Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer's-associated amyloid beta peptide.

Protein misfolding underlies the pathology of a large number of human disorders, many of which are age-related. An exception to this is preeclampsia, a leading cause of pregnancy-associated morbidity and mortality in which misfolded proteins accumulate in body fluids and the placenta. We demonstrate that pregnancy zone protein (PZP), which is dramatically elevated in maternal plasma during pregnancy, efficiently inhibits in vitro the aggregation of misfolded proteins, including the amyloid beta peptide (Aß) that is implicated in preeclampsia as well as with Alzheimer's disease. The mechanism by which this inhibition occurs involves the formation of stable complexes between PZP and monomeric Aß or small soluble Aß oligomers formed early in the aggregation pathway. The chaperone activity of PZP is more efficient than that of the closely related protein alpha-2-macroglobulin (α2M), although the chaperone activity of α2M is enhanced by inducing its dissociation into PZP-like dimers. By immunohistochemistry analysis, PZP is found primarily in extravillous trophoblasts in the placenta. In severe preeclampsia, PZP-positive extravillous trophoblasts are adjacent to extracellular plaques containing Aß, but PZP is not abundant within extracellular plaques. Our data support the conclusion that the up-regulation of PZP during pregnancy represents a major maternal adaptation that helps to maintain extracellular proteostasis during gestation in humans. We propose that overwhelming or disrupting the chaperone function of PZP could underlie the accumulation of misfolded proteins in vivo. Attempts to characterize extracellular proteostasis in pregnancy will potentially have broad-reaching significance for understanding disease-related protein misfolding.

Comparing indocyanine green, technetium, and blue dye for sentinel lymph node mapping in endometrial cancer.

BACKGROUND AND AIMS: With the debate over extent of lymphadenectomy in endometrial cancer, sentinel lymph node (SLN) mapping may provide a focused approach to evaluate the most relevant lymph nodes (LN) while minimizing the complications. We evaluated SLN mapping using filtered technetium(99), indocyanine green (ICG), and blue dye. METHODS: Prospective evaluation of 100 patients who underwent SLN mapping by using submucosal and deep stromal cervical injections of technetium(99), ICG, and blue dye as part of the staging for endometrial cancer. RESULTS: 286 SLNs were mapped (2.9 per patient) in 92% of patients. The bilateral detection rate was 76%. ICG had a significantly higher SLN detection rate than blue dye in both overall (87% vs 71%, respectively; p=0.005) and bilateral (65% vs 43%, respectively; p=0.002) detection, but similar SLN detection rates compared to technetium(99) in both overall (87% vs 88%, respectively; p=0.83) and bilateral (65% vs 71%, respectively; p=0.36) detection. In eight cases, the SLN was in the para-aortic area and in 14 cases in the pre-sacral, hypogastric vein, or parametrial area. In nine cases, the SLN was positive for metastasis, and in seven cases the SLN was the only positive node. One SLN was falsely negative. No complications or anaphylactic reactions occurred. CONCLUSION: Intra-operative SLN mapping using cervical injection is feasible in patients with endometrial cancer and yields adequate detection rates. It allows mapping of SLNs in areas (pre-sacral, hypogastric vein, parametrial) not routinely sampled. Given the poorer performance of blue dye, surgeons may omit its use if a combination of ICG and technetium(99) is used.

Mitogen-induced blastogenic responses of lymphocytes from marihuana smokers.

Blastogenic responses in vitro to phytohemagglutinin and pokeweed mitogen were examined in microcultures of peripheral blood lymphocytes from a group of 12 healthy, long-term marihuana smokers and a group of matched control subjects. With either mitogen, no significant difference in cellular incorporation of (3H)thymidine was noted between the groups. These results were interpreted to indicate that the functional status of blood lymphocytes was not altered by long-term smoking of marihuana.

Insulin initiation in type 2 diabetic patients admitted in hospital in France and follow-up at 1 year.

