When is it appropriate to prescribe postmenopausal hormone therapy?

OBJECTIVE: To develop evidence and consensus-based recommendations for the use of hormone therapy (HT) in postmenopausal women. DESIGN: Using evidence from clinical trials and other publications, a multidisciplinary group of women's health experts developed consensus-based recommendations for HT use in more than 300 clinical scenarios. These panelists utilized the RAND Appropriateness Method and a quantitative scale to rate the appropriateness of treatment options for women with various risk factors and clinical scenarios. RESULTS: The panel judged it appropriate to prescribe all forms of HT to women with intolerable menopause symptoms and usual (age-expected) risks of cardiovascular disease (CVD), venous thromboembolism (VTE), or stroke. Use of HT was judged not appropriate for the clinical scenarios of bone preservation, cosmetic appearance, current memory loss, loss of libido, or CVD protection. For a woman still using HT after 5 or more years, it was considered appropriate to recommend the options of stopping or lowering the dose even if stopping was previously attempted. In treating intolerable symptoms in the presence of some elevated risk for diseases related to HT, route of administration may affect appropriateness but prior stroke or TIA# is a contraindication. CONCLUSIONS: Standard HT is appropriate for women with intolerable menopause symptoms in the absence of HT-related risk factors (eg, CVD, stroke, VTE, breast cancer). Panelists judged it appropriate to repeatedly present the option of stopping or reducing the dose. In most cases, presence of risk factors makes standard-dose oral HT not appropriate; however, some women may be candidates for a different dose or route of administration.     

What risk of endocarditis is low enough to justify the omission of transoesophageal echocardiography in Staphylococcus aureus bacteraemia? A narrative review

BackgroundRecent criteria which can identify patients with Staphylococcus aureus bacteraemia (SAB) who are at very low risk of endocarditis raise the question of whether transoesophageal echocardiography (TOE) is appropriate for these patients.AimsTo estimate the probability of occult endocarditis complicating SAB below which a TOE-guided treatment strategy no longer offers the best 180-day survival, and to examine the key uncertainties affecting this result.SourcesEstimates of the parameters required to calculate the Pauker–Kassirer testing threshold were identified from studies published prior to 1 June 2017 using a composite search strategy that involved a systematic search for relevant controlled trials and guidelines, followed by a non-systematic iterative search of the observational literature.ContentEstimates of the necessary parameters were generally consistent across the literature with the exception of the procedural mortality of TOE. In our base-case scenario (TOE mortality 0.1%), the testing threshold for TOE in apparently uncomplicated SAB was a 1.1% probability of occult endocarditis. Sensitivity analyses revealed that the procedural mortality of TOE was a key uncertainty affecting estimates of the testing threshold.ImplicationsNone of the available clinical tools can place patients with SAB below this probability of endocarditis with 95% confidence. Future work in this area should concentrate on improving the precision of these tools and on exploring the value of alternative echocardiography strategies. In addition, a better understanding of the harms of TOE is required to ensure that recommendations regarding the role of this investigation in the management of patients with SAB are appropriate.     

When is electroconvulsive therapy appropriate for children and adolescents?

The indications for electroconvulsive therapy in children and adolescents are similar to those in adults, including severe affective, psychotic and catatonic pathology that has proven refractory to psychotropic medications and causes significant functional impairment. ECT may be indicated as well in specific pediatric neurological conditions. Multiple published reports demonstrate the safety and efficacy of ECT in pediatric patients with a wide range of psychopathology. ECT has also been successfully used in youth with autism and other neurodevelopmental disabilities who present with catatonic deterioration. However, resistance and stigma persist regarding the use of ECT in children and adolescents in both the professional and lay communities, creating barriers to pediatric ECT access. We argue that the use of ECT in children and adolescents is appropriate for specific clinical indications, and urge removal of impediments to ECT access in this population.     

What is the influence of hormone therapy on homocysteine and crp levels in postmenopausal women?

OBJECTIVE:

To evaluate the influence of estrogen therapy and estrogen-progestin therapy on homocysteine and C-reactive protein levels in postmenopausal women.

METHODS:

In total, 99 postmenopausal women were included in this double-blind, randomized clinical trial and divided into three groups: Group A used estrogen therapy alone (2.0 mg of 17β-estradiol), Group B received estrogen-progestin therapy (2.0 mg of 17 β-estradiol +1.0 mg of norethisterone acetate) and Group C received a placebo (control). The length of treatment was six months. Serum measurements of homocysteine and C-reactive protein were carried out prior to the onset of treatment and following six months of therapy.

