Publications

Evaluation of the safety of hormonal preparations for the treatment of female sexual dysfunction is important to assess the benefit-to-risk profile of these drugs and has been strongly encouraged by the Food and Drug Administration. LibiGel (Biosante Pharmaceuticals, Inc., Lincolnshire, IL), a low-dose testosterone gel, is under development for the treatment of hypoactive sexual desire disorder (HSDD) in oophorectomized women. To evaluate the long-term effects of LibiGel on risk for cardiovascular (CV) events, breast cancer, and general safety, a randomized, placebo-controlled clinical study using a novel adaptive design to optimize sample size and power is being conducted. The primary end point of the BioSante LibiGel Safety Study (BLISS) is a composite of CV events including death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, hospitalized unstable angina, and venous thromboembolic events. Breast cancer is a coprimary end point. Postmenopausal women (both surgically and naturally) with HSDD and increased risk for CV events will be followed up for up to 5 years postrandomization with an interim data analysis for regulatory approval after the last woman enrolled has been on therapy for at least 12 months. Determination of the number of subjects to enroll is based on an adaptive design that uses interim data to estimate the predictive probability of study success. In agreement with the Food and Drug Administration, LibiGel will be declared safe if the upper limit of the 97.2% CI of the hazard ratio is ≤2.0 or the upper bound of the 97.2% CI for the absolute difference between CV event rates per 100 person-years is ≤1% and the observed hazard ratio is ≤2.0. The BLISS study will define the CV safety profile of low-dose testosterone therapy in the formulation of LibiGel for postmenopausal women with HSDD, and the trial design may provide a paradigm for studies that aim to document long-term safety when the proposed outcome under study is an uncommon adverse event.

OBJECTIVE

To report findings and outcomes of dogs with reherniation of nuclear material within 7 days of hemilaminectomy for acute thoracolumbar (TL) intervertebral disk extrusion.

STUDY DESIGN

Retrospective case series.

ANIMALS

Chondrodystrophic dogs (n = 11).

METHODS

Dogs with acute neurologic decline within 1 week of surgical decompression for TL disk extrusion were identified. Advanced imaging was used to document extradural spinal cord compression at the previous surgery site. Ten dogs had a 2nd decompressive surgery to remove extruded nuclear material.

RESULTS

All dogs had acute neurologic deterioration (average, 2 neurologic grades) 2-7 days after initial hemilaminectomy. Computed tomography (CT; n = 10) or myelography (n = 1) documented extradural spinal cord compression compatible with extruded disk material at the previous hemilaminectomy site. Dogs that had a 2nd surgical decompression improved neurologically within 24 hours and were paraparetic at discharge. The single dog that did not have decompressive surgery did not regain deep nociception during 185-day follow-up.

CONCLUSIONS

Early reherniation at the site of previous hemilaminectomy can produce acute deterioration of neurologic function and should be investigated with diagnostic imaging. Repeat decompressive surgery can lead to functional recovery.

All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments. In the prevailing model of thermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue. Acting via the β(3)-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes, whereas it stimulates the expression of thermogenic genes, such as PPAR-γ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1) and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report in mice an unexpected requirement for the interleukin-4 (IL-4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increased thermogenic gene expression, fatty acid mobilization and energy expenditure, all in a macrophage-dependent manner. Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold.