Cyclic GMP in Liver Cirrhosis-Role in Pathophysiology of Portal Hypertension and Therapeutic Implications.

The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the "NO-paradox", referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.

The punched-out tissue complex (skin-bone "imprimatum") in shots from captive-bolt guns: does it act as a secondary projectile?

From the first half of the twentieth century to the present day, injuries and fatalities from captive-bolt livestock stunners are a major topic in forensic medicine. The vast majority of cases account for suicides with the frontal, temporal, parietal, and occipital regions being the most common sites of entrance (in descending order of frequency). Due to the limited length of the bolt, the corresponding wound channel within the braincase is only several centimeters long. It has been a controversial subject for a long time, whether the skin-bone complex punched out by the conically grooved end of the steel rod may act as a "secondary projectile" being propelled beyond the actual path of the bolt. To answer this question, experimental shots from various types of captive bolt-guns were fired to simulants. Video-documentation employing a high-speed motion camera showed that the punched-out pieces of skin and bone did not move further than the bolt. Thus, a secondary extension of the total wound channel could not be observed. However, the suction effect caused by the bolt's rearward movement may induce a slight retrograde displacement of the skin-bone complex.

Bullet wipe on the uppermost textile layer of gunshot entrance sites: may it be absent due to pre-existing blood staining?

Most gunshot entrance sites on human victims are localized in clothed body regions. Except for the use of lead-free ammunition, a positive color reaction of the sodium rhodizonate test indicates a primary target hit by the bullet. Any lead residue pattern in the area around the entrance hole allows approximate conclusions as to the firing distance in close and intermediate range shots, whereas the presence of a bullet wipe denotes an entrance site. A criminal case gave rise to an experimental study to clarify whether a blood-soaked garment being shot at as a primary target may lack a bullet wipe around the entrance hole. Distant-range shots were fired with a semi-automatic pistol (Heckler & Koch, Mod. USP Compact, cal. 9-mm Luger) using cartridges with jacketed round-nose bullets and a Sinoxid primer containing lead styphnate. In fabrics saturated with fluid blood, a wide area around the bullet entrance was densely covered with rhodizonate-positive microparticles simulating gunshot residues (GSR) from a close-range shot. In shots to fabrics oversaturated with blood, a typical bullet wipe was lacking, whereas lead-containing particles were spotted in the periphery. The results are discussed with respect to the aberrant appearance of bullet entrance sites in blood-soaked fabrics.

Wound morphology in contact shots from blank cartridge handguns: a study on composite models.

It is a well-known fact that blank cartridge guns can cause penetrating and even fatal injuries when discharged in contact or at very close ranges. In these cases, the gas jet perforates the skin leaving an entrance wound similar to that from a conventional gun. In order to investigate the wound morphology in contact shots from blank firearms, test shots were fired at composite models of pig skin and gelatin blocks using three different calibre 9-mm blank cartridge handguns (two pistols and one revolver) and two types of ammunition. It turned out that the penetrating gas jet produced roundish skin defects resembling bullet entrance holes. Small skin particles from the perforation site were dispersed in the underlying simulant where radiating cracks containing greyish gunshot residues indicated the original expansion of the inrushing combustion gases. Apart from the size of the permanent entrance hole in the skin and the final position of the displaced tissue particles, the penetration depth of the gas jet was determined. Under the specified conditions of the test shots, the zone of mechanical destruction within the simulant was 2.2 to 6.1 cm in length, which illustrates the injuring potential of contact shots inflicted with blank cartridge handguns.

Suicide with two makes of captive-bolt guns (livestock stunners) fired simultaneously to the forehead.

In humans, most fatalities from slaughterer's guns are suicides committed by persons familiar with stunning devices. The great majority of cases accounts for shots to the head, especially the frontal region. Only a small number of two subsequent cranial shots from captive-bolt humane killers have been reported up to now. In the case presented by the authors, a suicide by simultaneous shots to the head fired from two different makes of captive-bolt guns (one of them having two separate outlets for the combustion gases in the muzzle plane, the other type having no additional openings) is described for the first time. One of the shooting devices remained in firm contact with the left hand and produced patterned staining from rust corresponding to the surface relief of the gun. The medicolegal and criminalistic aspects of this unique case are discussed with reference to the pertinent literature.

Pseudo-tying injuries in a hanged person.

