Does pretreatment testing for serotonin transporter polymorphisms lead to earlier effects of drug treatment in patients with major depression? A decision-analytic model

BACKGROUND: An estimated 30% to 40% of patients with depression do not sufficiently respond to treatment with selective serotonin reuptake inhibitors (SSRIs) and the period in which treatment efficacy can be assessed is relatively long. Therefore, a test to identify potential nonresponders could be useful in the treatment of depression. Serotonin transporter gene (SLC6A4) variations have been reported to account for differences in the way individuals respond to SSRI treatment. OBJECTIVE: A decision-analytic model was used to assess whether pretreatment genetic testing for 5-HTTLPR, a polymorphism of the SLC6A4 genotype, could be an efficient tool in the treatment of depression. METHODS: A theoretical clinical decision-analytic model was constructed to compare the current treatment strategy in The Netherlands with an alternative strategy for the treatment of depression. Under treatment guidelines in The Netherlands, all patients with depression receive SSRI treatment (nontesting strategy). Under the alternative strategy, genetic testing would be performed to identify which class of antidepressant would be the best choice for initiation of treatment (genetic testing strategy). Probabilities (predicted results) for this model were based on data from previous studies and the opinions of experts in the field of psychopharmacology. To test the robustness of the model, 6- and 12-week remission rates for patients treated with SSRIs were varied in a sensitivity analysis using a predetermined range that was established based on expert opinion. Threshold analyses were performed on the parameters of serotonin transporter genotype frequency and response and nonresponse rates for patients receiving SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) to determine the value for a variable at which it could be concluded that a change in treatment strategy would be preferred. RESULTS: When genetic testing was performed before an antidepressant was prescribed, 64.6% of patients were predicted to be in remission after 6 weeks of treatment compared with 60.0% of patients who did not receive genetic testing. After 12 weeks, 79.5% of patients in the testing group who received an SNRI as initial treatment and 83.2% of those who received a TCA initially were predicted to be in remission compared with 76.7% of patients in the nontesting group. Sensitivity analyses indicated that the model was robust to variation of probability estimates within their plausible ranges. However, these findings were based on a theoretic model and did not include cost assessment. Pretreatment genetic testing must be evaluated further in randomized clinical trials and costs must be assessed before implementing this strategy in routine psychiatric practice can be recommended. CONCLUSIONS: The findings of this study suggest that performing genetic testing before prescribing antidepressant treatment may lead to greater numbers of patients experiencing remission early in treatment.     

Skin as marker for collagen type I/III ratio in abdominal wall fascia

Purpose

An altered collagen metabolism could play an important role in hernia development. This study compared collagen type I/III ratio and organisation between hernia and control patients, and analysed the correlation in collagen type I/III ratio between skin and abdominal wall fascia.

Methods

Collagen organisation was analysed in Haematoxylin–Eosin sections of anterior rectus sheath fascia, and collagen type I/III ratio, by crosspolarisation microscopy, in Sirius-Red sections of skin and anterior rectus sheath fascia, of 19 control, 10 primary inguinal, 10 recurrent inguinal, 13 primary incisional and 8 recurrent incisional hernia patients.

Results

Compared to control patients [7.2 (IQR = 6.8–7.7) and 7.2 (IQR = 5.8–7.9)], collagen type I/III ratio was significantly lower in skin and anterior rectus sheath fascia of primary inguinal [5.2 (IQR = 3.8–6.3) and 4.2 (IQR = 3.8–4.7)], recurrent inguinal [3.2 (IQR = 3.1–3.6) and 3.3 (IQR = 3–3.7)], primary incisional [3.5 (IQR = 3–3.9) and 3.4 (IQR = 3.3–3.6)] and recurrent incisional hernia [3.2 (IQR = 3.1–3.9) and 3.2 (IQR = 2.9–3.2)] patients; also incisional and recurrent inguinal hernia had lower ratio than primary inguinal hernia patients. Furthermore, collagen type I/III ratio was significantly correlated (r = 0.81; P < 0.001) between skin and anterior rectus sheath fascia. Finally, collagen organisation was comparable between hernia and control patients.

Conclusions

Furthermore, in both skin and abdominal wall fascia of hernia patients, collagen type I/III ratio was lower compared to control patients, with more pronounced abnormalities in incisional and recurrent inguinal hernia patients. Importantly, collagen type I/III ratio in skin was representative for that in abdominal wall fascia.     

Domains for activation and inactivation in G protein-coupled receptors – A mutational analysis of constitutive activity of the adenosine A2B receptor

G protein-coupled receptors (GPCRs) are a major drug target and can be activated by a range of stimuli, from photons to proteins. Most, if not all, GPCRs also display a basal level of biological response in the absence of such a stimulus. This level of so-called constitutive activity results from a delicate energy equilibrium that exists between the active and the inactive state of the receptor and is the first determinant in the GPCR activation mechanism. Here we describe new insights in specific regions of the adenosine A_2B receptor that are essential in activation and inactivation. We developed a new screening method using the MMY24 S. Cerevisiae strain by which we were able to screen for constitutively inactive mutants receptors (CIMs). We applied this screening method on a mutagenic library of the adenosine A_2B receptor, where random mutations were introduced in transmembrane domains four and five (TM4 and TM5) linked by extracellular loop 2 (EL2). The screen resulted in the identification of 22 single and double mutant receptors, all showing a decrease in constitutive activity as well as in agonist potency. By comparing these results with a previous screen of the same mutagenic library for constitutively active mutant receptors (CAMs), we discovered specific regions in this G protein-coupled receptor involved in either inactivation or activation or both. The results suggest the activation mechanism of GPCRs to be much less restricted to sites of high conservation or direct interaction with the ligand or G protein and illustrate how dynamic the activation process of GPCRs is.     

Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients

Critical illness is often associated with reduced TSH and thyroid hormone secretion as well as marked changes in peripheral thyroid hormone metabolism, resulting in low serum T(3) and high rT(3) levels. To study the mechanism(s) of the latter changes, we determined serum thyroid hormone levels and the expression of the type 1, 2, and 3 iodothyronine deiodinases (D1, D2, and D3) in liver and skeletal muscle from deceased intensive care patients. To study mechanisms underlying these changes, 65 blood samples, 65 liver, and 66 skeletal muscle biopsies were obtained within minutes after death from 80 intensive care unit patients randomized for intensive or conventional insulin treatment. Serum thyroid parameters and the expression of tissue D1-D3 were determined. Serum TSH, T(4), T(3), and the T(3)/rT(3) ratio were lower, whereas serum rT(3) was higher than in normal subjects (P < 0.0001). Liver D1 activity was down-regulated and D3 activity was induced in liver and skeletal muscle. Serum T(3)/rT(3) ratio correlated positively with liver D1 activity (P < 0.001) and negatively with liver D3 activity (ns). These parameters were independent of the type of insulin treatment. Liver D1 and serum T(3)/rT(3) were highest in patients who died from severe brain damage, intermediate in those who died from sepsis or excessive inflammation, and lowest in patients who died from cardiovascular collapse (P < 0.01). Liver D3 showed an opposite relationship. Acute renal failure requiring dialysis and need of inotropes were associated with low liver D1 activity (P < 0.01 and P = 0.06) and high liver D3 (P < 0.01) and skeletal muscle D3 (P < 0.05) activity. Liver D1 activity was negatively correlated with plasma urea (P = 0.002), creatinine (P = 0.06), and bilirubin (P < 0.0001). D1 and D3 mRNA levels corresponded with enzyme activities (both P < 0.001), suggesting regulation of the expression of both deiodinases at the pretranslational level. This is the first study relating tissue deiodinase activities with serum thyroid hormone levels and clinical parameters in a large group of critically ill patients. Liver D1 is down-regulated and D3 (which is not present in liver and skeletal muscle of healthy individuals) is induced, particularly in disease states associated with poor tissue perfusion. These observed changes, in correlation with a low T(3)/rT(3) ratio, may represent tissue-specific ways to reduce thyroid hormone bioactivity during cellular hypoxia and contribute to the low T(3) syndrome of severe illness.     

Effect of recombinant human erythropoietin on anaemia and disease activity in patients with rheumatoid arthritis and anaemia of chronic disease: a randomised placebo controlled double blind 52 weeks clinical trial.

OBJECTIVE: To study whether recombinant human erythropoietin (r-hu-Epo) improves anaemia and reduces disease activity in patients with rheumatoid arthritis and anaemia of chronic disease (ACD). METHODS: A 52 week placebo controlled randomised double blind trial with r-hu-Epo was performed in 70 patients with active rheumatoid arthritis and ACD. Thirty four patients were treated with 240 U kg-1 r-hu-Epo subcutaneously, initially three doses weekly, while 36 patients received placebo. RESULTS: A significant increase of haemoglobin from a median of 112 to 135 g litre-1 occurred in the Epo group within six weeks and could be sustained with reduced doses (median 240 U kg-1 once weekly). Sustained benefit compared to placebo was also apparent by six weeks for disease activity, as indicated by the Paulus 20% response rate. Of patients in the Epo group, 32% eventually showed a Paulus 20% response, compared to 8% of the placebo group (P = 0.016). Significant differences in favour of the Epo group were also observed in the secondary disease activity measures Ritchie index, number of swollen joints, pain score, ESR, and patients' global assessment of disease activity. C reactive protein concentrations did not change significantly. CONCLUSIONS: Treatment of ACD in rheumatoid arthritis with r-hu-Epo is effective in restoring normal haemoglobin levels and also exerts a beneficial effect on disease activity.     

Heart conduction disturbance: an HLA-B27 associated disease.

In recent studies from Sweden an increased prevalence of HLA-B27 associated diseases and of HLA-B27 was found in an unselected group of men with permanently implanted pacemakers and with a heart block. Furthermore, a significantly increased prevalence of HLA-B27 was found in men with a pacemaker who had no clinical or radiological signs of HLA-B27 associated disease. To obtain more insight into the association between HLA-B27 and heart block, and the possible role of HLA-B27 in causing this block, a study was made of 35 patients with a pacemaker and heart block of unknown cause, selected from a total group of 350 men with pacemakers who were still alive at the time of the study. One of these 35 men had ankylosing spondylitis and two patients had an asymptomatic sacroiliitis, but all three were HLA-B27 negative. HLA-B27 was present in five (14%) patients, which is a significantly higher prevalence than in healthy controls (17/292, 6%). This percentage is equal to the percentage of HLA-B27 positivity found in the Swedish study on unselected men with an implanted pacemaker, in whom the presence of an HLA-B27 associated disease had been excluded. It suggests that factors other than HLA-B27 are important in the pathogenesis of heart block in most patients.     

Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case-control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50-4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20-3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98-2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88-2.36; P=0.05) and 2.05 (95% CI 1.23-3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34-0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.