RESULTS:

After six months of treatment, there was a 20.7% reduction in homocysteine levels and a 100.5% increase in C-reactive protein levels in the group of women who used estrogen therapy. With respect to the estrogen-progestin group, there was a 12.2% decrease in homocysteine levels and a 93.5% increase in C-reactive protein levels.

CONCLUSION:

Our data suggested that hormone therapy (unopposed estrogen or estrogen associated with progestin) may have a positive influence on decreasing cardiovascular risk due to a significant reduction in homocysteine levels.     

How best is to discontinue postmenopausal hormone therapy: Immediate or tapered?

BACKGROUND: To evaluate the differences between the immediate and tapered cessation protocols of hormone therapy in terms of recurrence of menopausal symptoms. MATERIALS AND METHODS: In this prospective, randomized clinical study 70 consecutive patients in whom hormone therapy was no longer preferred were recruited from the menopause clinic of a university hospital and rank randomized into two groups. In group 1 (n=35) hormone therapy was immediately discontinued and in group 2 (n=35) the medication was tapered. Every patient was questioned about vasomotor symptoms before the initiation of hormone therapy at the first visit, and then revisited at the end of 2 and 4 weeks. RESULTS: We did not find any statistically significant difference between two protocols in terms of symptom severity and frequency at the end of 2 and 4 weeks of discontinuation. Although statistically insignificant, the symptoms tended to recur in fewer patients and in a less severe form in both groups when compared with their pretreatment status. CONCLUSIONS: Tapering or immediate discontinuing of hormone therapy did not affect the recurrence rate and severity of menopausal symptoms at the end of 4 weeks.     

What is the status of gene therapy for primary immunodeficiency?

The efforts to find satisfactory treatments for seriously ill patients with primary immunodeficiency have resulted in the development of important new therapeutic procedures with benefits reaching far beyond the relatively small number of patients affected with these rare disorders. Allogeneic bone marrow transplantation, immunoglobulin and enzyme replacement treatments and more recently gene therapy have all been introduced into clinical medicine as treatments for one or more of the primary immunodeficiency diseases. Beginning in 1990, gene-corrected T cells were first used to treat ADA deficiency SCID. With this demonstration that the gene-transfer procedure could be safely used to introduce functional transgenes into patient cells, clinical trials for a broad range of inherited disorders and cancer were started in the mid 90s. Of all these early clinical experiments, those addressing primary immunodeficiency have also been the most successful. Both ADA and X-SCID have now been cured using gene insertion into autologous bone marrow stem cells. In addition some patients with chronic granulomatous disease (CGD) have shown an unexpectedly high level of functionally corrected granulocytes in their blood following infusion of autologous gene-corrected bone marrow. There remain however a great many significant challenges to be overcome before gene therapy becomes the treatment of choice for these and other disorders. The use of genes as medicines is the most complex therapeutic system ever attempted and it may rake several more decades of work before its real potential as a treatment for both inherited and sporadic disorders if finally realized. Presented at the First Robert A Good Society Symposium, St. Petersburg, FL 2006.     

Expression of estrogen receptors-α and -β in primary breast neoplasms and tumors exposed to neoadjuvant hormonal therapy

We studied the content and expression of mRNA for estrogen receptors receptors- and - in breast tumors before and after 3-month neoadjuvant hormone therapy with antiestrogen tamoxifen and/or aromatase inhibitors. Expression of estrogen receptors- and - was most often detected in ER⁺PR⁺ tumors and most significantly decreased in these neoplasms after exemestane therapy. Immunocytochemical and radioligand assays showed that tamoxifen and anastrozole have little effect on the number of estrogen receptors- The number of progesterone receptors in tumors decreased by the end of anastrozole therapy. Estrogen receptors- were immunocytochemically revealed in 50% primary breast tumors. Anastrozole slightly decreased, while tamoxifen increased the incidence of these receptors. Interruption of signaling through estrogen receptors and suppression of estrogen biosynthesis had different effects on the receptor status of neoplasms and distribution of estrogen receptors- and -.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 11, pp. 559–562, November, 2004     

Binding of α-actinin to F-actin or to tropomyosin F-actin is a function of both α-actinin concentration and gel structure

