Albert G. Frauman

A protective role for protease-activated receptors in the airways.

The protection of cells in the upper intestine against digestion by pancreatic trypsin depends on the prostanoid prostaglandin E2 (PGE2) and is mediated by protease-activated receptors in the epithelium,. As the airway epithelium is morphologically similar and also expresses one of these receptors, PAR2 (ref. 3), and is a major source of PGE2 (ref. 4), we reasoned that bronchial epithelial PAR2 might also participate in prostanoid-dependent cytoprotection in the airways. Here we show that activation of PAR2, which co-localizes immunohistochemically with trypsin(ogen) in airway epithelium, causes the relaxation of airway preparations from mouse, rat, guinea-pig and humans by the release of a cyclooxygenase product from the epithelium. This physiological protective response in isolated airways also occurred in anaesthetized rats, where activation of PAR2 caused a marked and prolonged inhibition of bronchoconstriction. After desensitization of PAR2, the response to trypsin recovered rapidly by mechanisms dependent on de novo synthesis and trafficking of proteins. Our results indicate that trypsin released from the epithelium can initiate powerful bronchoprotection in the airways by activation of epithelial PAR2.

Patterns of care for men diagnosed with prostate cancer in Victoria from 2008 to 2011

Objective: To describe patterns of care for men diagnosed with prostate cancer in Victoria, Australia, between 2008 and 2011.

Thyroid‐associated ophthalmopathy: a practical guide to classification, natural history and management

Thyroid−associated ophthalmopathy (TAO) is an autoimmune disorder that can be divided into three clinical subtypes: congestive, myopathic and mixed ophthalmopathy. It is probably caused by immune cross‐reactivity between orbital and thyroid antigens. The best candidate antigens are the thyrotropin receptor and the novel protein, G2s, which is now identified as a fragment of the winged helix transcription factor, FOXP1. The relationship between radioiodine therapy and TAO is controversial, with two randomised controlled trials showing a transient worsening of the eye disease after treatment. The diagnosis of TAO is a clinical one, based on the presence of specific symptoms and signs. Orbital imaging, preferably magnetic resonance imaging, is useful when the diagnosis is in doubt and in patients with suspected optic neuropathy who may benefit from early intervention. Despite their lack of specificity, orbital antibodies may add weight to the diagnosis and may potentially be a useful tool in classifying the different subtypes of TAO and in monitoring disease activity. While antibodies against G2s and the thyrotropin receptor are seen in all subtypes, those against Fp and collagen XIII may be associated with the myopathic and congestive subtypes, respectively, where Fp is the flavoprotein subunit of the mitochondrial enzyme, succinate dehydrogenase. In most patients, TAO is self‐limiting and no specific treatment is required. When treatment is indicated, glucocorticoids are the mainstay of therapy. Orbital radiotherapy improves the efficacy of glucocorticoids, but is probably less beneficial as monotherapy. Orbital surgery is best reserved for patients with ‘burnt out’ inactive disease, but urgent orbital decompression may be required for optic neuropathy. The severity and clinical activity of TAO are important in determining the need for specific treatment and the likelihood of success with medical therapy, respectively. (Intern Med J 2004; 34: 482−491)

Evidence for activation of the renin–angiotensin system in the human prostate: increased angiotensin II and reduced AT1 receptor expression in benign prostatic hyperplasia

The expression and cellular localization of angiotensin II (Ang II) and AT1 receptor proteins were examined in the normal human prostate and benign prostatic hyperplasia (BPH) by immunohistochemistry. In the normal prostate, Ang II immunoreactivity was localized to the basal layer of the epithelium and AT1 receptor immunostaining was found predominantly on stromal smooth muscle and also on vascular smooth muscle of prostatic blood vessels. Ang II immunoreactivity was markedly increased in hyperplastic acini in BPH compared with acini in the normal prostate (normal: 7.4±0.2%, n=5 vs. BPH: 22.7±1.9%, n=5, p<0.001). However, AT1 receptor immunoreactivity was significantly decreased in BPH compared with the normal prostate [normal: 16.4±2.2%, n=4 vs. BPH: 9.4±1.3%, n=5, p<0.05 (p=0.025)]. The present study demonstrates the presence of Ang II peptide in the basal layer of the epithelium and AT1 receptors on stromal smooth muscle, suggesting that Ang II may mediate paracrine functions on cellular growth and smooth muscle tone in the human prostate. Furthermore, AT1 receptor down‐regulation in BPH may be due to receptor hyperstimulation by increased local levels of Ang II in BPH. These data extend previous findings in support of the novel concept that overactivity of the renin–angiotensin system (RAS) may be involved in the pathophysiology of BPH. Copyright