OBJECTIVES AND METHODS: The IDAHO 2 epidemiological survey was conducted in departments of diabetology in insulin-naïve type 2 diabetics for whom insulin was initiated. The objective was to assess the patients' profile, the treatments proposed during hospital stay and after one year. RESULTS: 797 patients were analysed. Their characteristics were: age 64+/-12 years, 49% males, weight: 78+/-17 kg, BMI: 29+/-6 kg/m2, diabetes duration 11 years, prevalence of complications: 68%, fasting blood glucose 13+/-6 mmol/l, HbA1c: 10+/-2.2%; treatment prior to insulin comprised: at least 2 OHA: 71% of cases, one: 21%, no OAD: 8%. At hospital discharge, 54% of the patients used basal insulin. After 1 year, 670 continued on insulin. The insulin initiation was accompanied by a decrease in the FBG level (baseline: 13+/-6 mmol/l; final: 8.5+/-2.75 mmol/l; P<0.0001) and a HbA1c improvement (baseline: 10+/-2.2%; final: 7.9+/-1.4%; P<0.0001). This was observed du-ring the first 6 months (HbA1c: 7.8%, P<0.0001 versus baseline). 80% of the patients remained on the same insulin regimen after 1 year: 35% had 1 injection/day, 44% had 2, 12% had 3 and 9% had a complex regimen. The weight gain, the final daily dose and hypoglycaemias increased with the number of injections. The mean daily insulin dose was 33 U/day (24 U with 1 injection/day). CONCLUSION: The IDAHO study shows that insulin is effective in type 2 diabetics however, management is inadequate with insulin therapy being initiated too late and at doses which are low after one year.

[Optimizing history taking for evaluating the risk of venous thromboembolism: the OPTIMEV study]. / Optimisation de l'interrogatoire dans l'évaluation du risque de maladie thromboembolique veineuse: l'étude OPTIMEV.

UNLABELLED: Venous thromboembolism (VTE) is a frequent disease and remains a major cause of mortality and morbidity among our patients. During the 20 past years, clinical description, diagnostic tools, and treatment have changed dramatically. Most published data describing risk factors for VTE no longer apply to the patients seen in daily practice. We present here the rationale, aims, and methodology of the OPTIMEV Study (OPTimisation de l'Interrogatoire pour la Maladie thromboEmbolique Veineuse). RATIONALE: Risk factors for VTE are numerous, complex and interactions between them and their clinical importance is difficult to measure (table I). For example, odds ratios for VTE recurrence vary greatly across longitudinal studies. We searched the National Library of Medecine (PubMed) and the Amedeo website using the following keywords: "venous thromboembolism", "pulmonary embolism", "deep vein thrombosis", "risk factors". We selected 84 relevant articles published between 1972 and 2005. Based on this literature analysis, we identified the following major risk factors: VTE recurrence, surgery, cancer, immobilization, age, biological factors. For these factors, data are lacking and some questions are proposed. OBJECTIVES: The broad objective of the study is to better evaluate clinical risk factors that fit today's practice against VTE. Specific aims are: 1) to determine whether risk factors are different between proximal and distal deep vein thrombosis (DVT); 2) to develop and prospectively validate a new prediction rule for outpatients. The primary hypothesis is that careful assessment of VTE recurrence, adequate surgical thromboprophylaxis, cancer staging, and varicose vein stratification according to the CEAP classification, is mandatory for accurate evaluation of thromboembolic disease risk. METHODS: We conducted a multicenter, prospective, cohort study of 10000 patients. Enrollees are inpatients and outpatients presenting with a clinical suspicion of VTE in Emergency Departments and outpatient clinics in France. 4173 patients have been enrolled at this time (Figure 2). All eligible patients are enrolled during a selected period of time through different seasons. Data are collected by physicians in charge of the patients using an electronic case recording form. Collected data include baseline characteristics, risk factors, results of diagnostic investigations. Outcome measures obtained through telephone interview at 3 and 12 months include cancer diagnosis, VTE recurrence, haemorrhagic events, treatments, death. Univariate and multivariate analysis will be performed using multilevel logistic regression. The study organization is performed by the Centre d'Investigation Clinique de Grenoble and is sponsored by the French Society of Vascular Medicine. First results, to be published in 2006, will allow development of new prediction rules for VTE diagnosis.

Chlormadinone acetate versus micronized progesterone in the sequential combined hormone replacement therapy of the menopause.

OBJECTIVE: The efficacy and safety of chlormadinone acetate (CA) versus micronized progesterone (P) were assessed in non-hysterectomized postmenopausal women. MATERIALS AND METHODS: This was a multicenter, randomized, parallel group study with a 6-month double-blind period followed by a 12-month open period. Patients were randomized to receive every month during 18 months percutaneous 17 beta-estradiol (E(2)) 1.5 mg/day from Day 1 to 24 of treatment cycle, combined from Day 11 to 24 to either CA 10 mg/day (n=167) or P 200 mg/day (n=169). Endometrial biopsy (EB, main analysis criterion) was performed at baseline, and at Day 18-24 of the 6th and 18th cycles. RESULTS: At Month 6, EB did not evidence any hyperplasia. EB were inadequate for assessment in 24.5% and 47.5% of patients in the CA and MP groups, respectively. CA was found to be as protective as P (96.3% and 92.0% of success). However, the hormonal status of the endometrium differed (P<0.001): a secretory endometrium was found in 81.5% of the CA patients, compared to 50.7% in the P group. These transformations resulted in predictable, cyclic bleeding in 94.5% of the CA patients, compared to only 62.3% of the P patients (P=0.0001). Unscheduled bleeding, spotting and/or metrorrhagia, were more frequent under P than under CA (17.9% and 13.7%, respectively). The beneficial effects on hot flushes were more important in the CA group than in the P (P<0.001). At Month 18, the biopsy and clinical results were similar to those obtained at Month 6. The safety profile, particularly the lipid one, was similar in both groups, except for drowsiness and dizziness, which were significantly more frequent under P than under CA. CONCLUSION: The progestative effects of CA on the endometrium and on menopause-related symptoms were at least as good as those of P. Moreover, CA resulted more often than P in secretory effects, and in satisfying bleeding patterns.