Summary We have studied by electron microscopy as well as by measurements of low shear viscosity, rigidity and binding, the effect of-actinin on the gel formed at 37° C with F-actin and with tropomyosin-decorated F-actin. Contrary to previous reports in the literature,-actinin at nanomolar concentrations is an efficient actin gelling protein, even at 37° C, provided that the concentration of actin (or of tropomyosin-decorated F-actin) is low (1.2–2.4 m). The binding of-actinin to F-actin, as a function of actin concentration, is anomalous. The amount of bound-actinin increases when actin concentration increases from 0 to 1.2 m but does not change significantly when actin concentration is further increased up to 48 m. A similar result is obtained with tropomyosin-decorated F-actin.These observations can be explained by an hypothesis that binding is a function of the-actinin — F-actin association constant as well as of the rigidity of the gel. When the concentration of actin increases, the rigidity of the gel also increases and more work is required to bring two actin filaments to the reaction distance with-actinin and, consequently, a larger-actinin concentration is required to attain the same ratio of bound-actinin to actin monomers in the filaments.     

Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency: When is it indicated,what is the goal and how to do it?

Pancreatic exocrine insufficiency with steatorrhea is a major consequence of pancreatic diseases (e.g. chronic pancreatitis, cystic fibrosis, severe acute necrotizing pancreatitis, pancreatic cancer), extrapancreatic diseases like celiac disease and Crohn's disease, and gastrointestinal and pancreatic surgical resections. Recognition of this entity is highly relevant to avoid malnutrition-related morbidity and mortality. Therapy of pancreatic exocrine insufficiency is based on the oral administration of pancreatic enzymes aiming at providing the duodenal lumen with sufficient amount of active lipase at the time of gastric emptying of nutrients. Administration of enzymes in form of enteric-coated minimicrospheres avoids acid-mediated lipase inactivation and ensures gastric emptying of enzymes in parallel with nutrients. Despite that, factors like an acidic intestinal pH and bacterial overgrowth may prevent normalization of fat digestion even in compliant patients. The present article critically reviews current therapeutic approaches to pancreatic exocrine insufficiency.     

Why does EBD need to diagnose and to therapy for patients,now?

G. Guyatt reported the first paper on Evidence Based Medicine(EBM) at 1991. Everybody could understand rapidly the necessary of EBM to diagnose and medical treat the patients from then. So, I will tell you the recent actions of EBLM committee of Japan Society of Clinical Laboratory Medicine (JSLM/C-EBLM) related with EBM. I define EBLM(Evidence-Based Laboratory Medicine) has the total functions to use the clinical laboratory data by evidence for the diagnosis and the therapy of patients. JSLM/C-EBLM was seted up at 1999 and supported EBD(Evidence-Based Diagnosis) Forums as the main action. JSLM/C-EBLM will make and use practically the new meta-analysis tools and educate about EBLM from now.     

Faecal carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae is common 12 months after infection and is related to strain factors

We aimed to determine the duration of faecal carriage of extended-spectrum β-lactamase (ESBL) -producing Enterobacteriaceae (EPE) in patients with clinical infection caused by an EPE, to study host strains during carriage, and to identify factors associated with prolonged carriage. Patients (n = 61) were followed with faecal samples and questionnaires about antimicrobial treatment and risk factors for EPE, 1, 3, 6 and 12 months after EPE infection. The EPE isolates were subjected to ESBL genotyping, epidemiological typing with pulsed-field gel electrophoresis and PCR-based replicon typing. Escherichia coli isolates were analysed with PCR for phylogrouping, detection of pabB (ST131) and virulence content. Patient-related and strain-related variables were compared for carriers and non-carriers at 12 months. Carriage of EPE was observed in 51 of 61 (84%) patients after 1 month, 36 of 61 (66%) after 3 months, 31 of 61 (55%) after 6 months and 26 of 61 (43%) after 12 months. Of the 26 carriers at 12 months, five had previous negative samples. In 17 of 61 patients, ESBL was found in a new bacterial species and/or strain during carriage. Among E. coli, 14 of 49 belonged to the international clone ST131. Phylogroup B2 and CTX-M-gr.-9 were associated with being carriers at 12 months (OR 4.3, 95% CI 1.1–16.3 and OR 6.4, 95% CI 1.3–30.9, respectively). In conclusion, EPE carriage is common 12 months after infection and persisting carriage may be associated with E. coli phylogroup B2 and CTX-M-gr.-9. The host strain frequently changes throughout carriage and negative samples do not imply eliminated carriage.     

Postmenopausal hormone therapy and breast cancer: What is the problem?