Protease-activated receptor (PAR) 1 but not PAR2 or PAR4 mediates endothelium-dependent relaxation to thrombin and trypsin in human pulmonary arteries

&NA; Endothelial protease‐activated receptors (PARs) may be important sensors of vascular inflammation and injury. Activation of endothelial PAR1 and PAR2 causes nitric oxide‐mediated arterial smooth muscle relaxation in a number of species and PAR4 activation causes similar responses in isolated rat aorta. However, it is unclear whether these receptors mediate such responses in human arteries because the most potent activators of PAR1, PAR2, and PAR4, thrombin and trypsin, cause endothelium‐dependent relaxation of human coronary arteries through a common PAR1‐like receptor. This study aimed to determine whether this unique pharmacology of PARs in human coronary arteries extends to human pulmonary arteries. PAR1 and PAR2 mRNA and protein were detected in human pulmonary arteries via reverse transcription polymerase chain reaction and immunohistochemistry, respectively. PAR4 mRNA was also detected in human pulmonary arteries. Contracted human pulmonary artery ring segments suspended for isometric tension measurement relaxed in a concentration‐ and endothelium‐dependent manner to thrombin (0.001–0.1 U/ml), trypsin (0.01–1 U/ml), and the PAR1‐activating peptide, SFLLRN (0.1–10 &mgr;M). By contrast, the PAR2‐ and PAR4‐activating peptides, SLIGKV and GYPGQV, respectively, caused neither contraction nor relaxation of precontracted human pulmonary arteries. Relaxations to thrombin and trypsin cross‐desensitized, while tachyphylaxis to SFLLRN abolished subsequent relaxations to both thrombin and trypsin. We conclude that human pulmonary arteries express PAR1, PAR2, and PAR4, but that only PAR1, or a PAR1‐like receptor, is coupled to endothelium‐dependent relaxation.

Is Fosfomycin a Potential Treatment Alternative for Multidrug-Resistant Gram-Negative Prostatitis?

BACKGROUND Multidrug-resistant gram-negative bacterial (MDR-GNB) infections of the prostate are an increasing problem worldwide, particularly complicating transrectal ultrasound (TRUS)-guided prostate biopsy. Fluoroquinolone-based regimens, once the mainstay of many protocols, are increasingly ineffective. Fosfomycin has reasonable in vitro and urinary activity (minimum inhibitory concentration breakpoint ≤64 µg/mL) against MDR-GNB, but its prostatic penetration has been uncertain, so it has not been widely recommended for the prophylaxis or treatment of MDR-GNB prostatitis. METHODS In a prospective study of healthy men undergoing a transurethral resection of the prostate for benign prostatic hyperplasia, we assessed serum, urine, and prostatic tissue (transition zone [TZ] and peripheral zone [PZ]) fosfomycin concentrations using liquid chromatography-tandem mass spectrometry, following a single 3-g oral fosfomycin dose within 17 hours of surgery. RESULTS Among the 26 participants, mean plasma and urinary fosfomycin levels were 11.4 ± 7.6 µg/mL and 571 ± 418 µg/mL, 565 ± 149 minutes and 581 ± 150 minutes postdose, respectively. Mean overall prostate fosfomycin levels were 6.5 ± 4.9 µg/g (range, 0.7-22.1 µg/g), with therapeutic concentrations detectable up to 17 hours following the dose. The mean prostate to plasma ratio was 0.67 ± 0.57. Mean concentrations within the TZ vs PZ prostate regions varied significantly (TZ, 8.3 ± 6.6 vs PZ, 4.4 ± 4.1 µg/g; P = .001). Only 1 patient had a mean prostatic fosfomycin concentration of <1 µg/g, whereas the majority (70%) had concentrations ≥4 µg/g. CONCLUSIONS Fosfomycin appears to achieve reasonable intraprostatic concentrations in uninflamed prostate following a single 3-g oral dose, such that it may be a potential option for prophylaxis pre-TRUS prostate biopsy and possibly for the treatment of MDR-GNB prostatitis. Formal clinical studies are now required.

