In vitro activities of ciprofloxacin and rifampin alone and in combination against growing and nongrowing strains of methicillin-susceptible and methicillin-resistant Staphylococcus aureus.

We characterized the effects of ciprofloxacin and rifampin alone and in combination on Staphylococcus aureus in vitro. The effects of drug combinations (e.g., indifferent, antagonistic, or additive interactions) on growth inhibition were compared by disk approximation studies and by determining the fractional inhibitory concentrations. Bactericidal effects in log-phase bacteria and in nongrowing isolates were characterized by time-kill methods. The effect of drug combinations was dependent upon whether or not cells were growing and whether killing or growth inhibition was the endpoint used to measure drug interaction. Despite bactericidal antagonism in time-kill experiments, our in vitro studies suggest several possible explanations for the observed benefits in patients treated with a combination of ciprofloxacin and rifampin for deep-seated staphylococcal infections. Notably, when growth inhibition rather than killing was used to characterize drug interaction, indifference rather than antagonism was observed. An additive bactericidal effect was observed in nongrowing bacteria suspended in phosphate-buffered saline. While rifampin antagonized the bactericidal effects of ciprofloxacin, ciprofloxacin did not antagonize the bactericidal effects of rifampin. Each antimicrobial prevented the emergence of subpopulations that were resistant to the other.     

Thrombopoietin, but not erythropoietin, directly stimulates multilineage growth of primitive murine bone marrow progenitor cells in synergy with early acting cytokines: distinct interactions with the ligands for c-kit and FLT3

Thrombopoietin (Tpo), the ligand for c-mpl, has been shown to be the principal regulator of megakaryocytopoiesis and platelet production. The ability of Tpo to potently stimulate the growth of committed megakaryocyte (Mk) progenitor cells has been studied in detail. Murine fetal liver cells, highly enriched in primitive progenitors, have been shown to express c-mpl, but little is known about the ability of Tpo to stimulate the growth and differentiation of primitive multipotent bone marrow (BM) progenitor cells. Here, we show that Tpo alone and in combination with early acting cytokines can stimulate the growth and multilineage differentiation of Lin- Sca-1+ BM progenitor cells. In particular, Tpo potently synergized with the ligands for c-kit (stem cell factor [SCF]) and flt3 (FL) to stimulate an increase in the number and size of clones formed from Lin- Sca-1+ progenitors. When cells were plated at 1 cell per well, the synergistic effect of Tpo was observed both in fetal calf serum-supplemented and serum-depleted medium and was decreased if the addition of Tpo to cultures was delayed for as little as 24 hours, suggesting that Tpo is acting directly on the primitive progenitors. Tpo added to SCF + erythropoietin (Epo)-supplemented methylcellulose cultures potently enhanced the formation of multilineage colonies containing granulocytes, macrophages, erythrocytes, and Mks. SCF potently enhanced Tpo-stimulated production of high-ploidy Mks from Lin- Sca-1+ progenitors, whereas the increased growth response obtained when combining Tpo with FL did not translate into increased Mk production. The ability of Tpo and SCF to synergistically enhance the growth of Lin- Sca-1+ progenitors was predominantly observed in the more primitive rhodamine 123(lo) fraction. Tpo also enhanced growth of Lin- Sca-1+ progenitors when combined with interleukin-3 (IL-3) and IL-11 but not with IL-12, granulocyte colony-stimulating factor, granulocyte-macrophage colony- stimulating factor, or Epo. Epo, which has high homology to Tpo, was unable to stimulate the growth of Lin- Sca-1+ progenitors alone or in combination with SCF or FL, suggesting that c-mpl is expressed on more primitive stages of progenitors than the Epo receptor. Thus, the present studies show the potent ability of Tpo to enhance the growth of primitive multipotent murine BM progenitors in combination with multiple early acting cytokines and documents its unique ability to synergize with SCF to enhance Mk production from such progenitors.     

Do we need to obtain consent for penile shortening as a complication of treatment for organ‐confined prostate cancer?

What's known on the subject? and What does the study add? Penile shortening after total prostatectomy has been consistently reported, but most studies are small. BAUS has incorporated penile shortening into their patient information leaflets, but claims it is attributable to an anatomical alteration alone. No other organization even mentions penile shortening in their advice. Our study shows that a true, and at least partially reversible, penile shortening occurs in a significant proportion of patients after total prostatectomy. The cause of the shortening is largely physiological and interlinked with the processes leading to erectile dysfunction.

OBJECTIVE

• ? To establish an evidence base to guide consenting for treatment of organ‐confined prostate cancer with regard to penile shortening.

MATERIALS AND METHODS

• ? We performed literature searches using the EMBASE, MEDLINE, AHMED and PsycINFO databases up to October 2011, looking for articles relating to surgical treatment of prostate cancer and penile shortening and articles relating to radiotherapy for prostate cancer and penile shortening. We also looked at further references in the papers identified.

RESULTS

• ? We found 16 original papers and three review articles with measurements of penile shortening after total prostatectomy (TP).
• ? Penile shortening was generally considered in conjunction with erectile dysfunction (ED).
• ? Three further articles address psychological and consent issues.
• ? We found two articles regarding penile shortening after radiotherapy for prostate cancer.

