Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers.

The multiple-dose pharmacokinetics, safety, and tolerability of oral bosentan, a selective endothelin receptor antagonist, were investigated in healthy male volunteers. In study A, an ascending-dose, double-blind, placebo-controlled trial, doses of 100, 200, 500, and 1000 mg bosentan or placebo were given once daily for 8 days as tablets (100 and 500 mg dose strength). In study B, a double-blind, placebo-controlled trial, 500 mg tablets of bosentan or placebo tablets were given once daily for 8 days with two additional single intravenous dose administrations of 250 mg bosentan 48 hours before the first and 24 hours after the last oral dose. The drug was very well tolerated. No effects on pulse rate, ECGs, or clinical laboratory tests were observed. Marginal effects on blood pressure were seen in subjects only when standing. The oral bioavailability of bosentan was 43% to 48%, with a small interindividual variability of 20%. Doses above 500 mg did not lead to significant further increases in plasma levels of bosentan. From the first to the last day of the oral treatment phase, plasma concentrations of bosentan decreased by 30% to 40% due to a 2-fold increase in plasma clearance. Absorption and plasma protein binding did not change. The 24-hour urinary excretion of 6 beta-hydroxycortisol was increased in parallel by approximately 1.7-fold, indicating induction of cytochrome P450 3A isozymes. The two metabolites of bosentan reached plasma concentrations well below those of bosentan and will most likely not contribute to the pharmacological activity.     

Contribution of patient and hospital characteristics to adverse patient incidents.

The 1974 medical malpractice "crisis" brought about extensive legislation and insurance regulation in the United States. Hospitals in many states are now required to support risk management programs that include investigation and systematic analyses of adverse patient incidents. However, no research supports the hypothesis that systematic analysis of adverse patient incidents can identify contributory factors. In this study, a simple prediction model was used to estimate relationships between adverse incidents and selected patient and environmental characteristics in a large hospital. While some of the incident-characteristic relationships were significant, none of the estimated equations yielded results that could be logically translated into policy recommendations for the hospital. These results point to the need for further research. The benefits that positive research results would have for patients, hospitals, an the bill-paying public are obvious. Additional negative results would suggest that many legislative bodies and regulatory agencies were presumptions in requiring hospitals to conduct analyses of incidents.     

Differential typology among patients with hard and soft suicide methods

Two samples of patients admitted during one year after suicide attempts were compared: patients of the University Surgical Department in Heidelberg and a random sample of those who were admitted to the detoxication ward of the University Department for Internal Medicine. The frequency of patients who used "hard" methods was 10% of those using "soft" methods. Patients with hard suicide methods displayed more social desintegration, were more often psychiatrically ill, had a shorter presuicidal phase, a shorter time span from decision to execution of the suicidal attempt, more negative self-esteem and more chronic suicidality. Aggressiveness was low in both groups. Although the number of patients with "hard" suicidal methods is small and does not justify a special service in the Surgical Hospital, these patients need particularly careful supervision because of their psychopathological and psychosocial profile.     

Contaminated sediments from tributaries of the Great Lakes: Chemical characterization and carcinogenic effects in medaka (Oryzias latipes)

Sediments from four inshore industrial sites and a reference site in the Great Lakes were extracted with organic solvents to produce a crude extract, which was separated on alumina into two fractions: predominantly polycyclic aromatic hydrocarbons; and predominantly nitrogencontaining polycyclic aromatic compounds. Crude extracts were redissolved in acetone and analyzed by gas chromatography and gas chromatography-mass spectrometry. The acetone-redissolved crude extracts from the four industrialized sites contained 5.6–313.3 g total polycyclic aromatic compounds/g sediment and 3.0–36.4 g other compounds/g sediment. In addition to the typical EPA priority pollutants, a substantial amount (228.7 g/g sediment) of alkyl-polycyclic-aromatic compounds was detected in sediments from one of the industrialized sites. Extracts from the reference site contained 1.55 g total polycyclic aromatic compounds/ g sediment. Medaka (Oryzias latipes) were exposed to multiple pulse doses of acetone-redissolved extracts and fractions. Medaka were also exposed to a known carcinogen, methylazoxymethanol acetate, to verify that chemicals produced tumors in the test fish. Acetone-redissolved extracts and fractions from contaminated sediments were toxic to medaka. Fin erosion and non-neoplastic liver abnormalities were more prevalent in medaka after exposure to acetoneredissolved extracts and fractions from contaminated sediments. Neoplasms previously associated with chemical exposure in wild fishes were induced in medaka exposed to acetone-redissolved extracts and fractions from two of the contaminated sites, but not from the reference site or controls. These findings further support the hypothesis that chemical contaminants in sediments are involved in epizootics of neoplasms in wild fishes at contaminated sites.     