Long-Term Use of Intranasal Insulin in Insulin-Dependent Diabetic Patients

This study, in 3 phases, compared the long-term acceptability and efficacy of insulin administered by nasal spray with an intensified subcutaneous regimen in nine type I (insulin-dependent) diabetic subjects on baseline therapy with ultralente insulin. In phase 1, patients were begun and stabilized on a regimen of ultralente daily and Actrapid insulin three times daily. Phase 2 consisted of 4 mo of this intensified subcutaneous regimen. In phase 3, intranasal administration of insulin, with 1% (wt/vol) sodium glycocholate, replaced Actrapid insulin for 4 mo. Glycemic control was compared in each of the three phases. It was possible to maintain the dose of ultralente insulin relatively constant in only six of the nine subjects during the intranasal phase of the study. The six subjects showed a significant rise in glycosylated hemoglobin during the intranasal phase (10.4 ± 0.6% intranasal vs. 9.1 ± 0.3% subcutaneous, P < .05) but not in plasma or urinary glucose levels. There was no significant change in the incidence of hypoglycemic episodes during intranasal insulin therapy in this group. The other three subjects were considered treatment failures. Six of the nine original subjects expressed a preference for intranasal insulin, and one subject complained of mild nasal irritation insufficient to cease treatment. The intranasal route of administration of insulin has the potential to replace short-acting insulin as an adjunct to longer-acting insulin in some insulin-treated diabetic patients.

Progression of proteinuria in type 1 and type 2 diabetes.

A longitudinal study evaluating the time course of the transition from normal to micro‐albuminuria, and then on to macroalbuminuria, was made over a mean period of 7 years in a cohort of 52 patients with Type 1 diabetes and 61 patients with Type 2 diabetes. Transient episodes of micro‐ and macroalbuminuria were often observed before the ultimate development of persistent Albustix‐positive proteinuria. The transition from normal to micro‐albuminuria and from micro‐ to macroalbuminuria was characterized by rises in renal albumin clearance accompanied by lesser rises in total proteinuria.

Effects of Alendronate on Bone Density in Men with Primary and Secondary Osteoporosis

Abstract: Alendronate has been reported to increase bone mineral density (BMD) and reduce fracture risk in women with osteoporosis. As there are no proven safe and effective treatments available for men with osteoporosis, we compared the effects of alendronate (10 mg/day) on BMD, measured using dual-energy X-ray absorptiometry, in a 12-month prospective, controlled, open label study involving (i) men with primary (n= 23) or secondary osteoporosis (n= 18), (ii) postmenopausal women with primary (n= 18) or secondary (n= 21) osteoporosis, and (iii) 29 male and 14 female untreated controls matched by age, height and weight. The patients had one or more vertebral fractures and ranged in age from 34.6 to 85.1 years. BMD was detectably increased relative to baseline by 6 months, and increased by comparable amounts in males and females with primary or secondary osteoporosis. At 12 months, lumbar spine BMD was 5.4%± 1.1% to 7.0%± 2.2% higher in the treated groups compared with baseline and controls (p<0.05 to 0.0001). Trochanteric BMD increased by 2.6%± 1.5% and 3.7%± 1.7% in treated men with primary and secondary osteoporosis, respectively (p = 0.06 to 0.08), and by 3.9%± 1.3% in treated women with primary osteoporosis (p<0.01) after 12 months. No significant changes were detected at the femoral neck or Ward’s triangle. BMD remained unchanged in controls. We infer that alendronate has comparable incremental effects on BMD in men and women with primary and secondary osteoporosis within 12 months of treatment. The changes are in the order of 0.5 SD – effects associated with a clinically worthwhile reduction in fracture risk. The data provide room for optimism regarding the role of alendronate in the treatment of osteoporosis in men. Randomized, double-masked and placebo-controlled trials are needed to confirm these preliminary findings and demonstrate antifracture efficacy using vertebral and nonvertebral fracture rates as the primary endpoint.

Functional angiotensin II type 2 receptors inhibit growth factor signaling in LNCaP and PC3 prostate cancer cell lines.

There is clear evidence of a tissue‐based renin‐angiotensin system in the prostate and studies to date suggest that AT1‐receptor blocking drugs inhibit the growth of some prostate cancer cell lines and delay the development of prostate cancer. The present studies examine the action of Ang II in two prostate cancer cell lines and report the presence of functional AT2‐receptors that regulate the actions of growth factors.