Functional overexpression of wild‐type p53 correlates with alveolar cell differentiation in the developing human lung

At 15 weeks after conception (a.c.), the human pulmonary acinus is lined by distal low‐columnar and more proximal cuboidal cells that are successive stages in alveolar type II cell differentiation (pseudoglandular period of lung development). From 16 weeks a.c. onward, there are also 'flatter' cells that are intermediate stages in the differentiation of cuboidal type II cells into squamous type I cells (canalicular period). We investigated the role of wild‐type p53 protein and the proliferation marker Ki‐67 in the differentiation of type II and type I cells in these two periods. Serial sections from fetal lungs (n = 30) were immunoincubated with antibodies against p53 and Ki‐67. The presence of prospective type II and type I cells was confirmed using immunohistochemistry for surfactant protein SP‐A as a differentiation marker and light and electron microscopy. The p53 and Ki‐67 positive nuclei were quantified per alveolar cell phenotype (i.e., low‐columnar; cuboidal; flatter). The occurrence of cell apoptosis was studied using propidium iodide (PI) and 4′,6′‐diamino‐2‐phenylindol dihydrochloride (DAPI) staining. The combined increase in p53 expression and decrease in Ki‐67 expression during alveolar epithelial cell differentiation suggests that wild‐type p53 protein plays a role in the differentiation of alveolar type II and type I cells in the human lung, and that this function is mediated through cell cycle arrest. The rare incidence of apoptotic nuclei in alveolar type II cells, together with their absence in alveolar type I cells, supports the view that p53 is involved in the differentiation, rather than the death, of alveolar epithelial cells. Anat Rec 263:25–34, 2001. © 2001 Wiley‐Liss, Inc.     

Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells

Androgen ablation is the primary treatment modality for patients with metastatic prostate cancer; however, the role of androgen receptor signaling in prostate cancer development remains enigmatic. Using a series of genetically defined immortalized and tumorigenic human prostate epithelial cells, we found that introduction of the androgen receptor induced differentiation of transformed prostate epithelial cells to a luminal phenotype reminiscent of organ-confined prostate cancer when placed in the prostate microenvironment. Moreover, androgen receptor expression converted previously androgen-independent, tumorigenic prostate epithelial cells into cells dependent on testosterone for tumor formation. These observations indicate that androgen receptor expression is oncogenic and addictive for the human prostate epithelium.     

The Children's Somatization Inventory: further evidence for its reliability and validity in a pediatric and a community sample of Dutch children and adolescents

OBJECTIVE: To examine the psychometric properties of the Children's Somatization Inventory (CSI) in the Netherlands. METHOD: The CSI and a number of personality and psychopathology questionnaires were administered to Dutch schoolchildren (N = 479), children referred to a pediatric clinic (N = 63), and children's parents. RESULTS: Factor analysis yielded a number of factors that have also been found in previous research, viz., pain/weakness, gastrointestinal symptoms, and pseudoneurological symptoms. The reliability (internal consistency) of the CSI was satisfactory. Furthermore, support was obtained for the validity of the CSI. More specifically, the scale correlated in a theoretically meaningful way with child and parent reports of personality and psychopathology, and discriminated well between healthy and pediatric children. Finally, highly similar psychometric properties were obtained for the Parent version of the CSI (i.e., PCSI). CONCLUSION: The Dutch version of the CSI seems to be a reliable and valid self-report measure for assessing somatization symptoms in children and adolescents.     

Characterization of iodothyronine sulfatase activities in human and rat liver and placenta

