achalasia with dementia. Megaesophagus may, therefore, be a significant finding at autopsy that may either be a primary cause of unexpected death or else may exacerbate or compound the effects of pre-existing underlying disease.

[Fatal attacks of zoo animals on humans--a case report]. / Tödliche Angriffe auf Menschen durch Wildtiere in zoologischen Gärten: ein kasuistischer Beitrag.

Media reports about fatal work accidents in zoos caused by zoo animals seem to appear in increasing numbers all around the world. In many cases the cause of such an accident can only be clarified by a detailed reconstruction of the event in combination with the autopsy results. This applies particularly in cases where no eyewitnesses were present. This report is about the case of a musk ox that killed its keeper, in which the fatal accident could be completely reconstructed.

Fatal pyomyositis: a report of 8 autopsy cases.

Pyomyositis is an acute bacterial infection manifesting as pyemic abscess formation in the skeletal muscles. We examined 8 autopsy cases (seven males, one female; age range 21-75 years) of fatal nontropical pyomyositis to better describe individual case characteristics and pathologic features of this rare disease. The pathogen most frequently involved was Staphylococcus aureus. In most cases, there were several abscesses and multiple sites involved. The trunk, shoulder girdle, and thigh muscles were most frequently affected and involvement of multiple sites was a common finding. In 6 cases, a recent trauma had occurred to the anatomic location where the pyemic abscesses were found. Three deceased were known as intravenous drug abusers. Except for the presence of pyomyositis, liver diseases such as cirrhosis in 3 cases, and a fatty liver in 2 cases were the most frequent autopsy findings. Death was due to sepsis in all cases. Because pyomyositis may develop in association with intravenous catheterization in the clinical setting, the question whether pyomyositis was caused by an infected or improperly placed indwelling intravenous catheter may be of forensic importance in the light of alleged medical malpractice. According to our observations, severe underlying illnesses seem not always necessary for fatal outcome of pyomyositis. Because a detailed dissection of superficial as well as deep skeletal muscles during autopsy is a prerequisite for the diagnosis, the disease may be overlooked when this essential step is not performed.

Vertebral column kyphoscoliosis and unexpected death.

A case of spontaneous gastric perforation is reported in a 75-year-old woman due to massive hemorrhaging from a benign gastric ulcer. Blood was prevented from leaving the stomach due to posterior displacement and rotation of the stomach associated with marked underlying vertebral column kyphoscoliosis. Significant deformity of the spine had caused malpositioning of the stomach as a result of the abnormal shape of the peritoneal and chest cavities. This in turn had led to mechanical obstruction and prevented egress of blood arising from a bleeding arteriole in the base of a chronic gastric ulcer. Rapid distension had resulted from the inability to spontaneously decompress the stomach, which in turn had led to rupture.

Pathology of fatal traumatic and nontraumatic clostridial gas gangrene: a histopathological, immunohistochemical, and ultrastructural study of six autopsy cases.

We prospectively investigated six fatal cases of clostridial gas gangrene using autopsy, histology, immunohistochemistry, microbiology, and scanning electron microscopy. The causative pathogen was Clostridium perfringens in four cases, C. sordellii in one case, and a mixed infection with both C. perfringens and C. sordellii in one case. According to the previous medical history and autopsy findings, clostridial infection was related to trauma in three cases. Characterized by extensive tissue necrosis and total absence of an accompanying leukocyte infiltration and tissue inflammatory response, the histopathological picture of clostridial gas gangrene is distinctly different from other bacterial infections. In medicolegal casework, the proof of the source of infection and the portal of entry of the responsible pathogen is not always an easy task, especially in the absence of trauma.

[An extreme case of undoing and posing in a case of murder-suicide. A forensic pathological approach to crime scene investigation]. / Ein extremer Fall von "Undoing" bei einem erweiterten Suizid. Ein rechtsmedizinischer Beitrag zur Tatortanalyse.

A 7-year-old boy was killed by his father by manual strangulation during a murder-suicide. After the killing of the son, the father showed typical "undoing" behaviour: He changed the boy's clothes and laid him down on the bed. Then he placed candles around his head, put pictures of the parents' wedding around him and a crucifix and a picture of the family into his hands. He broke off a rose in a vase next to the bed, lit the candles and took photographs of his dead son. Later he called his wife, threatened to kill the son and finally called the police to confess the murder and to announce his forthcoming suicide.