A 50-year-old man was found hanged on the concrete dam of a water reservoir. The ligature, a braided rope made of synthetic fibres, was attached to a lamp on the dam crest. The length of the rope between the fastening point and the noose was about 4m. At autopsy, stretchmark-like intimal tears of the carotid arteries were found, but the full pattern of (internal) decapitation and severance of the cervical spine was not present. The right wrist showed two almost circular, ribbon-like abrasions initially suggesting that the man had been tied before hanging. When the ligature was examined, horny scales adhered to the noose, but were also detected away from the slip-knot. By means of a DNA analysis the epidermal traces could be assigned to the deceased. The overall picture of the findings suggested that the man had roped down from the dam crest with the ligature wrapped around his right wrist thus abrading the skin.

A patterned abrasion caused by the impact of a cartridge case may simulate an atypical muzzle imprint mark.

In contact shots, the muzzle imprint is an informative finding associated with the entrance wound. It typically mirrors the constructional components being in line with the muzzle or just behind. Under special conditions, other patterned skin marks located near a gunshot entrance wound may give the impression to be part of the muzzle imprint. A potential mechanism causing a patterned pressure abrasion in close proximity to the bullet entrance site is demonstrated on the basis of a suicidal shot to the temple. The skin lesion in question appeared as a ring-shaped excoriation with a diameter corresponding to that of the cartridge case. Two hypotheses concerning the causative mechanism were investigated by test shots: - After being ejected, the cartridge case ricocheted inside a confined space (car cabin in the particular case) and secondarily hit the skin near the gunshot entrance wound. - The ejection of the cartridge case failed so that the case became stuck in the ejection port and its mouth contacted the skin when the body collapsed after being hit.

Fatal contact shot to the chest caused by the gas jet from a muzzle-loading pistol discharging only black powder and no bullet: case study and experimental simulation of the wounding effect.

In modern medico-legal literature, only a small number of publications deal with fatal injuries from black powder guns. Most of them focus on the morphological features such as intense soot soiling, blast tattooing and burn effects in close-range shots or describe the wound ballistics of spherical lead bullets. Another kind of "unusual" and potentially lethal weapons are handguns destined for firing only blank cartridges such as starter and alarm pistols. The dangerousness of these guns is restricted to very close and contact range shots and results from the gas jet produced by the deflagration of the propellant. The present paper reports on a suicide committed with a muzzle-loading percussion pistol cal. 45. An unusually large stellate entrance wound was located in the precordial region, accompanied by an imprint mark from the ramrod and a faint greenish discoloration (apparently due to the formation of sulfhemoglobin). Autopsy revealed an oversized powder cavity, multiple fractures of the anterior thoracic wall as well as ruptures of the heart, the aorta, the left hepatic lobe and the diaphragm. In total, the zone of mechanical destruction had a diameter of approx. 15 cm. As there was no exit wound and no bullet lodged in the body, the injury was caused exclusively by the inrushing combustion gases of the propellant (black powder) comparable with the gas jet of a blank cartridge gun. In contact shots to ballistic gelatine using the suicide's pistol loaded with black powder but no projectile, the formation of a nearly spherical cavity could be demonstrated by means of a high-speed camera. The extent of the temporary cavity after firing with 5 g of black powder roughly corresponded to the zone of destruction found in the suicide's body.

The varying size of exit wounds from center-fire rifles as a consequence of the temporary cavity.

To study the question whether and how the size and position of the temporary cavity influence the morphology and especially the size of a bullet exit wound, test shots were fired to composite models consisting of gelatine and pig soft tissue covered with skin (at the exit site). The dimensions of the composite model were determined such that the exit planes were located either at the level of the narrow channel or within the temporary cavity or behind it. The chronological sequence of wound formation and its relation to the current position of the bullet were documented by means of a high-speed camera. Test shots were fired from a distance of 10 m using 5.56 × 45 mm cartridges with full metal-jacketed pointed bullets (v 0 ∼ 912 m/s, E 0 ∼ 1,663 J). The study proved that the extension and position of the temporary wound cavity was decisive for the size of the exit wound: An exit plane within the cavity resulted in particularly large skin lesions, whereas the wound diameters were much smaller if the exit plane was located in front or behind the cavity. The exit hole reaches its maximum size only after the bullet has left the target synchronous to the staggered expansion of the temporary cavity.

Primarily unrecognized thoracoabdominal impalement in a motorcyclist.