In conditions associated with high serum iodothyronine sulfate concentrations, e.g. during fetal development, desulfation of these conjugates may be important in the regulation of thyroid hormone homeostasis. However, little is known about which sulfatases are involved in this process. Therefore, we investigated the hydrolysis of iodothyronine sulfates by homogenates of V79 cells expressing the human arylsulfatases A (ARSA), B (ARSB), or C (ARSC; steroid sulfatase), as well as tissue fractions of human and rat liver and placenta. We found that only the microsomal fraction from liver and placenta hydrolyzed iodothyronine sulfates. Among the recombinant enzymes only the endoplasmic reticulum-associated ARSC showed activity toward iodothyronine sulfates; the soluble lysosomal ARSA and ARSB were inactive. Recombinant ARSC as well as human placenta microsomes hydrolyzed iodothyronine sulfates with a substrate preference for 3,3'-diiodothyronine sulfate (3,3'-T(2)S) approximately T(3) sulfate (T(3)S) > rT(3)S approximately T(4)S, whereas human and rat liver microsomes showed a preference for 3,3'-T(2)S > T(3)S > rT(3)S approximately T(4)S. ARSC and the tissue microsomal sulfatases were all characterized by high apparent K(m) values (>50 microM) for 3,3'-T(2)S and T(3)S. Iodothyronine sulfatase activity determined using 3,3'-T(2)S as a substrate was much higher in human liver microsomes than in human placenta microsomes, although ARSC is expressed at higher levels in human placenta than in human liver. The ratio of estrone sulfate to T(2)S hydrolysis in human liver microsomes (0.2) differed largely from that in ARSC homogenate (80) and human placenta microsomes (150). These results suggest that ARSC accounts for the relatively low iodothyronine sulfatase activity of human placenta, and that additional arylsulfatase(s) contributes to the high iodothyronine sulfatase activity in human liver. Further research is needed to identify these iodothyronine sulfatases, and to study the physiological importance of the reversible sulfation of iodothyronines in thyroid hormone metabolism.     

Returning to midwifery

A staff midwife describes what it is like to be back on the Maternity Unit after a break of 11 years and a "return to practice" course. It is a steep learning curve but she finds the work fulfilling.     

Emotional blunting associated with SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses?

Anecdotal and published case reports suggest that some patients taking selective serotonin reuptake inhibitors (SSRI) experience diminution in emotional responsiveness. This study aims to define the individual components of emotion disturbed in these patients. Fifteen patients reporting SSRI-induced sexual dysfunction completed the Laukes Emotional Intensity Scale (LEIS), a questionnaire about various emotions. Compared to controls, patients reported significantly (p<0.05) less ability to cry, irritation, care about others' feelings, sadness, erotic dreaming, creativity, surprise, anger, expression of their feelings, worry over things or situations, sexual pleasure, and interest in sex. Total score on the LEIS did not correlate with total score on the Hamilton Depression Rating Scale. In our sample, 80% of patients with SSRI-induced sexual dysfunction also describe clinically significant blunting of several emotions. Emotional blunting may be an under-appreciated side-effect of SSRIs that may contribute to treatment non-compliance and/or reduced quality of life.     

Investigation of G72 (DAOA) expression in the human brain

Background

Systematic reviews based on efficacy trials are inconclusive about which second generation antipsychotic drug (SGA) should be preferred in normal clinical practice, and studies with longer duration and more pragmatic designs are called for. Effectiveness studies, also known as naturalistic, pragmatic, practical or real life studies, adhere to these principles as they aim to mimic daily clinical practice and have longer follow-up.

Objective

To review the head-to-head effectiveness of SGAs in the domains of global outcomes, symptoms of disease, and tolerability.

Methods

Searches were made in Embase, PubMED, and the Cochrane central register of controlled trials for effectiveness studies published from 1980 to 2008, week 1. Different combinations of the keywords antipsychotic*, neuroleptic* AND open, pragmatic, practical, naturalistic, real life, effectiveness, side effect*, unwanted effect*, tolera* AND compar* AND random* were used.

Results

Sixteen different reports of randomized head-to-head comparisons of SGA effectiveness were located. There were differences regarding sample sizes, inclusion criteria and follow-up periods, as well as sources of financial sponsorship. In acute-phase and first-episode patients no differences between the SGAs were disclosed regarding alleviating symptoms of disease. Olanzapine was associated with more weight gain and adverse effects on serum lipids. In the chronic phase patients olanzapine groups had longer time to discontinuation of treatment and better treatment adherence compared to other SGAs. The majority of studies found no differences between the SGAs in alleviating symptoms of psychosis in chronically ill patients. Olanzapine was associated with more metabolic adverse effects compared to the others SGAs. There were surprisingly few between-drug differences regarding side effects. First generation antipsychotics were associated with lower total mental health care costs in 2 of 3 studies on chronically ill patients, but were also associated with more extrapyramidal side effects compared to the SGAs in several studies.

Conclusion

In chronically ill patients olanzapine may have an advantage over other SGAs regarding longer time to treatment discontinuation and better drug adherence, but the drug is also associated with more metabolic side effects. More effectiveness studies on first-episode psychosis are needed.