The Present and Future of Clinical Psychology in Private Practice

This article discusses clinical psychologists' current concerns, challenges, and opportunities in private practice. The future of clinicians in independent practice is presented within two paradigms, namely, psychology as a health profession, and psychology as life enhancement. Finally, the author argues that psychotechnology, corporate clinical psychology, and psychology as life enrichment will evolve within the future of clinical psychological independent practice.     

Haemoglobin at time of referral prior to dialysis predicts survival: an association of haemoglobin with long-term outcomes

Haemoglobin (Hgb) levels are known to be associated with numerousadverse outcomes in both chronic kidney disease (CKD) and non-CKDpatients. This analysis evaluates the association of baseline haemoglobinlevels on survival in CKD patients, who are followed by nephrologists,irrespective of glomerular filtration rate (GFR), prior to initiationof renal replacement therapy (RRT) and erythropoietin hormonereplacement therapy. Analysis of data from the provincial database (PROMIS, PatientRegistration and Outcome Management Information System) in BritishColumbia, Canada, was undertaken. Records used for the analysisincluded all CKD patients at first registration: GFR <60ml/min/1.73 m², not yet on dialysis, starting from May 1998to October 2002, and who had complete data (defined as age andgender, diabetic status, eGFR and Hgb levels). The primary objective of this study was to determine the associationof Hgb and survival controlling for eGFR at first registrationvalue, age, gender and diabetic status. Multivariate Cox proportionalhazards analysis with time to death as outcome variable wasperformed. The cohort included 3028 patients: the mean age was 65 years,28% were diabetic, and the mean eGFR in the cohort was 21 ml/min/1.73m². The cohort is representative of the BC CKD and dialysispopulation regarding ethnicity: 64% Caucasian, 32% Asian. Medianfollow-up was 27 months, 1 year survival was 0.92, 2 year survivalwas 0.85. Hgb at initial registration is a statistically independentpredictor of survival (RR = 0.875 for every 10 g/l, 95% CI:0.835–0.917, P = 0.0001), after adjusting for age, gender,diabetic status and baseline eGFR. Further analysis, controllingfor RRT, demonstrated a similar association between Hgb andsurvival (RR = 0.853 for every 10 g/l, 95% CI: 0.799–0.910,P = 0.0001), after adjusting for above variables. Substantialvariation in Hgb values exists at all GFR levels. These findings underscore the importance of evaluating Hgb atall GFR levels, and the need to study the impact of modificationof Hgb at different GFR levels on survival.     

Growth inhibition of estrogen independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist of LH-RH,an analog of somatostatin,or a combination

Summary Female BDF₁ mice inoculated with MXT (3.2) estrogen independent mouse mammary carcinoma were treated for three weeks with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) agonist [D-Trp⁶]LH-RH, the antagonist SB-75, the somatostatin analog RC-160, or combinations. The lack of estrogen dependence of the tumor was proved by bilateral surgical ovariectomy, which had no effect. In two experiments, treatment with 25µg/day doses of each analog alone resulted in a significant inhibition of tumor growth as shown by a 40–53% inhibition of tumor volumes, 38–43% decrease in tumor weights, and histological signs of tumor regression. However, the combination of SB-75 or [D-Trp⁶]LH-RH with somatostatin analog RC-160 caused greater reduction of tumor volume (68 and 61%) or tumor weights (59 and 56%), than single analogs, and histologically the occurrence of apoptosis and decrease in AgNOR numbers was more pronounced in the groups receiving combination therapy. Specific binding sites for [D-Trp⁶]LH-RH, EGF, and IGF-I were demonstrated in the tumor membranes. The binding capacity of LH-RH receptors was decreased by treatment with the analogs, the greatest down-regulation being caused by combination therapy. A significant decrease in EGF binding capacity was observed after treatment with the LH-RH analogs, alone or especially in combination with somatostatin analog RC-160. The combination of these analogs also caused a reduction in IGF-I receptors. The finding that LH-RH agonists and antagonists and somatostatin analogs inhibit the growth of estrogen independent mammary tumors, and that combinations are more effective than single analogs, might be of practical importance in human breast cancer therapy.     

Ventral specification and perturbed boundary formation in the mouse midbrain in the absence of Hedgehog signaling.

