5-HTT genotype and inertia of negative affect in adolescents and young adults from the general population.

The study aims to replicate the previous found association of 5-HTTLPR and inertia of negative affect in daily life of adolescents and young adults. Data of 877 adolescents (aged 14-21 years) of the Behavior and Mind Health (BeMIND) study (epidemiological cohort study, Dresden, Germany) were genotyped for 5-HTTLPR/rs25531, grouped into SS/SLG/SLA/LGLA/LGLG vs. LALA, and provided ratings on negative affect items, depression and anxiety (Patient-Reported Outcomes Measurement Information System) eight times a day over 4 days. Multilevel regression models did not reveal an association of 5-HTTLPR genotype and inertia of negative affect, nor associations with inertia of anxiety or depression. Inertia of negative affect seems not to be a psychological mechanism through which 5-HTTLPR acts on psychopathology.

Pulmonary interstitial glycogenosis - A systematic analysis of new cases.

BACKGROUND: Pulmonary interstitial glycogenosis (PIG) is a rare paediatric interstitial lung disease of unknown cause. The diagnosis can only be made by lung biopsy. Less than 100 cases have been reported. Clinical features, treatment and outcomes have rarely been assessed systematically in decent cohorts of patients. METHODS: In this retrospective multicentre study, the clinical presentation, radiologic findings, pattern of lung biopsy, extrapulmonary comorbidities, treatment and outcome of eleven children with PIG were collected systematically. RESULTS: 10/11 children presented with respiratory distress immediatly after birth and 8/11 needed invasive ventilation. In 8/11 children extrapulmonary comorbidities were present, congenital heart defects being the most common. 7/11 children received systemic glucocorticoids and of these four showed a clear favorable response. During a median follow-up of 3.0 years (range 0.42-12.0) one child died, while 10 patients improved. Chest CT-scans showed ground-glass opacities (7/10), consolidations (6/10), linear opacities (5/10) and mosaic attenuation (4/10) without uniform pattern. Besides interstitial thickening related to undifferentiated glycogen positive mesenchymal cells all tissue samples showed growth abnormalities with reduced alveolarization. CONCLUSIONS: PIG is associated with alveolar growth abnormalities and has to be considered in all newborns with unexplained respiratory distress. Apparent treatment benefit of glucocorticosteroids needs to be evaluated systematically.

Attachment representations, patterns of emotion regulation, and social exclusion in patients with chronic and episodic depression and healthy controls.

BACKGROUND: The experience of social exclusion (ostracism) is linked to the etiology and maintenance of depression. Most individuals experience emotional stress in states of social exclusion. Insecurely attached individuals, especially with an unresolved trauma, show maladaptive coping in response to social stress. The present study examines (a) the differences with regards to attachment representations in episodic (ED) and chronic depressive (CD) inpatients and (b) how ostracism affects their emotional reactions. METHODS: Patients with CD (n=29) and ED (n=23) and healthy control subjects (n=29) were interviewed using the Adult Attachment Projective Picture System (AAP), a valid measure to assess attachment representation; and played a virtual ball tossing game simulating social exclusion (Cyberball). Multiple depression-related risk and protective factors were considered. We hypothesized that CD patients show the most severe attachment disorganization and are emotionally most affected by the social exclusion situation. Moreover, we explored the interaction between ostracism and attachment. RESULTS: Contradicting our hypotheses, ED and CD individuals were almost akin with regards to their attachment insecurity/disorganization and reactions to Cyberball. An emotionally altered reaction to social exclusion was identified in the insecure-disorganized depressive subgroup. LIMITATIONS: Small sample size hampering further subgroup analyses. The ED sample may include single CD subjects with recent manifestation. CONCLUSIONS: The pattern of emotion regulation in the depressive groups matches with findings from clinical studies, including attachment research. The relationship between attachment representations and ostracism should be further investigated in larger samples of depressive individuals.

Promising pharmacological agents in the management of acute spinal cord injury.

The search for a pharmacologic treatment of acute spinal cord injury (SCI) dates back to the 1960s. It was not until 1990 that the pharmacologic agent methylprednisolone demonstrated improved outcomes in humans. Methylprednisolone has shown superiority to placebo in humans in two large, multicenter trials, and is the standard of care thus far. Other potentially useful agents include tirilazad, ganglioside (GM-1), and naloxone. Additional studies are needed for these agents to determine the optimal dose and timing of administration.

Hematologic and clinical chemistry reference values in red lories (Eos spp.).

We established reference ranges for three hematologic and 15 clinical chemistry parameters of 40 clinically healthy birds of the genus Eos. The following species were included to the study: Eos histrio (n = 19), Eos squamata (n = 8), Eos bomea (n = 5), Eos reticulata (n = 4), Eos cyanogenia (n = 4). Detailed information concerning methodology, which is often missing in papers dealing with reference values, is included. As far as possible, data are compared with literature, and some thoughts on obvious deviations are given. The problem of establishing reference values in rare species is reviewed.