[Not enough help for themselves--the risk of physicians to commit suicide]. / Zu wenig Hilfe für sich selbst--Arzte in Suizidgefahr.

Physicians seem unwilling to deal with their own suicidal problems professionally. Suicide is a repressed topic. According to international studies, medical students and physicians are clearly over-represented among suicide victims. Committing suicide stands in sharp contrast to the positive image physicians enjoy as competent, strong helpers transmitting positive energy. Various studies and meta-analyses show that physicians use knowledge specific to their profession and are therefore "more successful" than the general population in committing suicide. Moreover, the data reveal a number of risk factors specifically correlating with medical practice. This is confirmed by an increased number of suicides during medical training and professional life in comparison with the general population. Gender-specific analyses show an even higher suicide risk for female physicians. In this context it cannot be excluded that out of "professional respect" cardiovascular causes of death are sometimes falsely documented in death certificates instead of suicide. Despite their special education, physicians are not very good at diagnosing their own emotional disorders and asking colleagues for adequate professional help. They rather tend to camouflage their own psychological problems also because they are afraid of occupational and personal discrimination.

[Premature detachment of the placenta due to kicks to the lower abdomen]. / Vorzeitige Plazentalösung--ausgelöst durch Tritte gegen das Abdomen.

An 18-year-old woman in an advanced stage of pregnancy was admitted to hospital for gynaecological emergency treatment with pain after kicks to the lower abdomen. Premature detachment of the placenta was diagnosed and an immediate Caesarian section was performed. Although the newborn was resuscitated at once by the medical team, it died two days later in the paediatric hospital from multiorgan failure. The autopsy results together with the pathological findings of the palcenta proved the causal context between the kicks, the premature detachment of the placenta and the hypoxia requiring postnatal resuscitation, so that the perpetrator was found guilty.

Synthesis and evaluation of ATP-binding site directed potential inhibitors of nucleoside triphosphatases/helicases and polymerases of hepatitis C and other selected Flaviviridae viruses.

5'-O-(4-fluorosulphonylbenzoyl)-esters of ribavirin (FSBR), adenosine (FSBA), guanosine (FSBG) and inosine (FSBI) were obtained by acylation of the 5'-OH of adenosine, guanosine, inosine, and ribavirin with 4-fluorosulphonylbenzoyl chloride (FSBCI) in HMPA. The above derivatives were tested as inhibitors of nucleoside triphosphatase (NTPase)/helicase activities of Flaviviridae: hepatitis C virus (HCV), West Nile virus (WNV), Japanese encephalitis virus (JEV) and dengue virus (DENV) and polymerase activity of HCV and WNV. When the unwinding activity of viral NTPase/helicases was tested under standard conditions, only weak inhibition was obtained with FSBI (IC50 > or = 120 microM) and in the case of FSBG even an activation was seen. The preincubation of the NTPase/helicases with the 5'-O-FSB derivatives increased the inhibitory effect. Screening of the 5'-O-FSB derivatives on inhibition of the WNV and HCV RNA polymerases employing GTP or UTP substrates revealed rather modest inhibitory effect. FSBI exhibited the highest inhibitory activity against WNV (IC50 = 70 microM with UTP substrate) and HCV polymerase (IC50 = 80 microM with GTP substrate). Other 5'-O-FSB derivatives were very weak inhibitors or completely failed to show any activity against HCV and WNV enzymes. In contrast to the NTPase/helicases the preincubation of the polymerases did not influence the inhibition.

Halogenated benzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses.

