Semen analysis in chronic bacterial prostatitis： diagnostic and therapeutic implications

The significance and diagnostic value of semen analysis in chronic bacterial prostatitis has been extensively debated and remains controversial. To investigate the diagnostic relevance of semen culture in the bacteriological workup of prostatitis patients, we retrospectively analyzed a clinical database of 696 symptomatic patients. All patients were routinely subjected to a four-glass test, followed by semen culture and analysis. This allowed to dissect from the database three different diagnostic scenarios, and to compare the ＇two-glass＇ pre-/post- massage test and the standard ＇four-glass＇ test with a ＇five-glass＇ test （four-glass plus post-VB3 semen culture）. The ＇five-glass＇ test showed 3.6- or 6.5-fold increases in relative sensitivity and lesser reductions （-13.2% or -14.7%） in relative specificity for traditional uropathogens （TUs） compared with the four-glass or two-glass test, respectively. The area under the ROC curve and Jouden＇s index were increased, whereas positive and negative likelihood ratios were lower than comparators, indicating that the ＇five-glass＇ assay may be superior in confirming the negative outcome of both standard tests. The five-, four-, and two-glass tests detected TUs （Enterobacteriaceae, Enterococci, etc.） in 120, 33, and 20 patients and unusual pathogens （Streptococci, other Gram-positive species, Mycoplasmata, and others） in 130, 56, and 45 patients, respectively. When patients were subjected to pharmacological treatment, including a combination of a fluoroquinolone and a macrolide, no differences in eradication rates were observed between groups diagnosed with different tests, irrespective of pathogen category. Eradication was associated with long-term sign/symptom remission; no significant intergroup differences in sign/symptom scores were observed throughout a 24-month off-therapy follow-up period. In conclusion, our data support the usefulness of semen analysis in the diagnostic workup ofprostatitis patients when this test is used to complement the four-glass Meares and Stamey test. Improvement of microbiological assays conveys important diagnostic and therapeutic implications.     

Olanzapine pamoate for the treatment of schizophrenia

Introduction: Nonadherence is still a major problem in the long-term treatment of schizophrenia. Long-acting injectable or depot atypical antipsychotics are associated with better maintenance. Olanzapine pamoate, available since 2010, is the second depot atypical antipsychotic. Areas covered: This review covers data on the efficacy and tolerability/safety of olanzapine pamoate, the long-acting formulation of the atypical antipsychotic olanzapine. Administered as a pamoate salt, it has an elimination half-life of 30 days, allowing a 2- or 4-week injection interval. Antipsychotic efficacy was documented in an 8-week trial in 404 acutely ill schizophrenia patients with maintenance therapy in a 24-week trial in 1065 chronic patients. The side-effect profile is comparable to that of oral olanzapine. The most relevant adverse event is the post-injection delirium/sedation syndrome, occurring at a rate of 0.07% of injections or 1.4% of patients. It requires administration by qualified personnel in settings where a post-injection observation period for 3 h by medical personnel is available. Expert opinion: Olanzapine pamoate is an efficacious formulation, particularly for patients with a history of good response to oral olanzapine and doubtful adherence. Psychiatrists should reconsider their negative attitudes toward long-acting or depot antipsychotics and should offer this administration to the majority of patients, not only to a negatively selected population.     

Pharmacogenetic characterization of indacaterol,a novel β2-adrenoceptor agonist

Background and purpose:

Indacaterol is a novel β₂-adrenoceptor agonist in development for the treatment of chronic obstructive pulmonary disease. The aim of this study was to investigate the comparative pharmacology of indacaterol in recombinant cells expressing the common polymorphic variants of the human β₂-adrenoceptor and in human primary airway smooth muscle (ASM) cells.

Experimental approach:

Chinese hamster ovarian-K1 cell lines expressing high and low levels of the common human β₂-adrenoceptor variants were generated [Gly16-Glu27-Val34-Thr164(GEVT), RQVT, GQVT] and also the rare GQVI variant. Human primary ASM cells were isolated from explants of trachealis muscle. Adenosine-3′,5′-cyclic-monophosphate production was used as an outcome measure.

Key results:

In both the low- and high-expression recombinant GEVT ‘wild type’ cell lines indacaterol is a high-efficacy agonist. Salmeterol and formoterol were identified as low- and high-efficacy agonists, respectively, and showed similar potencies to indacaterol irrespective of the β₂-adrenoceptor genotype. The I164 variant cell line was associated with a reduced capacity to generate adenosine-3′,5′-cyclic-monophosphate in response to β₂-adrenoceptor agonist. In the human primary ASM cells indacaterol gave a maximal response intermediate between that of salmeterol and formoterol.

Conclusions and implications:

These data demonstrate that indacaterol is a high-efficacy agonist in recombinant cell systems but acts with lower efficacy in human primary ASM cells. No marked genotype-dependent effects were observed for common variants; however, changes in I164 receptor activity were identified, which were dependent on the level of expression of β₂-adrenoceptors.     

