Aromatase inhibition by the antifungal ketoconazole

The aromatase inhibitory properties of the antifungal ketoconazole were compared with those of aminoglutethimide. In rat granulosa cells ketoconazole and aminoglutethimide showed IC50 values for aromatase inhibition of 2 X 10(-6) and 6 X 10(-7) M respectively. In the rat, in vivo, ketoconazole was 5 times less potent than aminoglutethimide. In young women, 400 mg of ketoconazole only marginally lowered plasma levels of estradiol-17 beta. It is concluded that ketoconazole is not a compound of choice for clinical use as an aromatase inhibitor.     

Downgrade of cardiac defibrillator devices to pacemakers in elderly heart failure patients: clinical considerations and the importance of shared decision-making

Netherlands Heart Journal - Implantable cardioverter defibrillators are implanted on a large scale in patients with heart failure (HF) for the prevention of sudden cardiac death. There are...     

Biographical memoir: Alexander Beaumont Hope,Australian biophysicist, 1928–2008

This introductory article is the first of four short articles from the Tribute to Alex Hope Symposium held at the 2008 Australian Society for Biophysics meeting in Canberra, Australia, as a tribute to Professor Alex Hope, who died in July last year. As well as briefly introducing the other three articles by three former PhD students, it will also be a biographical memoir of Alex Hope.     

Maternal effects reduce oxidative stress in female nestlings under high parasite load

Mothers can adjust the phenotype of their offspring to the local environment through a modification of their egg investment and/or nestling provisioning. However, offspring health may be severely impaired if the conditions experienced by nestlings do not match with those anticipated by the mother. If maternal effects differentially affect the sexes or if one sex is more strongly affected by an environmental stressor, fitness benefits may also differ between male and female offspring. Here, we study maternal effects in male and female great tit Parus major nestlings by means of an ectoparasite treatment before egg‐laying combined with a partial cross‐foster experiment between broods of infested and uninfested nests. Nestlings that were raised in their own nest experienced the same conditions before and after cross‐fostering (either in parasite infested or uninfested nests), while cross‐fostered ones experienced different conditions (either changing from infested to uninfested or the other way around). We measured effects on nestling plasma levels of oxidative stress [reactive oxygen metabolites (ROMs) and total antioxidant capacity (OXY)], body condition (body size and mass) and post‐fledging survival. Daughters, but not sons, from matching conditions showed the lowest ROM and high OXY levels when exposed to parasites, while there was no effect of parasite exposure in any of both sexes in case of a mismatch. In contrast, body condition and post‐fledging survival were not (or only slightly) affected by any of the experimental treatments. Results of this study show that maternal effects can affect oxidative stress levels of nestlings in a sex‐specific way and that the outcome depends on the exposure to environmental stressors, such as parasites.     

Short report: The potential of PCR on skin flakes from bed linens for diagnosis of scabies in an outbreak

BackgroundScabies outbreaks are common in nursing homes in the Netherlands. In October 2018, a local public health service (PHS) in The Hague was notified of a new scabies outbreak in a nursing home in that region. The PHS initiated an outbreak investigation. Cases were defined as: possible (reported symptoms), probable (scabies-like lesions) and confirmed (PCR or microscopy in skin flakes). Head-to-toe examinations were performed of all residents and those staff members who reported symptoms suggestive of scabies. Skin scrapings of lesions were tested either with microscopy or by PCR. Experimentally for case finding, skin flakes from bed linens of residents who reported symptoms of itchiness but did not have primary lesions were sent for PCR testing.Principal findingsAll residents (41) and 37/44 staff were included in this outbreak investigation. We identified 30 possible, four probable and six confirmed cases. The overall attack rate for probable/confirmed cases was 10/78 (13%). Of the six confirmed cases, two were confirmed by PCR, three by microscopy, and one showed positive findings with both techniques. Two out of the three bed-linen specimens were PCR-positive.ConclusionsIn this outbreak of scabies in a nursing home, PCR was used on skin flakes from bed linens, which led to the detection of two additional cases. This illustrates the potential of PCR during the investigation of scabies outbreaks.     

Logistic models describing effects of temperature and humidity on residual effectiveness of chlorpyrifos and cyfluthrin formulations against German cockroaches (Dictyoptera: Blattellidae).

