The probability of treatment success,failure and duration—what can be learned from empirical data to support decision making in clinical practice?

Empirical methods have been found to be superior to clinical judgment for the purpose of correctly identifying patients at risk for treatment failure and, hence, to enhance psychotherapy outcomes. The development and evaluation of an empirical approach aimed at supporting clinical decisions during the course of psychotherapy is described. The tool provides predictions based on a patient‐specific sampling strategy called the nearest neighbors method and on growth curve approaches to model an expected treatment course for each patient. Using session‐by‐session data from an outpatient center in the US (N = 4365), this new empirically derived decision model was evaluated and compared with a clinically based approach loosely based on an adaptation of clinically significant change concepts. The empirically derived decision system was found to be superior to the rational clinically based one in almost all measures of prediction accuracy, indicating its potential to identify patients at risk for treatment failure. Copyright © 2006 John Wiley & Sons, Ltd.     

Parental perception of neonatal intensive care in public sector hospitals in South Africa.

BACKGROUND: Little is known about parental experience and decision making with regard to premature infants requiring intensive care in developing countries. We undertook this study to characterise parents' experience of physician counselling and their role in making life-support decisions for very low-birth-weight (VLBW) (birth weight < 1 501 g) infants born in South Africa's public-sector neonatal intensive care units (NICUs). METHODS: Parents of surviving VLBW infants treated in three Johannesburg-area public hospitals and attending follow-up clinics in August 2001 were interviewed regarding their experience of perinatal counselling on outcomes (pain, survival, disability), perception of actual and optimal decision making, and satisfaction with NICU communication. RESULTS: Parents of 51 infants were interviewed. Seventy-five per cent of parents reported antenatal counselling by physicians on at least one perinatal topic (severe disability, pain, death, finances or religious/moral considerations). The majority of parents (> 60%) who received counselling thought that these topics had been discussed adequately. Most parents reported that doctors had the primary decision-making role, either without consulting them (41%) or after consulting them (37%). Joint decision making was rare (14%). Parents wanted more input in life-support decisions than they reported being given. CONCLUSION: Counselling is not consistently provided in public-sector hospitals in Johannesburg. Parents of premature infants want a larger share in NICU decision making than they currently experience. Most parents were satisfied with communication later during their infant's hospitalisation. South Africa presents a unique opportunity to study the use of advanced medical technologies in a nation with marked disparities in access to care.     

Development of nitric oxide synthase-defined neurons in the sea urchin larval ciliary band and evidence for a chemosensory function during metamorphosis.

We previously reported that initiation of metamorphosis of larvae of Lytechinus pictus is negatively regulated by nitric oxide (NO) and cGMP. We have examined the expression of nitric oxide synthase (NOS) and cGMP in cells of the developing larva. A section of the post-oral ciliary band of feeding larvae includes neural cells defined by their expression of both NOS and the echinoderm neural-specific antibody 1E11. These neurons project processes to the pre-oral neuropile during larval development. Larvae regenerated this section of the ciliary band after its excision, complete with NOS-defined neurons that projected again to the pre-oral neuropile. Excision of ectoderm containing the post-oral ciliary band prevented a behavioral and morphogenetic response of competent larvae to biofilm, and delayed initiation of metamorphosis. Elevated cGMP levels were detected in several larval and juvenile cell types prior to metamorphosis. Treatment of larvae with ODQ, an inhibitor of soluble guanylate cyclase, decreased cGMP levels and induced metamorphosis while a generator of NO counteracted this effect, indicating inhibition of metamorphosis by NO operates via interaction with soluble guanylate cyclase. We discuss these observations, proposing that the NOS-defined neurons in the post-oral ciliary band have a chemosensory function during settlement and metamorphosis that involves morphologically specialized ectoderm and manipulation of fluid flow. We provide a tentative cellular model of how environmental signals may be transduced into a metamorphic response.     

