Stroke, myocardial infarction, acute and chronic inflammatory diseases: caspases and other apoptotic molecules as targets for drug development

Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models for drug discovery. Control of cell proliferation, differentiation, activation and cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.     

Nasal and auricular inverted papillomas

We report a rare case of an inverted papilloma with an unusual clinical course: development in the middle ear, multiples recurrences, and invasion of the temporal bone.     

Aging of population and medical workforce: a prospective view of health care provision in France in the year 2025

In 2011, the first generations of the French baby-boom will reach their 65th anniversary. In the same year the first cohorts of the French medical "graduate boom" (doctors graduated during the boom period 1974-1994) will reach their retirement age. From 2010 to 2025, French population will increase 4% but the French elderly will increase 40%. Depending on medical student intake policy adopted today, the French medical profession will decrease slowly or drastically. But the most striking feature of the period will be the aging of the medical workforce. Doctors aged 55 years and over will be between 42% and 47% of the medical workforce in 2025, as compared to 41% in 2010 and 14% in 2000. A great amount of factors--of which the demographic ones--will contribute to raise the demand for health care in the two coming decades. On the other side, the demographic change undergone by the medical profession (decrease of the total number, increase of the aged doctors, increase of the female doctors...) will decrease the amount of supply. However, the first problem facing the country is not how to raise the amount of supply but how to finance the forthcoming sharp growth of demand. The problem is not specific to France, as pointed out in a paper drafted twenty years ago.     

Retinal function loss after monocarboxylate transport inhibition

PURPOSE: To test the proposal that inhibiting monocarboxylate transport in the rat retina results in altered retinal function measured using the electroretinogram (ERG) and to evaluate the efficacy of exogenous metabolic substrates to restore any functional deficit. METHODS: Full-field white-flash ERGs were measured after monocarboxylate transport inhibition with intravitreal injection of alpha-cyano-4-hydroxycinnamic acid (4-CIN, 10 mM), and functional recovery was assessed after the introduction of various exogenous metabolic substrates (10 mM): lactate, pyruvate, alpha-ketoglutarate, alanine, succinate, and glutamine. The efficacy of glutamine as a metabolic substrate was also considered in the presence of phosphate-activated glutaminase inhibition (6-diazo-5-oxo-norleucin, 10 mM) or aminotransferase inhibition (aminooxyacetic acid, 10 mM). Pyruvate and alanine recovery was also assessed after aminooxyacetic acid application. RESULTS: 4-CIN application resulted in an increased phototransduction amplitude but a mild reduction of gain. A greater reduction of postreceptoral b-wave and oscillatory potential amplitudes (80%) was observed, along with delayed implicit times (35 ms). Partial recovery of b-wave amplitudes was achieved with exogenous lactate (24%), pyruvate (27%), alpha-ketoglutarate (27%), alanine (25%), and succinate (26%), whereas glutamine provided 62% recovery. However, none of the substrates improved phototransduction gain. Both 6-diazo-5-oxo-norleucin and aminooxyacetic acid completely suppressed the glutamine-induced b-wave recovery. Aminooxyacetic acid also abolished the b-wave recovery from 4-CIN afforded by pyruvate and alanine. CONCLUSIONS: The greater loss of the b-wave and oscillatory potentials may reflect preferential routing of amino acid carbon skeletons to oxidative metabolic pathways, which in turn reduces glutamate availability for neurotransmission between photoreceptors and ON-bipolar cells. The reduction in log S provides evidence that inhibition of monocarboxylate transport produced some metabolic dysfunction in the rat.     

Selective ganglion cell functional loss in rats with experimental glaucoma

PURPOSE: To characterize retinal functional consequences of elevated intraocular pressure (IOP) in a rat model of experimental glaucoma. METHODS: Unilateral elevation of IOP was produced by hypertonic saline injection into an episcleral vein in 20 adult male Brown-Norway rats. IOP was measured in both eyes of awake animals four to five times per week. After 5 weeks, animals were dark adapted overnight (>12 hours) and full-field electroretinograms (ERGs) were obtained simultaneously from both eyes. Scotopic ERG stimuli were brief white flashes (-6.64-2.72 log cd-s/m(2)). Photopic responses were also obtained (0.97-2.72 log cd-s/m(2)) after 15 minutes of light adaptation (150 cd/m(2)). Eyes were processed the following day for histologic evaluation by light microscopy, including masked determination of optic nerve injury grade (ONIG; 1, normal; 5, severe, diffuse damage). RESULTS: Among experimental eyes, the group average IOP (+/-SD) was 34.5 +/- 4.1 mm Hg, whereas the average for control eyes was 28.1 +/- 0.5 mm Hg (t = 7.1, P < 0.0001). The average ONIG for experimental and control eye groups, respectively, was 3.4 +/- 1.7 and 1.0 +/- 0.02 (t = 6.3, P < 0.0001). The ONIG increased with mean IOP in experimental eyes (r(2) = 0.78, P < 0.0001) and was unrelated to mean IOP in control eyes (r(2) = 0.09, P = 0.18). In experimental eyes with relatively mild IOP elevation (mean IOP < 31 mm Hg) and no structural (histologic) damage to the optic nerve evident by light microscopy (ONIG = 1.1 +/- 0.2, n = 5), there was a selective reduction of the positive scotopic threshold response (pSTR; P < 0.001), whereas other ERG components remained unaltered. In four of the five eyes, pSTR amplitude was reduced by more than 50%, whereas all five had normal scotopic a-wave, b-wave, and OP amplitudes. Eyes with mean IOP of more than 35 mm Hg had reduced a-wave, b-wave, and oscillatory potential (OP) amplitudes. CONCLUSIONS: As demonstrated by prior studies, selective loss of the pSTR is indicative of selective retinal ganglion cell (RGC) injury. In this rat model of experimental glaucoma, selective RGC functional injury occurred before the onset of structural damage, as assessed by light microscopy of optic nerve tissue. The highest IOP levels resulted in nonselective functional loss. Thus, in rodent models of experimental glaucoma, lower levels of chronically elevated IOP may be more relevant to human primary chronic glaucoma.