In traffic accidents, fatal impalements are mostly seen in vehicle occupants injured by penetrating blunt-tipped objects such as fence posts or iron bars. Compared with this group of road users, the medical literature lacks reports on impaled motorcyclists. The article presents a case which deserves attention in several respects: 1. Both the impaling object and the victim were moving at the moment of penetration. 2. The lethal impalement trauma remained unrecognized until autopsy, particularly since the causative object did not get stuck in the wound track. 3. Two different body parts (head and trunk) were consecutively affected analogous to re-entry wounds in gunshots and stabs. 4. Due to the tubular shape and the sharp-edged end of the penetrating instrument (stanchion of a broken front-wheel's fork), clothing and soft tissues were punched out along the wound channel and partly remained lodged in the tube's cavity.

Muzzle-loading weapons discharging spherical lead bullets: two case studies and experimental simulation using a skin-soap composite model.

In current forensic practice, fatal injuries from black powder guns are rare events. In contact and close-range shots, the intensity of GSR deposition (soot, powder particles) is much greater than that in shots with smokeless powder ammunition. The same applies to any burning effects from the combustion gases. Besides, a wad of felt interposed between the propellant and the lead bullet may enter the wound channel. Apart from these findings seen in close-range shots, another characteristic feature results from the mostly spherical shape of the missiles causing maximum tissue damage at the entrance site. Two fatal injuries inflicted with muzzle-loading weapons are reported. In the first case, suicide was committed with a cal. 11.6 mm miniature cannon by firing a contact shot to the back of the neck. In test shots using black powder (1 and 2 g) as propellant, the mean bullet velocity measured 1 m away from the weapon was 87.11 and 146.85 m/s, respectively, corresponding to a kinetic energy of 32.49 and 92.95 J, respectively. Contact test shots to composite models consisting of ballistic soap covered by pig skin at the entrance site were evaluated by CT and revealed cone-like cavitations along the bullet path as known from spherical missiles and penetration depths up to 25 cm. The second case presented deals with a homicidal close-range shot discharged from a muzzle-loading percussion pistol cal. .44. The skin around the entrance site (root of the nose) was densely covered with blackish soot and powder particles, whereas the eyebrows and eyelashes showed singeing of the hairs. The flattened bullet and the wad had got stuck under the scalp of the occipital region. In both cases, there was a disproportionally large zone of tissue destruction in the initial parts of the wound tracks.

Modification of hematoma findings in the breast region.

Subcutaneous bruises caused by blunt injury are common findings in medicolegal case work. If the hematoma involves the anterior thoracic wall, bruises are mostly absent in the region of the nipples and the surrounding areola. A similar phenomenon has already been described for hypostatic skin hemorrhages. A possible explanation for both phenomena is the special tissue texture in the nipple-areola complex. Based on four cases from the forensic autopsy material and two cases from clinical forensic examinations, the macromorphological findings and the histological correlates are presented.

GSR deposition along the bullet path in contact shots to composite models.

In contact shots, all the materials emerging from the muzzle (combustion gases, soot, powder grains, and metals from the primer) will be driven into the depth of the entrance wound and the following sections of the bullet track. The so-called "pocket" ("powder cavity") under the skin containing soot and gunpowder particles is regarded as a significant indicator of a contact entrance wound since one would expect that the quantity of GSR deposited along the bullet's path rapidly declines towards the exit hole. Nevertheless, experience has shown that soot, powder particles, and carboxyhemoglobin may be found not only in the initial part of the wound channel, but also far away from the entrance and even at the exit. In order to investigate the propagation of GSRs under standardized conditions, contact test shots were fired against composite models of pig skin and 25-cm-long gelatin blocks using 9-mm Luger pistol cartridges with two different primers (Sinoxid® and Sintox®). Subsequently, 1-cm-thick layers of the gelatin blocks were examined as to their primer element contents (lead, barium, and antimony as discharge residues of Sinoxid® as well as zinc and titanium from Sintox®) by means of X-ray fluorescence spectroscopy. As expected, the highest element concentrations were found in the initial parts of the bullet tracks, but also the distal sections contained detectable amounts of the respective primer elements. The same was true for amorphous soot and unburned/partly burned powder particles, which could be demonstrated even at the exit site. With the help of a high-speed motion camera it was shown that for a short time the temporary cavitation extends from the entrance to the exit thus facilitating the unlimited spread of discharge residues along the whole bullet path.