Investigations of the immunomodulatory effect of cyanobacterial extracts]

Resulting from the knowledge that cyanobacteria (blue-green algae) are able to produce pharmacologically active substances the aqueous extracts from several cyanobacteria species and strains (Microcystis aeruginosa, Synechocystis aquatilis, Oscillatoria redekei, Anabaena flos-aque, Aphanizomenon flos-aquae, Oscillatoria rubescens, Oscillatoria tenuis) were tested for their immunomodulating activity. Extracts from Oscillatoria redekei 051, Oscillatoria tenuis 01 and Synechocystis aquatilis 428 caused an immunosuppression. They inhibited not only the incorporation of 3H-thymidine into mitogen stimulated lymphocytes but reduced also the number of plaque-forming cells of mice as shown by hemolysis-plaque-assay. Only extracts from Oscillatoria redekei 051 did not show any cytotoxic effects in lymphocyte cytotoxic test. This may be an evidence for a specific action on the proliferation of lymphocytes.     

Uptake of technetium 99m MDP by hepatoblastoma

Focal uptake of ^99mTc-MDP was seen in a case of hepatoblastoma. The focal uptake corresponded to an area of calcification on CT, which was shown histologically to consist of osteoid with mineralization. The mechanism of uptake by the tumor in this case is likely to be the same as for skeletal uptake.     

Pathogenesis of nodular goiter and its implications for surgical management

Despite sufficient iodine supply, goiter continues to be of considerable surgical significance in formerly endemic countries. It now appears that iodine deficiency and increased thyrotropin stimulation are not the only causes of goiter. Xenotransplantation of human thyroid tissue onto nude mice allowed study of the regulation of growth and function in human goiter tissue. Grafts of human thyroid tissue growing in nude mice could be shown to react to endogenous mouse thyrotropic stimulation and suppression. 131I autoradiographs of xenotransplanted goiter tissue showed as marked a heterogeneity as did the original goitrous tissue prior to transplantation. There was no firm correlation between the morphologic appearance of a follicle and its iodine metabolism. Scintigraphically "cold" and "hot" goiter tissue differed from each other quantitatively but not qualitatively; i.e., both "hot" and "cold" tissue were composed of metabolically active and nonactive follicles. Iodine organification was not completely suppressible by thyroxine treatment; this indicates autonomous functional activity. The distribution of proliferating tissue labeled by 3-H-thymidine did not parallel the distribution of functionally active tissue labelled by 131I. Thyroxine treatment did not completely inhibit 3-H-thymidine incorporation, indicating autonomous growth. Thus, our pathogenetic concept of goiter formation is based on three mainstays: (1) goiter heterogeneity, (2) autonomy of growth and function, and (3) dissociation of growth and function in human goiter tissue. Thus, the surgeon dealing with goiter ought to remove all pathologically altered tissue, i.e., nodular tissue, irrespective of its appearance on scintiscans.     

Conformational analysis and molecular modeling of 1-phenyl-, 4-phenyl-, and 1-benzyl-1,2,3,4-tetrahydroisoquinolines as D1 dopamine receptor ligands