Comparative endometrial histology in postmenopausal women with sequential hormone replacement therapy of estradiol and, either chlormadinone acetate or micronized progesterone.

OBJECTIVES: To determine the endometrial response in postmenopausal women treated with a sequential hormone replacement therapy (HRT) of estradiol and, either chlormadinone acetate (CA) or micronized progesterone (MP). METHODS: Three hundred and thirty-six postmenopausal women with a normal endometrium were randomized in the double-blind study. All patients received percutaneous estradiol 1.5 mg/day from day 1 to day 24 and either CA 10 mg/day or oral MP 200 mg/day from day 10 to day 24. The total duration of treatment was 18 months. Endometrial biopsies were performed before treatment and between day 18 and day 24 of the 18th month of HRT. RESULTS: Of the 336 patients selected, 317 had a biopsy at inclusion. Of them, 244 patients (124 in the CA group and 120 in the P group) were suitable for evaluation for analysis at the 18th month. Insufficient sampling occurred in 33.9% in the CA group and 60% in the MP group (probably atrophic). No case of hyperplasia could be reported in both groups. The endometrium was atrophic in 19.5 versus 27.1%, proliferative in 3.7 versus 8.3% and secretory in 76.8 versus 62.5% in CA and MP groups, respectively. It was possible to see histological differences induced by the two progestins. The CA endometria showed fewer glands lined by a cubo-cylindrical epithelium, with an edematous stroma, compared to the MP endometria which had more glands lined by a cylindrical epithelium, stroma being poorly edematous. These figures varied in intensity due to the length of progestative impregnation, predecidualization occurring later in the CA group, with distended capillaries. CONCLUSIONS: These results show that CA 10 mg/day is a powerful progestin compared to MP 200 mg/day, on weakly estradiol-primed endometria, giving a molecule-specific histological aspect with a good endometrial safety.

[Observational study of criteria involved in the choice of hormone replacement therapy (HRT), when initiated and subsequently adapted]. / Etude observationnelle des critères déterminant le choix du traitement hormonal de la ménopause, lors de l'instauration et son adaptation.

OBJECTIVES: Multicentre observational longitudinal prospective study in France; search for criteria involved in the choice of the initial dose of oestrogen at the initiation of hormone replacement therapy (HRT); search for explicative and predictive factors for treatment adaptation. STATISTICS: description and analysis (factorial analysis of multiple correspondences) of the criteria involved in the choice of the initial dose of oestrogen; percentage of women with treatment adaptation ; analysis (univariate, multivariate) of predictive factors for adaptation. RESULTS: Six hundred and fifty postmenopausal women, first treated with HRT, with complete data on modification (or not) of their treatment were included. Initial estrogen dose was dose 1 (or low dose) in 66% of patients, dose 2 (or standard dose) in 34 % of patients (N = 643). The preponderant type of HRT use was discontinuous sequential therapy and transdermal formulation. Criteria involved in the choice of the low initial dose (dose 1) were moderate hot flushes, complaint about weight gain, choice of the patient, breast tolerability, uterine bleeding, general safety, hepatic first pass. Criteria involved in the choice of the standard initial dose (dose 2) were important hot flushes, and prevention of postmenopausal osteoporosis. Treatment was adapted in 369 patients e.g. 56.8% of the population (95% CI: 53-60.6 %). The main changes (N = 291) were in 37.5% of the cases (N = 109) a decrease in the dose of estrogen (16.7% of the women (N = 37) initially under dose 2 - or standard dose) or an increase in the dose of oestrogen (17.1% of the women (N = 72) initially under dose 1 - or low dose). In 25% of the cases, there was a change in the dose or type of progestogen, in favor of norpregnane or pregnane derivates. DISCUSSION AND CONCLUSION: The following factors were associated with a decreased probability of treatment adaptation: more than 5 hot flushes at enrolment, initial dose chosen taking into account tolerance factors, history of hysterectomia, and known diabetes. Conversely, the existence of antihypertensive treatment was associated with an increased probability of treatment adaptation.