[Improved tumor stent for internal palliative urinary diversion]. / Neu entwickelter Tumorstent zur internisierten palliativen Harnableitung.

The disadvantages of high flexible endoureteral stents (DJ) in case of tumorinduced extrinsic ureteral compression are due to an insufficient vertical stability of the used stents leading to stent-compression and consecutive hydro- or pyonephrosis. The new developed tumor-stent used in case of tumor-induced ureteral compression is available from 6 to 8 French in diameter and 24 to 32 cm in length. The corpus consists of a combination of high-stability plastics but is of sufficient elasticity in length. Both ends consist of extremely elastic J-parts guaranteeing an exact fixation. As against common DJ's with the same outside-diameter the new stent has a comparable interior diameter and compared to used "old" tumor stents promises a higher interior flow in case of extrinsic diseases. The application can be undertaken in well-known technique, needs no special instrumentation and no learning-curve. To date 52 stents at our urologic departments were placed without any problems, the latest remaining for 15 months. Tumor-induced compression or a higher rate of encrustation could not be seen. All patients tolerated these stents well. In our opinion the new stabilized endoureteral stent can be seen as a better solution instead of percutaneous nephrostomy or frequent stent changing in patients with tumor induced extrinsic ureteral compression.

Promising pharmacological agents in the management of acute spinal cord injury.

The search for a pharmacologic treatment of acute spinal cord injury (SCI) dates back to the 1960s. It was not until 1990 that the pharmacologic agent methylprednisolone demonstrated improved outcomes in humans. Methylprednisolone has shown superiority to placebo in humans in two large, multicenter trials, and is the standard of care thus far. Other potentially useful agents include tirilazad, ganglioside (GM-1), and naloxone. Additional studies are needed for these agents to determine the optimal dose and timing of administration.

New endoureteral double-J stent resists extrinsic ureteral compression.

The disadvantages of highly flexible endoureteral (double J) stents in the face of tumor-induced extrinsic ureteral compression are a consequence of insufficient cross-sectional stability, leading to stent compression and thus to hydronephrosis or pyonephrosis. The newly developed tumor stent, which is used in cases of tumor-induced ureteral compression, is available in sizes from 6F to 8F in diameter and 24 to 32 cm in length. The shaft consists of a combination of high-stability plastics that presents sufficient elasticity in length. Both ends are made of extremely elastic J parts, guaranteeing stable fixation. Compared with common double-J stents with the same outside diameter, the tumor stent possesses a comparable interior diameter and compared with available stents promises sufficient interior flow in the face of extrinsic diseases. The application can be undertaken using well-known endoscopic techniques, needs no special instrumentation, and entails no learning curve. To date, 49 stents were placed at our urologic departments without any problems, the latest stent remaining for 15 months. Tumor-induced compression or a higher rate of encrustation were not seen. All patients tolerated these stents well. In our opinion, the new stabilized endoureteral stent can be seen as a better solution than percutaneous nephrostomy or frequent stent changing to tumor-induced extrinsic ureteral compression.

Sedatives, analgesics, and paralytics in the ICU.

OBJECTIVE: To solicit practitioner-perceived opinions regarding current sedative/analgesic/paralytic practice including drug selection, admixture methods, and methods of assessing patient response to therapy via surgery tool; and to assess sedative/pain/paralytic drug use patterns including dosage, route selection, and combination therapy by collecting actual drug administration data from multiple centers. METHODS: Respondents completed a survey and collected drug administration data for 5 consecutive days in the intensive care unit (ICU) in which they practiced. PARTICIPANTS: One hundred thirty-eight members of the Society of Critical Care Medicine Clinical Pharmacology and Pharmacy section and the Critical Care Practice Research Network of the American College of Clinical Pharmacy agreed to participate in the study. RESULTS: Fifty-one percent of the participants completed surveys, and 45% returned drug administration data collection forms. Patients received sedative/pain/paralytic therapy 62% of the 5 days studied. The most frequently received drugs were opiates, followed by benzodiazepines. Intermittent intravenous injection, oral/enteral, and continuous infusion methods were used in most patients. Combination therapy was used 25% of the time, with benzodiazepine/opiate combinations used most often (46%). Administration protocols were rarely used. Paralytic agents were occasionally administered without sedative/pain therapy. CONCLUSIONS: Patients received these agents during the majority of their ICU stay. Multicenter drug use data suggested a preference for opiate and benzodiazepine therapy. Many centers used continuous infusion therapy despite minimal pharmacokinetic/pharmacodynamic information on ICU patients. Further studies are needed to standardize end points, as well as obtain both pharmacokinetic/pharmacodynamic and stability data in ICU patients.

Deprotonation and hydride shifts in nitrenium and iminium forms of aminoimidazole-azaarene mutagens.