Children and adolescents with velocardiofacial syndrome: a volumetric MRI study

OBJECTIVE: Velocardiofacial syndrome is a common genetic condition often accompanied by mild cognitive impairment. Children and adolescents with velocardiofacial syndrome also are at greater risk for developing serious neuropsychiatric disorders in adulthood, particularly schizophrenia-like disorders. The purpose of this preliminary study was to 1) elucidate through brain imaging the neurobiological basis of cognitive and neuropsychiatric problems in velocardiofacial syndrome, and 2) consider the association between variations in neuroanatomy in velocardiofacial syndrome subjects and the associated neurobehavioral phenotype. METHOD: Fifteen children and adolescents with velocardiofacial syndrome were matched by age and gender with 15 comparison subjects. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of specified brain tissues and regions. Rater-blind morphometric analyses were conducted to examine tissue volumes of the four lobes and the cerebellum. RESULTS: Total brain volume was approximately 11% smaller in the children with velocardiofacial syndrome. Gray matter volume was reduced to a lesser extent (7.5%) than white matter volume (16.3%). Multivariate analyses of variance indicated a distinct pattern of regional morphological variation among the children with velocardiofacial syndrome. Specifically, frontal lobe tissue tended to be enlarged relative to the overall reduction in brain volume. Normal symmetry of parietal lobe tissue observed in the comparison group was not evident in the velocardiofacial syndrome group. This loss of symmetry was attributable to a significant reduction of gray matter in the left parietal lobe. CONCLUSIONS: Aberrant brain morphology is associated with velocardiofacial syndrome. These changes are potentially related to the language and learning deficits associated with the syndrome and may provide clues about neurodevelopmental pathways associated with schizophrenia.     

Zum anatomischen Substrat der epigastrischen Aura Ein Fallbericht

Epigastric sensations are the most frequent type of aura in medial temporal lobe epilepsy. Until now, the site of the symptomatogenic zone of the epigastric aura remains controversial. The temporal lobe has been discussed, as well as the insular cortex. The case presented here supports the assumption of an insular origin of the epigastric aura. A 44-year-old male suffered from typical psychomotor seizures preceded by an epigastric aura. Imaging revealed a cavernoma located in the right insular region, the ipsilateral temporal lobe being otherwise unremarkable. The lesion was surgically removed, leaving the temporal lobe untouched. Apart from one clinical episode that was unlike his habitual seizures, the patient remained free of seizures (including auras). We conclude that the insular cortex was most likely the symptomatogenic zone for this patient's epigastric auras. Although it can not be excluded that this patient's aura resulted from ictal activation of other brain structures, the successful lesionectomy is in favor of our hypothesis.     

Kahnbeinfrakturen – Diagnostik, Klassifikation und Therapie

Herbert's classification of scaphoid fractures provides the underlying rationale for treatment according to the fracture type. A CT bone scan in the long axis of the scaphoid is the best means of differentiating between stable and unstable fractures. This is difficult from conventional X-rays due to the particular three-dimensional anatomy of the scaphoid. To avoid long-term plaster immobilization and to diminish the risk of a nonunion, unstable fractures of type B should be fixed operatively. With headless screws such as the Herbert screw, which are now available in a cannulated shape, the majority of scaphoid fractures of type B1 and B2 can be stabilized using minimally invasive procedures. Severely displaced fractures require the classical open palmar approach. Proximal pole fractures (B3) are best managed from the dorsal approach, using the Mini-Herbert screw. Stable fractures of type A2 can be treated conservatively in a below-elbow cast or, alternatively, stabilized percutaneously, which allows early mobilization.     

Colorectal cancer screening knowledge, attitudes, and beliefs among veterans: does literacy make a difference?

PURPOSE: To evaluate whether lower literacy is associated with poorer knowledge and more negative attitudes and beliefs toward colorectal cancer screening among veterans without recent colorectal cancer screening. PATIENTS AND METHODS: Three hundred seventy-seven male veterans, age 50 years and older, who had not undergone recent colorectal cancer screening, were surveyed about their knowledge, attitudes, and beliefs regarding colorectal cancer screening. Patients' literacy was assessed with the Rapid Estimate of Adult Literacy in Medicine, an individually administered screening test for reading. RESULTS: Thirty-six percent of the 377 men had an eighth grade literacy level or higher. Men with lower literacy were 3.5 times as likely not to have heard about colorectal cancer (8.8% v 2.5%; P =.006), 1.5 times as likely not to know about screening tests (58.4% v 40.9%; P =.0001), and were more likely to have negative attitudes about fecal occult blood testing (FOBT), but not about flexible sigmoidoscopy. Specifically, men with lower literacy skills were two times as likely to be worried that FOBT was messy (26.7% v 13.3%; P =.008), 1.5 times as likely to feel that FOBT was inconvenient (28.7% v 18%; P =.05), and four times as likely to state they would not use an FOBT kit even if their physician recommended it (17.9% v 4.0%; P =.02). CONCLUSION: Limited literacy may be an overlooked barrier in colorectal cancer screening among veterans.