Proof of concept pilot study: prevalence of grass virus infection and the potential for effects on the allergenic potency of pollen

Background

Wild plants harbour a variety of viruses and these have the potential to alter the composition of pollen. The potential consequences of virus infection of grasses on pollen-induced allergic disease are not known.

Methods

We have collected pollen from Dactylis glomerata (cocksfoot; a grass species implicated as a trigger of allergic rhino-conjunctivitis) from Wytham Wood, Oxfordshire UK. Extracts were prepared from pollen from uninfected grass, and from grass naturally infected by the Cocksfoot streak potyvirus (CSV). Preparations of pollen from virus-infected and non-infected grasses were employed in skin testing 15 grass pollen-allergic subjects with hayfever. Allergen profiles of extracts were investigated by Western blotting for IgE with sera from allergic subjects.

Results

The prevalence of CSV infection in cocksfoot grasses sampled from the study site varied significantly over an eight-year period, but infection rates of up to 70% were detected. Virus infection was associated with small alterations in the quantities of pollen proteins detected by polyacrylamide gel electrophoresis, and in the patterns of allergens identified by Western blotting with IgE from grass pollen allergic subjects. For individual subjects there were differences in potencies of standardised extracts of pollen from virus-free and virus-infected plants as assessed by skin testing, though a consistent pattern was not established for the group of 15 subjects.

Conclusion

Infection rates for CSV in cocksfoot grass can be high, though variable. Virus-induced alterations in components of grass pollen have the potential to alter the allergenic potency.

     

Umstellung von typischen auf atypische Neuroleptika Richtlinien zur ambulanten und stationären Behandlung

The introduction of atypical antipsychotics has presented new options for the pharmacological treatment of schizophrenic patients. It is assumed that in the near future, neuroleptic medication will shift from conventional to atypical antipsychotics for an increasing number of patients. The present article addresses guidelines for the conversion from conventional to atypical neuroleptics in inpatient and outpatient settings.     

Systemic stromal effects of estrogen promote the growth of estrogen receptor-negative cancers

Numerous hormonal factors contribute to the lifetime risk of breast cancer development. These include inherited genetic mutations, age of menarche, age of menopause, and parity. Inexplicably, there is evidence indicating that ovariectomy prevents the formation of both estrogen receptor (ER)-positive and ER-negative breast cancers, suggesting that ER-negative breast cancers are dependent on ovarian hormones for their formation. To examine the mechanism(s) by which this may be occurring, we investigated the hypothesis that steroid hormones promote the outgrowth of ER-negative cancers by influencing host cell types distinct from the mammary epithelial cells. We used a novel xenograft mouse model of parturition-induced breast carcinoma formation, in which the tumors that arise following pregnancy lack the expression of nuclear hormone receptors, thereby recapitulating many clinical cases of this disease. Despite lacking ER expression, the tumors arising following pregnancy in this model require circulating estrogens for their formation. Moreover, increasing the levels of circulating estrogens sufficed to promote the formation and progression of ER-negative cancers, which was accompanied by a systemic increase in host angiogenesis and was attendant with the recruitment of bone marrow-derived stromal cells. Furthermore, bone marrow cells from estrogen-treated mice were sufficient to promote tumor growth. These results reveal a novel mechanism by which estrogens promote the growth of ER-negative cancers.     

Conformational changes at the nucleotide site in the presence of bound ADP do not set the velocity of fast Drosophila myosins

The conformational changes in myosin associated with ADP release and their influence on actin sliding velocity are not understood. Following actin binding, the myosin active site is in equilibrium between a closed and open ADP bound state, with the open state previously thought to favor ADP release and thus expected to be favored in faster myosins. However, our recent work with a variety of myosins suggests the opposite, that the open conformation is dominant in slower myosins, which have higher ADP affinities. To test if this correlation holds for fast myosin isoforms, we determined the relationships between conformational pocket dynamics, ADP affinity and velocity of four Drosophila myosins: indirect flight muscle (IFM) myosin (IFI), embryonic muscle myosin (EMB) and two IFI/EMB chimeras. Electron paramagnetic resonance spectra of nucleotide-analog spin probes (SLADP) bound to IFI subfragment-1 in the absence of actin showed a high degree of immobilization, indicating a predominately closed nucleotide pocket. The A·M·SLADP spectra of all four myosins in fibers (actin bound) also indicated an equilibrium favoring the closed conformation with the closed state closing even further. However, the energetics of pocket closure did not correlate with Drosophila myosin actin velocity suggesting our previous model relating pocket dynamics to velocity does not hold for fast myosin isoforms. We conclude that for these fast myosins, and possibly other fast myosins, velocity is controlled by factors other than the ratio of open to closed nucleotide pocket conformation.