Multifactored logistic models were developed for chlorpyrifos and cyfluthrin formulations based on mortality data from laboratory studies with the German cockroach, Blattella germanica (L.). Insecticides were applied to stainless steel surfaces and aged at three different temperatures (23, 30, and 37 degrees C) and two levels of relative humidity (40 and 70%). After the insecticides dried, the treated panels were placed opposite plywood panels to simulate a crack and crevice application. At appropriate aging times, treated panels were removed from environmental chambers for bioassay. The combined effects of high temperature, high humidity, and aging of residues caused the greatest decline in cockroach mortality for chlorpyrifos. Increasing temperature and aging of residues resulted in decreased cockroach mortality for cyfluthrin formulations; however, mortality was greater than 87% for all formulations through 84 d. Information from this study can be incorporated into integrated pest management programs for German cockroaches.     

Discovery of “punch-through” or membrane electrical breakdown and electroporation

As part of a detailed study in Alex Hope’s laboratory of the V–I characteristics of the membrane of the giant cells of Chara corallina, it was discovered that at a well defined potential difference of around 500 mV (depending on the temperature), the cell membrane undergoes a reversible electrical breakdown. The author coined the word “punchthrough” to describe this electrical breakdown phenomenon. Detailed studies followed on the nature of this electrical breakdown phenomenon, in various cells, aimed at elucidating the physical mechanism(s) involved. The applications and the significance of the phenomenon that were subsequently developed in later years were not foreseen at that time. Electrical breakdown/electroporation is now a commonplace procedure and has entered into the mainstream biological vocabulary. Here we trace its humble beginnings to experiments carried out in Alex Hope’s laboratory and review briefly some of the aspects of this phenomenon and its applications that were developed much later by others as well as the author. The discovery of membrane electrical breakdown described below took whilst the author was his student of Alex Hope but whilst Alex was away on sabbatical leave in the UK. Because this occurred in his absence, Alex Hope elected to not put his name on the paper that described the discovery in 1965.     

Combination of chemotherapy and radiotherapy. II. Differential effect on the medullary syndrome of irradiation combined with the drug administered in fractional doses and at various times]

We have studied the effect of 5-Fu in fractional doses on the medullar syndrome after a single whole body cobalt irradiation in mice. The bone marrow is not sensitive to the fractionation of 5-Fu and it is the single dose of 5-Fu injected 72 hours after the irradiation which is the most effective.     

P450-dependent enzymes as targets for prostate cancer therapy

Metastatic prostate adenocarcinoma is a leading cause of cancer-related deaths among men. First line treatment is primarily aimed at blocking the synthesis and action of androgens. As primary endocrine treatment, androgen deprivation is usually achieved by orchidectomy or LHRH analogues, frequently combined with androgen receptor antagonists in order to block the residual adrenal androgens. However, nearly all the patients will eventually relapse. Available or potential second line therapies include, among others, alternative endocrine manipulations and chemotherapy.

Cytochrome P450-dependent enzymes are involved in the synthesis and/or degradation of many endogenous compounds, such as steroids and retinoic acid. Some of these enzymes represent suitable targets for the treatment of prostate cancer.

In first line therapy, inhibitors of the P450-dependent 17,20-lyase may achieve a maximal androgen ablation with a single drug treatment. Ketoconazole at high dose blocks both testicular and adrenal androgen biosynthesis but its side-effects, mainly gastric discomfort, limit its widespread use. A series of newly synthesized, more selective, steroidal 17,20-lyase inhibitors related to 17-(3-pyridyl)androsta-5,16-dien-3β-ol, may open new perspectives in this field.

In prostate cancer patients who relapse after surgical or medical castration, therapies aiming at suppressing the remaining adrenal androgen biosynthesis (ketoconazole) or producing a medical adrenalectomy (aminoglutethimide + hydrocortisone) have been used, but are becoming obsolete with the generalization of maximal androgen blockade in first line treatment. The role of inhibition of aromatase in prostate cancer therapy, which was postulated for aminoglutethimide, could not be confirmed by the use of more selective aromatase inhibitors, such as formestane.

An alternative approach is represented by liarozole fumarate (LIA), a compound that blocks the P450-dependent catabolism of retinoic acid (RA). In vitro, it enhances the antiproliferative and differentiation effects of RA in cell lines that express RA metabolism, such as F9 teratocarcinoma and MCF-7 breast carcinoma cells. In vivo, monotherapy with LIA increases RA plasma levels and, to a greater extent, endogenous tissue RA levels leading to retinoid-mimetic effects. In the rat Dunning prostate cancer models, it inhibits the growth of androgen-independent as well as androgen-dependent carcinomas relapsing after castration. Concurrently, changes in the pattern of cytokeratins characteristic of increased differentiation were observed. Early clinical trials show that LIA, in second or third line therapy in metastatic prostate cancer, induces PSA responses in about 30% of unselected patients. In some patients regression of soft tissue metastasis has been observed. In a subgroup of patients, an important relief of metastatic bone pain was also noted.