CONCLUSIONS

• ? There is no doubt that TP leads to penile shortening in some patients, but the mechanism remains debatable.
• ? Given current evidence, it is likely that several factors contribute and early penile rehabilitation for ED, by any method, appears to positively influence the changes leading to penile shortening.
• ? We advise explicit mentioning of penile shortening in the consent process for TP and potentially also for radiotherapy for prostate cancer. We also advise early penile rehabilitation to improve the patient's own body image and, in turn, quality of life, even in patients who do not seek treatment specifically for ED. The choice of treatment method should be left to the patient.

     

Advances in the management of high-risk localised and metastatic prostate cancer

At the third annual Interactive Genitourinary Cancer Conference, held in Budapest from 30 April to 1 May 2011, the latest developments in the management of patients with high-risk localised and metastatic prostate cancer were discussed. Prostate cancer is the most common cancer in Western men and, for advanced disease, no curative agents are available. For men with high-risk localised disease there is debate about the best treatment approaches, with both radical prostatectomy and radiation therapy shown to improve outcomes. These approaches have started to be augmented as new techniques and therapies are developed. For instance, radiation therapy combined with androgen deprivation therapy has been shown to be more efficacious than radiation therapy alone, and there may also be a role for adjuvant/neoadjuvant chemotherapy. Ultimately a multidisciplinary approach will most probably result in the best outcomes for patients. The use of androgen deprivation therapy in men with prostate cancer needs to be monitored carefully, given that it results in adverse alterations in several metabolic parameters and an increased risk of further coronary events in men with cardiovascular disease in some studies. Until recently there were limited options for the management of men with advanced prostate cancer, but new agents for use in the post-docetaxel setting have recently been approved. These are cabazitaxel and abiraterone acetate, which have both shown a significant survival benefit in patients who have progressed on docetaxel. Additional agents, for these patients and for patients at other stages of disease, are in the later stages of development. The development of new agents has been aided by a greater understanding of the molecular mechanisms of resistance to current therapies and the recognition of new pathophysiological pathways. As the number of available therapeutic options increases, it will become increasingly important to tailor treatments to the individual patient. This may require the development of novel biomarkers or the use of existing or new predictive tools based on prognostic factors. To ensure optimal patient care, early and continuous involvement of the multidisciplinary team will be required.     

Viral vectored granulocyte-macrophage colony stimulating factor inhibits vaccine protection in an SIV challenge model: protection correlates with neutralizing antibody

In a previous vaccine study, we reported significant and apparently sterilizing immunity to high-dose, mucosal, simian immunodeficiency virus (SIV) quasi-species challenge. The vaccine consisted of vectors based on vesicular stomatitis virus (VSV) expressing simian immunodeficiency virus (SIV) gag and env genes, a boost with propagating replicon particles expressing the same SIV genes, and a second boost with VSV-based vectors. Concurrent with that published study we had a parallel group of macaques given the same doses of vaccine vectors, but in addition, we included a third VSV vector expressing rhesus macaque GM-CSF in the priming immunization only. We report here that addition of the vector expressing GM-CSF did not enhance CD8 T cell or antibody responses to SIV antigens, and almost completely abolished the vaccine protection against high-dose mucosal challenge with SIV. Expression of GM-CSF may have limited vector replication excessively in the macaque model. Our results suggest caution in the use of GM-CSF as a vaccine adjuvant, especially when expressed by a viral vector. Combining vaccine group animals from this study and the previous study we found that there was a marginal but significant positive correlation between the neutralizing antibody to a neutralization resistant SIV Env and protection from infection.     

Coronary arteritis in nonspecific aortoarteritis

Nonostial distal coronary artery involvement in nonspecific aortoarteritis is rare. We report a 35-year-old patient with features of nonspecific aortoarteritis who had an inferolateral myocardial infarction and on coronary angiography was shown to have severe disease of the left circumflex artery in its middle third.     

Highly specific and sensitive hybridoma antibodies against the alpha-subunit of human glycoprotein hormones

The free alpha-subunit of human CG (hCG-alpha) has been detected in pregnancy as well as in several endocrine and nonendocrine tumors. In order to facilitate the detection of these tumors, we have developed, by hybridoma technology, very sensitive and highly specific antibodies to hCG-alpha, A2D4 and A2-58. Employing these antibodies, assays were developed to detect picogram levels of the free alpha-subunit. These antibodies have negligible cross-reactivity with intact hCG (A2D4, 0.17%; and A2-58, 1.75%). Pituitary hormone standards of human LH, human FSH, and human TSH from NIH showed cross-reactivity with these antibodies. However, the cross-reactivity was found to be due to the contamination of the hormone preparations with alpha-subunit. The antibodies have no effect on the binding of hCG to its receptor. They cross-react to the same extent with the deglycosylated hCG-alpha and alpha-subunits of all other human glycoprotein hormones but do not react with alpha-subunits of glycoprotein hormones from other species. We have purified these antibodies to homogeneity by DEAE Affi-Gel Blue and affinity chromatography. Both these antibodies belong to immunoglobulin M subclass.