Conformational studies on a series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1,2,3,4-tetrahydroisoquinolines that possess an identical substituent pattern to the prototypical D1 dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine (1)] were performed with use of molecular mechanics calculations [MM2(85), with newly developed aromatic halide bending and torsional parameters that are now incorporated into MM2(87)], single-crystal X-ray analysis, and high-field NMR spectroscopy. The synthesis and biological testing of compounds 2-7 has been previously reported. The test compounds were compared both quantitatively and graphically to compound 1. Calculations on both the free-base and protonated forms of each compound were carried out. To insure that conformation space was adequately sampled, the test compounds were energy minimized from different starting geometries; ring inversion of the heterocycle was employed, as were dihedral driver calculations on the phenyl or benzyl rings. For N-methyl-6-chloro-7-hydroxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (2), it was determined that the torsion angle tau(C8a-C1-C12-C17) had energy minima at approximately 60 degrees and 240 degrees. This finding was corroborated by NMR studies that indicated a dramatic upfield chemical shift of ArH8 after ring cyclization. The nitrogen lone pair or hydrogen vector was approximately orthogonal to the plane of the substituted aromatic ring in the tetrahydroisoquinolines; this explained the upfield chemical shift of the vicinal chiral proton (H1). In all instances, the 6-membered heterocyclic ring in the energy-minimized structures preferred the half-chair conformation with the phenyl rings pseudo-equatorial. Distance comparisons of the proposed pharmacophoric atoms (Cl, N, O, centroid of the phenyl or benzyl ring) showed that the phenyl or benzyl centroid to ammonium H distance, Cl to N distance, and distance of the nitrogen above or below the plane of the isoquinoline aromatic ring are the distances most highly correlated with biological activity (r = 0.82, 0.75, 0.81, respectively). Resolution and single-crystal X-ray analysis of compound 2 showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-1. Least-squares fitting of the energy-minimized structures with SYBYL molecular modeling software showed (S)-(+)-2, rather than (R)-(-)-2, gave a better fit to (R)-1. Volume determinations derived from SYBYL multifit analyses aided in receptor mapping to qualitatively describe areas of "active" pharmacophore space as well as areas of "inactive" substituent space.(ABSTRACT TRUNCATED AT 400 WORDS)     

Bb2Bb3 regulation of murine Lyme arthritis is distinct from Ncf1 and independent of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase

Several quantitative trait loci regulating murine Lyme arthritis severity have been mapped, including a highly significant linkage found on chromosome 5, termed Bb2Bb3. Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species. To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice. This increased Lyme arthritis severity, whereas the reciprocal transfer conferred protection from disease. A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1. Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles. Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex. Together, these results argue that Ncf1 is not a candidate gene for regulation of Lyme arthritis and reveal Lyme arthritis to be independent of NADPH oxidase activity, distinguishing it from other models of rheumatoid arthritis.     

Proteinase-activated receptor 2 activation in the airways enhances antigen-mediated airway inflammation and airway hyperresponsiveness through different pathways

BACKGROUND: Serine proteinases such as mast cell tryptase, trypsin-like enzymes, and certain allergens are important in the pathogenesis of asthma. These proteinases can activate the proteinase-activated receptor (PAR)-2, which has been shown to be upregulated in the airways of patients with asthma. OBJECTIVE: The purpose of this study was to investigate PAR-2 activation in the airways during allergen challenge and its effects on the 2 principle features of asthma, airway inflammation and airway hyperresponsiveness (AHR). METHODS: Proteinase-activated receptor 2 activating peptide SLIGRL-NH2 (PAR-2 activating peptide [ap]) or control peptide LSIGRL-NH2 (PAR-2 control peptide [cp]) was administered alone or in conjunction with ovalbumin intranasally to mice, and AHR and airway inflammation were evaluated. RESULTS: PAR2ap did not induce AHR or airway inflammation in ovalbumin-sensitized mice that had not been challenged with ovalbumin. When administered with ovalbumin, PAR-2ap enhanced AHR and airway inflammation compared with ovalbumin administered alone or with PAR-2cp. The enhanced AHR persisted for 5 days, whereas the enhancement to airway inflammation dissipated. Mice administered PAR-2ap alone during the 5 days after the final antigen challenge demonstrated an additional enhancement to airway inflammation compared with the control animals. PAR-2ap administered with allergen increased TNF and IL-5 mRNA in lung tissue and IL-13 and TNF in bronchoalveolar lavage fluid. CONCLUSION: Exogenous PAR-2 activation in parallel with allergen challenge enhances allergen-mediated AHR and airway inflammation through distinct mechanisms. PAR-2 activation can also enhance established airway inflammation even when dissociated from exposure to allergen. Therefore, PAR-2 activation may play a pathogenic role in the development of AHR and airway inflammation.