Although Hedgehog (HH) signaling plays a critical role in patterning the ventral midbrain, its role in early midbrain specification is not known. We examined the midbrains of sonic hedgehog (Shh) and smoothened (Smo) mutant mice where HH signaling is respectively attenuated and eliminated. We show that some ventral (Evx1+) cell fates are specified in the Shh-/- mouse in a Ptc1- and Gli1-independent manner. HH-independent ventral midbrain induction was further confirmed by the presence of a Pax7-negative ventral midbrain territory in both Shh-/- and Smo-/- mice at and before embryonic day (E) 8.5. Midbrain signaling centers are severely disrupted in the Shh-/- mutant. Interestingly, dorsal markers are up-regulated (Wnt1, Gdf7, Pax7), down-regulated (Lfng), or otherwise altered (Zic1) in the Shh-/- midbrain. Together with the increased cell death seen specifically in Shh-/- dorsal midbrains (E8.5-E9), our results suggest specific regulation of dorsal patterning by SHH, rather than a simple deregulation due to its absence.     

Recirculating and germinal center B cells differentiate into cells responsive to polysaccharide antigens

Antibodies against bacterial capsular polysaccharides play a critical protective role. Responses to these antigens can occur without the help or control of T cells and are associated with marginal zone (MZ) B cells. Capsular antigens are diverse and some cross-react with self-carbohydrate epitopes. This diversity may explain the recruitment of non-autoreactive recirculating B cells and memory B cells to the MZ in addition to other B cells, some of which are weakly autoreactive cells, that are recruited to the MZ without entering the recirculating pool. To test whether memory B cells respond to polysaccharide-based antigens, mice with hapten-specific memory B cells were challenged with hapten-polysaccharide. Hapten-specific plasma cells producing high affinity antibody with Ig V-region mutations were induced. To test whether naive recirculating B cells can form MZ cells that respond to polysaccharide, recirculating B cells from lymph nodes were transferred into Rag-1-deficient mice. MZ cells differentiated from the donor cells without proliferation or T cell help and responded to polysaccharide-based antigen. The differentiation of B cells both from germinal centers and the recirculating pool to the MZ phenotype is likely to make an important contribution to the repertoire of B cells that respond to polysaccharide antigens.     

Efficacy of HIV-specific and 'antibody-independent' mechanisms for complement activation by HIV-infected cells.

Previous studies in this laboratory have shown that efficient activation of complement (C) on HIV isolates and HIV-infected cells requires the binding of specific anti-HIV antibodies, while other investigators have observed 'antibody-independent' C activation. In an attempt to clarify these disparate findings, we investigated the effect of several variables on C activation by HIV-infected cells using flow cytometric analysis of C3 deposition. Antibody-mediated C activation using pooled sera from infected persons or human MoAbs directed against the V3 region of gp120 was always substantially higher than activation without antibody. Normal human serum (NHS) from a subset of HIV antibody-negative donors did, however, induce low levels of C3 deposition. Differences in C3 activation between the various NHS did not correlate with total haemolytic C levels or mannose-binding protein (MBP) levels. IgM isolated from NHS that induced high levels of C activation was at least partly responsible for the 'antibody-independent' C activation. Although there appeared to be a correlation between NHS that induced C activation and the presence of anti-blood type B IgM, absorption of anti-B did not abrogate the C3 deposition. Additionally, MoAb to the B antigen did not induce C3 deposition. These studies show that IgM in sera from HIV-uninfected donors can induce C3 deposition on HIV-infected cells, but that specific antibody-dependent C activation is substantially more efficient. Therefore, 'antibody-independent' C activation on HIV-infected cells may, in some cases, be more accurately described as HIV-cross-reactive antibody-dependent C activation.     

Interferon-α activates cytotoxic function but inhibits interleukin-2-mediated proliferation and tumor necrosis factor-α secretion by immature human natural killer cells

