The etiology, pathophysiology, and natural history of Menière's syndrome are poorly understood. The reported studies have had inadequate followup or insufficient numbers of patients to allow conclusions about the natural history. Our study group was 119 patients who had the classic symptom complex of episodic vertigo, tinnitus, and hearing loss in the year 1970. After initial review of these charts, follow-up information was obtained by questionnaire, telephone interview, chart review, or repeat examination, when possible, both in 1983 and in 1988, for a total followup of 18 years. In the patients with followups of at least 14 years, vertiginous episodes had disappeared completely in 50% of patients and somewhat resolved in 28%; hearing was absent in 48% and worse in 21%. Surprisingly, 43% of patients underwent surgery at some point for control of vertigo. Bilateral disease was present initially in 13% and developed subsequently in 45% of patients. Other areas reviewed included the efficacy of long-term medical treatment, frequency and severity of vertiginous attacks, and contralateral ear symptoms.

Latrotoxins (LaTXs) are presynaptic pore-forming neurotoxins found in the venom of Latrodectus spiders. The venom contains a toxic cocktail of seven LaTXs, with one of them targeting vertebrates (α-latrotoxin (α-LTX)), five specialized on insects (α, β, γ, δ, ε- latroinsectotoxins (LITs), and one on crustaceans (α-latrocrustatoxin (α-LCT)). LaTXs bind to specific receptors on the surface of neuronal cells, inducing the release of neurotransmitters either by directly stimulating exocytosis or by forming Ca2+-conductive tetrameric pores in the membrane. Despite extensive studies in the past decades, a high-resolution structure of a LaTX is not yet available and the precise mechanism of LaTX action remains unclear. Here, we report cryoEM structures of the α-LCT monomer and the δ-LIT dimer. The structures reveal that LaTXs are organized in four domains. A C-terminal domain of ankyrin-like repeats shields a central membrane insertion domain of six parallel α-helices. Both domains are flexibly linked via an N-terminal α-helical domain and a small β-sheet domain. A comparison between the structures suggests that oligomerization involves major conformational changes in LaTXs with longer C-terminal domains. Based on our data we propose a cyclic mechanism of oligomerization, taking place prior membrane insertion. Both recombinant α-LCT and δ-LIT form channels in artificial membrane bilayers, that are stabilized by Ca2+ ions and allow calcium flux at negative membrane potentials. Our comparative analysis between α-LCT and δ-LIT provides first crucial insights towards understanding the molecular mechanism of the LaTX family.

BackgroundInsulin resistance in diabetes mellitus has been associated with mitochondrial dysfunction. Defects at the level of mitochondria are also characteristic of heart failure. We assessed changes in cardiac insulin response and mitochondrial function in a model of pressure overload‐induced heart failure.Methods and ResultsRats underwent aortic banding to induce pressure overload. At 10 weeks, rats showed cardiac hypertrophy and pulmonary congestion, but left ventricular dilatation and systolic dysfunction were only evident after 20 weeks. This contractile impairment was accompanied by mitochondrial dysfunction as shown by markedly reduced state 3 respiration of isolated mitochondria. Aortic banding did not affect systemic insulin response. However, insulin‐stimulated cardiac glucose uptake and glucose oxidation were significantly diminished at 10 and 20 weeks, which indicates cardiac insulin resistance starting before the onset of mitochondrial and contractile dysfunction. The impaired cardiac insulin action was related to a decrease in insulin‐stimulated phosphorylation of insulin receptor β. Consistently, we found elevated activity of protein tyrosine phosphatase 1B (PTP1B) at 10 and 20 weeks, which may blunt insulin action by dephosphorylating insulin receptor β. PTP1B activity was also significantly increased in left ventricular samples of patients with systolic dysfunction undergoing aortic valve replacement because of aortic stenosis.ConclusionsPressure overload causes cardiac insulin resistance that precedes and accompanies mitochondrial and systolic dysfunction. Activation of PTP1B in the heart is associated with heart failure in both rats and humans and may account for cardiac insulin resistance. PTP1B may be a potential target to modulate insulin sensitivity and contractile function in the failing heart.