Observational studies provide evidence that breast cancer risk is increased with long-term oral use of postmenopausal estrogen replacement therapy (ET). Various large cohort studies have shown that the addition of a progestogen in combined hormone replacement therapy (EPT) increases this risk further. Prospective, randomized controlled trials have confirmed this for the continuous combined regimen. So, why not tell our patients, “Stop using ET and EPT, it is dangerous to your health!”? The answer is: there are too many problems to allow such an oversimplified, definite statement. What is the problem? There is more than one!The problems are as follows:

• •There are many observational studies, but these are not consistent in their results.
• •Relative risk increases, if any, are small and thus often statistically non-significant.
• •Observational studies have inherent biases that cannot be corrected for; therefore evidence should come from randomized clinical trials (RCTs).
• •There are no RCTs that provide evidence as to the breast cancer risk with ET, compared to EPT in the same study population.
• •In the three large RCTs available, the populations studied are: not representative, too old and without climacteric complaints, and therefore lacking any indication for postmenopausal hormone therapy (HT).
• •The data obtained thus far do not apply to non-oral routes, neglect the difference in progestogens, and do not address tibolone, a valuable alternative to classical HT in Europe.
• •And finally, are these epidemiological findings biologically plausible? Can estrogens cause breast cancer and why then does the Women's Health Initiative (WHI) RCT not find this? And how can the addition of a progestogen increase the ET risk further as progestogens are pro-apoptotic and down-regulate estrogen receptors as well as local estrogen biosynthesis?

In conclusion, we have a problem as we cannot formulate any general advice that holds for the majority of European postmenopausal women due to lack of consistency, lack of biological plausibility, and lack of relevance of randomized clinical trial data to our daily practical work.So, we have a problem and not a firm basis for undisputable statements.     

Binding of the Drosophila cytokine Spätzle to Toll is direct and establishes signaling

The extracellular protein Sp?tzle is required for activation of the Toll signaling pathway in the embryonic development and innate immune defense of Drosophila. Sp?tzle is synthesized as a pro-protein and is processed to a functional form by a serine protease. We show here that the mature form of Sp?tzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. Sp?tzle specifically bound to Drosophila cells and to Cos-7 cells expressing Toll. Furthermore, in vitro experiments showed that the mature form of Sp?tzle bound to the Toll ectodomain with high affinity and with a stoichiometry of one Sp?tzle dimer to two receptors. The Sp?tzle pro-protein was inactive in all these assays, indicating that the pro-domain sequence, which is natively unstructured, acts to prevent interaction of the cytokine and its receptor Toll. These results show that, in contrast to the human Toll-like receptors, Drosophila Toll requires only an endogenous protein ligand for activation and signaling.     

Temporal evolution of human autoantibody response to cytoplasmic rods and rings structure during anti-HCV therapy with ribavirin and interferon-α

Autoantibodies to inosine monophosphate dehydrogenase-2 (IMPDH2), an enzyme involved in de novo biosynthesis of guanine nucleotides, are observed in a subset of hepatitis C virus (HCV) patients receiving interferon alpha (IFN-α) plus ribavirin. Anti-IMPDH2 antibodies display a peculiar cytoplasmic “rod/ring” (RR) pattern in IIF-HEp-2. We examined the dynamics of anti-RR autoimmune response with respect to immunoglobulin isotypes, titer, avidity, and protein targets in 80 sequential samples from 15 HCV patients (plus 12 randomly selected anti-RR-positive, totalizing 92 samples) collected over an 18-month period, including samples collected before, during, and after IFN-α + ribavirin treatment. Immunoprecipitation showed reactivity with the 55 kDa IMPDH2 protein in 12/15 patients (80 %) and 11/15 (73 %) reacted with IMPDH2 in a sandwich ELISA. During treatment, anti-IMPDH2 autoantibodies hit their highest levels after 6–12 months of treatment and decreased post-treatment, while anti-HCV antibodies levels were stable over time. Anti-IMPDH2 IgM levels increased up until the sixth month of treatment and remained stable thereafter, while IgG levels increased steadily up to the twelfth month. Both IgG and IgM decreased during the post-treatment period. IgG avidity increased steadily up to the twelfth month of treatment. In conclusion, this study showed that the temporal kinetics of IFN-α + ribavirin-induced humoral autoimmune response to IMPDH2 exhibited a considerably delayed pace of increase in antibody levels and avidity as well as in isotype class switch in comparison with a conventional humoral response to infectious agents. These unique findings uncover intriguing differences between the autoimmune response and the immune response to exogenous agents in humans.