[Recurrent respiratory infections in patients with chronic obstructive bronchitis: medical treatment and costs]. / Infections respiratoires récidivantes du sujet atteint de bronchite chronique obstructive: prise en charge médicale et coûts.

The objective of this study is to describe usual medical management and costs associated with recurrent respiratory infections in subjects with chronic obstructive bronchitis in France. A prospective survey was performed in Autumn 1994 on a national sample of private practice pulmonologists (N = 71). Two hundred forty-four patients, presenting at least one infection of the lower respiratory tract, were included. Bronchitis was the most frequent acute exacerbation observed (94%). Pneumonia concerned 9% of the patients. Biological tests, X-rays and pulmonary function tests were prescribed for, respectively, 59, 65 and 45% of the patients. Following the visit, 15 patients were hospitalized (6%). The direct medical cost per acute exacerbation was estimated 3,289 francs (1994 value) of which 60% were hospital-related. An average 10.4 day sick-leave was prescribed to 21% of patients in employment. For those patients, this sick-leave was associated to an extra-cost of 1,264-1,876 francs for Social Security and of 0-2,553 francs out of pocket per episode varying according to their Benefit Regimen.

[A comparative controlled trial of 2 administration modalities of tiopronin in rheumatoid arthritis]. / Essai contrôlé comparatif de deux modalités d'administration de la tiopronine dans la polyarthrite rhumatoïde.

Thiopronin is a second line drug for rheumatoid arthritis with proven efficacy in controlled trials versus a placebo, D-penicillamine, or gold salts. This 4-month study was aimed mainly at comparing the efficacy and safety of two thiopronin regimens, i.e., 1 g/d for 2 weeks followed by 1.5 g/d (regimen A) versus 0.5 g/d for 1 month, 0.750 g/d during the second month, then 1 g/d (regimen B). Because earlier investigations have suggested a role for copper in the activity of D-penicillamine, a secondary goal of this study was to evaluate whether the clinical effects of thiopronin were related to changes in serum copper and ceruloplasmin levels. Among the 61 included patients, 32 received regimen A and 29 regimen B. The primary efficacy criterion was the physician's overall efficacy assessment. Efficacy was rated good or excellent in 65.5% of regimen A patients and 55.6% of regimen B patients. Eighteen of the 32 regimen A patients and 23 of the 29 regimen B patients experienced at least one adverse event (p = 0.055). Failure to tolerate the drug required withdrawal in 12 of the 32 regimen A patients (37.5%) versus 11 of the 29 regimen B patients (37.9%). Declines in serum copper and ceruloplasmin levels were not correlated with treatment efficacy or tolerance. These findings, together with previously reported data, suggest that treatment should be initiated in a dosage of 1 g/day and that thiopronin-related adverse events are not dose-dependent.

When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide?

OBJECTIVE: To evaluate the efficacy and safety of adding sulfasalazine to leflunomide treatment compared with switching to sulfasalazine alone in patients with RA with an inadequate response to leflunomide monotherapy. METHODS: Patients with active RA ((DAS28) >3.2) who were enrolled in the first open label phase of the RELIEF study received leflunomide for 24 weeks. Inadequate responders then entered the double blind phase and received a further 24 weeks' treatment with leflunomide (20 mg once daily) plus sulfasalazine (final dose 2 g once daily), or placebo plus sulfasalazine (dose as above). The primary efficacy variable was the DAS28 response rate, and secondary efficacy outcomes were ACR 20%, 50%, and 70% response rates. Adverse events, including standard laboratory tests, were recorded. RESULTS: 106 inadequate responders entered the double blind phase; 56 received leflunomide plus sulfasalazine, and 50 placebo plus sulfasalazine. In the intention to treat population, more patients receiving leflunomide plus sulfasalazine (25/56 (45%)) achieved a DAS28 response than those receiving placebo plus sulfasalazine (17/50 (34%)) (p = 0.179). In week 24 completers, more patients receiving leflunomide plus sulfasalazine (17/56 (30%)) were DAS28 responders than those receiving placebo plus sulfasalazine (10/50 (20%)) (p = 0.081). Comparable numbers in each group were ACR 20% responders; the ACR 50% response rate was significantly higher in the leflunomide plus sulfasalazine group (8.9%) than in the placebo plus sulfasalazine group (0%) (p = 0.038). The safety profiles of both groups were comparable. CONCLUSION: Patient numbers are small and firm conclusions cannot be reached, but a non-significant benefit is indicated for combining leflunomide with sulfasalazine compared with switching to sulfasalazine alone in patients inadequately responding to leflunomide.