The mutagenicity of many 2-aminoimidazole-azaarenes (AIA) is thought to be mediated by the nitrenium form of the exocyclic amine. This hypothesis is supported by the numerous correlations found between calculated and experimentally-measured chemical properties for the nitreniums and the mutagenic potencies of the nitreniums and their parent amines. One factor favoring high mutagenic potency is the presence of a methyl substituent in the 1- or 3-imidazole position. In this paper, we investigate both the deprotonation of the imidazole ring nitrogens in non-N-methylated AIA mutagens and the plausibility of a chemical pathway involving a 1-4 hydride shift to form an iminium ion, thereby stabilizing the cationic N-methyl substituted AIA mutagens. It has been widely noted that factors that stabilize the nitrenium moiety lead to significantly higher mutagenic potency; hence, the transformation of the nitrenium to a more stable species might be expected to increase the potency, provided that it does not eliminate the electrophilic reactivity of the compound. Using ab initio quantum chemistry and polarizable continuum solvation models, we find that the imidazole ring nitrogens of the nitrenium ions are extremely acidic. This suggests that upon formation of the exocyclic nitrenium these sites will deprotonate to form a neutral imine. We have also studied the 1-4 hydride shift from an imidazole ring methyl to the exocyclic nitrenium to form an iminium. We predict that for AIA mutagens with just two fused rings the resulting iminium species are more stable in the gas phase than the corresponding nitreniums. For mutagens with larger conjugated systems, the nitrenium is stabilized by resonance and is more stable than the corresponding iminium. In the aqueous phase, however, the iminium form is predicted to be more stable than the nitreniums for all polycyclic compounds studied. Although equilibrium calculations favor the iminium form, these have been experimentally shown to be short-lived and their actual concentration will depend on the complex kinetics of AIA mutagen metabolism. The quantum chemical results also show a strong correlation between the relative iminium-nitrenium energy difference and the charge on the exocyclic nitrogen.

Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes.

A set of 16 mutagenic aminoimidazo-azaarenes, including four that have been isolated from cooked foods and identified as bacterial mutagens and rodent carcinogens, was selected from a larger series previously published [Hatch et al. (1991): Environ Mol Mutagen 17:4-19] for an in-depth structure-activity study using computational methods. Structural features believed to affect mutagenic potency were tabulated. Molecular orbital energies and other electronic properties of these compounds were calculated using Huckel, semiempirical AM1, and ab initio quantum mechanical methods. Factor interrelationships were studied by multiple linear regression and canonical correlation analyses. Our goal was an improved understanding of the chemical basis of mutagenicity for this class of heterocyclic amines. The major findings were as follows: 1) mutagenic potency is related to the size of the aromatic ring system; 2) potency is enhanced by the presence and location of an N-methyl group; 3) potency is enhanced by addition of ring nitrogen atoms in pyridine, quinoline, and quinoxaline configurations; 4) potency is inversely related to the energy of the LUMO (lowest unoccupied molecular orbital) of the parent amines; 5) potency is directly, though weakly, related to the LUMO energy of the derived nitrenium ions; and 6) the calculated thermodynamic stability of the nitrenium ions (relative to the parent amine) is directly correlated with nitrenium LUMO energy and with the negative charge on the exocyclic nitrogen atom. Although this study raises several intriguing issues relating mutagenicity to chemical properties, further study will be required to determine the plausibility of the nitrenium ion as the ultimate mutagen for binding to DNA.

Dibenzo[a,f]quinolizines: syntheses and cytostatic activity in estrogen-sensitive tumor cells.

A number of methoxy-substituted 7,11b,12,13-tetrahydro-6H-dibenzo-[a,f]quinolizines with short alkyl groups in position 6 or 12 were synthesized by the Bischler-Napieralski reaction using the appropriate starting material followed by a second ring closure reaction involving a base-generated benzyne intermediate. The methoxy functions in positions 2 or 3 and 9 were cleaved with BBr3 and the free hydroxy groups converted into the acetates. The enantiomers of two of these derivatives were separated by liquid chromatography on triacetylcellulose. Compounds with alkyl substituents bind strongly to the estrogen receptor except those with a cis-orientation at the central ring connection. The RBA values ranged from 2.2-10.8 (17 beta-estradiol: RBA = 100). There was no major difference in binding between the (+) and (-)-enantiomers. The 3,9-diacetoxy-6-alkyl derivatives also showed binding affinity for the progesterone receptor (RBA: 1.2-3.1). The 2,9-diacetoxydibenzoquinolizines trans-61 and -6m with ethyl and propyl respectively in position 12 strongly inhibited the growth of hormone-sensitive MCF-7 breast cancer cells at concentrations of 10(-6) M and higher but were inactive in hormone-independent MDA-MB 231 breast cancer cells. Preliminary tests with hormone-dependent MXT mouse mammary tumors as model showed that these compounds have also antineoplastic activity in vivo. Derivative trans-61 at a dose of 20 mg/kg body weight, administered 3 times/week, inhibited the growth of these tumors by 78% (tamoxifen: 76% inhibition). Studies on the estrogenic and antiestrogenic properties of these agents in mice revealed that they are mixed agonists/antagonists with strong antiestrogenic activity at low doses but significant estrogenic effects at higher doses.