A search has been initiated for lead inhibitors of the nonstructural protein 3 (NS3)-associated NTPase/helicase activities of hepatitis C virus, the related West Nile virus, Japanese encephalitis virus and the human mitochondrial Suv3 enzyme. Random screening of a broad range of unrelated low-molecular mass compounds, employing both RNA and DNA substrates, revealed that 4,5,6,7-tetrabromobenzotriazole (TBBT) hitherto known as a potent highly selective inhibitor of protein kinase 2, is a good inhibitor of the helicase, but not NTPase, activity of hepatitis C virus NTPase/helicase. The IC50 is approximately 20 micro m with a DNA substrate, but only 60 micro m with an RNA substrate. Several related analogues of TBBT were enzyme- and/or substrate-specific inhibitors. For example, 5,6-dichloro-1-(beta-d-ribofuranosyl)benzotriazole (DRBT) was a good, and selective, inhibitor of the West Nile virus enzyme with an RNA substrate (IC50 approximately 0.3 micro m), but much weaker with a DNA substrate (IC50 approximately 3 micro m). Preincubation of the enzymes, but not substrates, with DRBT enhanced inhibitory potency, e.g. the IC50 vs the hepatitis C virus helicase activity was reduced from 1.5 to 0.1 micro m. No effect of preincubation was noted with TBBT, suggesting a different mode of interaction with the enzyme. The tetrachloro congener of TBBT, 4,5,6,7,-tetrachlorobenzotriazole (TCBT; a much weaker inhibitor of casein kinase 2) is also a much weaker inhibitor than TBBT of all four helicases. Kinetic studies, supplemented by comparison of ATP-binding sites, indicated that, unlike the case with casein kinase 2, the mode of action of the inhibitors vs the helicases is not by interaction with the catalytic ATP-binding site, but rather by occupation of an allosteric nucleoside/nucleotide binding site. The halogeno benzimidazoles and benzotriazoles included in this study are excellent lead compounds for the development of more potent inhibitors of hepatitis C virus and other viral NTPase/helicases.

Localisation of the human hSuv3p helicase in the mitochondrial matrix and its preferential unwinding of dsDNA.

We characterised the human hSuv3p protein belonging to the family of NTPases/helicases. In yeast mitochondria the hSUV3 orthologue is a component of the degradosome complex and participates in mtRNA turnover and processing, while in Caenorhabditis elegans the hSUV3 orthologue is necessary for viability of early embryos. Using immunofluorescence analysis, an in vitro mitochondrial uptake assay and sub-fractionation of human mitochondria we show hSuv3p to be a soluble protein localised in the mitochondrial matrix. We expressed and purified recombinant hSuv3p protein from a bacterial expression system. The purified enzyme was capable of hydrolysing ATP with a K(m) of 41.9 micro M and the activity was only modestly stimulated by polynucleotides. hSuv3p unwound partly hybridised dsRNA and dsDNA structures with a very strong preference for the latter. The presented analysis of the hSuv3p NTPase/helicase suggests that new functions of the protein have been acquired in the course of evolution.

Nucleotide triphosphatase/helicase of hepatitis C virus as a target for antiviral therapy.

The RNA nucleoside triphosphatase (NTPase)/helicases represent a large family of proteins that are detected in almost all biological systems where RNA plays a central role. The enzymes are capable of enzymatically unwinding duplex RNA structures by disrupting the hydrogen bonds that keep the two strands together. The strand separating activity is associated with hydrolysis of nucleoside triphosphate (NTP). Because of this, potential specific inhibitors of NTPase/helicases could act by one or more of the following mechanisms: (i) inhibition of NTPase activity by interference with NTP binding, (ii) inhibition of NTPase activity by an allosteric mechanism and (iii) inhibition of the coupling of NTP hydrolysis at the unwinding reaction. There are also other inhibitory mechanisms conceivable, which may involve a modulation of the interaction of the enzyme with its RNA substrate, for example, (iv) the competitive inhibition of RNA binding and (v) the inhibition of the unwinding by sterical blockade of the translocation of the NTPase/helicase along the polynucleotide chain. NTPase/helicase has also been identified in the viral genome of hepatitis C virus (HCV) which is a member of the Flaviviridae family. It is conceivable that the inhibition of the unwinding activity of the enzyme leads to the inhibition of virus replication and this may represent a novel antiviral strategy. This review updates the current spectrum of inhibitors targeting different mechanisms by which the NTPase and/or helicase activities of the HCV NTPase/helicase are inhibited. Consequently, some of the compounds might be important as antiviral agents against HCV.