Natural killer (NK) cells play an important role in host defense mechanisms against infection and neoplasia. Interferon- (IFN-) has been shown to activate NK cells and to augment their cytotoxic activity, albeit its role in the maturation pathway of NK cells has not been elucidated. The present study examined whether IFN- activates the immature NK subset (Free cells) to become cytotoxic and also ascertained whether IFN- uses the same pathway of activation as that mediated by interleukin-2 (IL-2). Incubation of sorted Free cells overnight with IFN- resulted in augmentation of their cytotoxic function against NK sensitive target cells. The enhanced cytotoxic activity was not accompanied by a new recruitment of NK-target binder cells but by an increase in the frequency of killer cells in the conjugate fraction. Activation of the Free subset by IFN- resulted in upregulation of CD69, CD11b, and CD2 surface expression and stimulated secretion of IFN-. Unlike IL-2, IFN- did not stimulate the Free cells to proliferate or secrete TNF- and activation of cytotoxicity and modulation of surface antigens by IFN- were independent of TNF-. The failure of IFN- to stimulate secretion and proliferation by Free cells appeared to be mediated by negative signals. This was corroborated in experiments demonstrating that when Free cells were cultured with both IFN- and IL-2, a significant inhibition was observed for both the IL-2 dependent secretion of TNF- and proliferation. These results demonstrate that IFN- serves as both an activator and a regulator of NK function. Further, activation of the immature Free NK cells by IL-2 and IFN- proceeds by TNF--dependent and independent pathways, respectively. The findings also support our contention that the mechanism of activation of the cytotoxic machinery of NK cells is not linked to the mechanism of activation of cytokine secretion and/or proliferation.Abbreviations used IFN interferon - IL interleukin - PBL peripheral blood leukocytes - PE phycoerythrin - PE-GAM PE-conjugated Fab2 goat anti-mouse IgG - NK natural killer - NRS normal rabbit serum - TNF tumor necrosis factor - FCS fetal calf serum - FITC fluorescein isothiocyanate - PBS phosphate-buffered saline - MACS magnetic cell sorting - ELISA enzyme-linked immunosorbent assay - BSA bovine serum albumin - PKC protein kinase C - mAb monoclonal antibody - PBMC peripheral blood mononuclear cells - BCLL B-chronic lymphocytic leukemia - E effector - T target     

A pharmacokinetic approach to the establishment of biopharmaceutic characteristics of different acetylsalicylic acid formulations in man

Eleven acetylsalicylic acid (ASA) formulations were administered to 26 healthy volunteers in a cross-over design. The properties of the preparations differed from conventional, effervescent, buffered to buccal. The objectives of this study were:

• 1 Consideration of the general aspects of a biopharmaceutical study: which parameter for which biopharmaceutic characteristic?
• 2 Measurement of the kinetic parameters of ASA: first-pass effect, mean residence time, mean appearance time, total body clearance, apparent volume of distribution, half-lives, etc.
• 3 Comparison of the formulations.

Most of the formulations yield mean residence times for ASA of 0.3–1.0h, which do not differ significantly (p > 0.05). For most of the products the first-pass effect is about 40 per cent; the average values of the apparent volume of distribution and whole body clearance, corrected for the first-pass effect, are about 201 and 650 ml min^?1, respectively. Peak levels are reached slowly for the buccal formulations, and rapidly for the buffered products. It is difficult, especially for ASA, to characterize the gastro-intestinal absorption with pharmacokinetic model parameters, because the first-pass effect is large and often elimination of ASA is faster than absorption. The model-independent approach has the special advantages of calculating reliable pharmacokinetic parameters, and creating theoretical possibilities to characterize the absorption patterns of the different formulations in a quantitative way. No significant differences in the values of the parameters are found between most of the formulations. The ASA first-pass effect is reasonably constant and buccal application has no advantage. Enteric coating of the outer layer of ASA formulations causes inconsistent absorption and may be categorized under ‘artificial mistakes’.     

DIM对人激素非依赖性前列腺癌细胞PC3M的生长抑制作用

目的：探讨3,3-二吲哚基甲烷(3,3-Diindolylmethane,DIM) 对人激素非依赖性 前列腺癌细胞PC3M的生长抑制作用。方法：应用MTT生长抑制实验观察不同浓度DIM对PC3M细胞增殖活性的影响，流式细胞术观察不同浓度DIM对PC3M细胞的细胞周期及细胞凋亡的影响。结果：不同浓度的DIM对PC3M细胞有显著的增殖抑制作用（P<0.05），药物浓度为10、30、60和120 μmol•L^-1时，抑制率分别为35.6%、58.8%、76.6%和90.5%。当 药物浓度为60 μmol•L^-1时，细胞周期停滞在G₁期，并诱导22.6％的PC3M细胞发生凋亡。结论：DIM可抑制PC3M细胞增殖，并诱导其凋亡，为DIM用于激素非依赖性前列腺癌的治疗提供了实验依据。