Two-gun suicide by simultaneous shots to the head: interdisciplinary reconstruction on the basis of scene investigation, autopsy findings, GSR analysis and examination of firearms, bullets and cartridge cases.

Suicidal shots fired simultaneously to the head from two handguns are rare. The authors report about a recent case in which a Smith & Wesson cal. 9 mm pistol and a Smith & Wesson cal. .357 Magnum revolver were used. Sitting on a sofa, a 33-year-old man (member of a shooting club) fired two simultaneous shots to the head; the pistol held in the left hand was discharged into the left temple, and the revolver held in the right hand was fired into the mouth. Both weapons remained in the respective hands. An upside-down muzzle imprint in the left temporal region and recoil injuries of a mandibular incisor, and the lower lip indicated that both the pistol and the revolver had been held in an inverted manner at the time of discharge. Blood stains (backspatter) and gunshot residues were present on both firing hands, whereas forward spatter originating from the exit wounds was deposited on the wall behind the suicide's head.

Pulmonary arteriovenous malformation causing sudden death due to spontaneous hemothorax.

A sudden death due to hemothorax caused by spontaneous rupture of a congenital pulmonary arteriovenous malformation (AVM) is reported. A 44-year-old woman died unexpectedly with chest pain and dyspnea. The post-mortem examination revealed a massive right-sided hemothorax arising from a subpleural AVM of the upper lobe. There were multiple telangiectases in the tongue and the tonsils, as typically associated with Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia, HHT). The post-mortem molecular genetic analysis proved the presence of a disease-causing mutation in the endoglin gene constituting a predisposition for pulmonary AVMs. According to the literature, almost half of the AVMs in the lung are seen in HHT patients. Based on the presented case and the relevant literature, the article addresses the forensic aspects of fatal hemothorax and the importance of detecting the source of bleeding.

In vitro study of bacterial degradation of ethyl glucuronide and ethyl sulphate.

Recent studies show that ethyl glucuronide (EtG) can be decomposed by bacteria; whilst so far no degradation of ethyl sulphate (EtS) has been observed. In the present study, in vitro experiments with bacterial colonies were performed. Bacteria (Escherichia coli, Klebsiella pneumoniae, Clostridium sordellii) were isolated from autopsy material (liver, heart blood, urine, ascites, pericardial fluid, pleural fluid) tested for beta-glucuronidase activity, and three bacterial strains were added to nutrient-deficient medium containing EtG and/or EtS and incubated at 36 +/- 1 degrees C. Samples were taken after various intervals up to 11 days, and EtG and EtS were determined by electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS). EtG was degraded by E. coli and C. sordellii--complete degradation occurred in the range of 3-4 days--and these bacteria exhibited beta-glucuronidase activity. EtS was not affected within 11 days of incubation.

Postmortem "delivery" in a pregnant fire victim.

A 23-year-old woman traveling in the front passenger seat of a car was killed in a traffic accident involving two rear-end collisions. After the second rear-end collision, the car caught fire. While the driver could be rescued, the pregnant passenger remained inside the car. After the fire had been extinguished, a charred body was found in a pugilistic attitude with an exposed abdominal cavity and a ruptured anterior wall of the gravid uterus. Between the woman's legs, an almost unburned fetus was found with body measurements corresponding to a gestational age of 28 weeks. The placenta had remained inside the uterine cavity and was still connected with the fetus via the umbilical cord. In conclusion, the rupture of the pregnant uterus with expulsion of the fetus had to be considered a secondary event due to the initial heating and subsequent shrinking of the uterine wall.

Patterned imprint mark due to the folded shoulder stock: a possible finding in contact shots from submachine guns.

The muzzle imprint (barrel mark) is a pressure abrasion typically associated with contact shots. Apart from the contours of the actual muzzle profile, other constructional parts such as the front sight and/or the recoil spring guide of semiautomatic pistols may be imprinted next to the bullet entrance wound. In some types of submachine guns the shoulder stock can be folded forward so that its end partly encircles the muzzle. If such a weapon was in contact with the skin at the instant of discharge, a corresponding contusion mark is to be expected. The imprint configuration may point to the type of weapon and to the way in which the gun had been held when firing the shot. The paper presents the injury pattern in a 36-year-old man who committed suicide with a Scorpion SA Vz 61 submachine gun cal. 7.65mm Browning from former Czechoslovakia.