Wavefront-guided treatment of abnormal eyes using the LADARVision platform

PURPOSE: To evaluate the clinical results of Alcon LADARVision4000 wavefront-guided customized treatment of eyes with myopia and/or astigmatism, and clinically significant visual symptoms related to the presence of higher order aberrations. METHODS: Seven consecutive abnormal eyes from seven patients underwent wavefront-guided CustomCornea (1 PRK, 6 enhancements after previous LASIK) to correct low and higher order aberrations, using the Alcon LADARVision4000 platform. Eyes were examined at 1 to 3 months after treatment; the longest follow-up examination was used for analysis. Uncorrected and best spectacle-corrected visual acuity, manifest refractive spherical equivalent error, and subjective visual symptoms were measured, as well as wavefront measurement of higher order aberrations. RESULTS: All seven eyes had an improvement in UCVA. One eye gained 2 lines of BSCVA, four eyes gained 1 line, and no eye lost any lines. Manifest refractive spherical equivalent error was slightly hyperopic in all eyes (+0.12 to +1.50 D). All eyes showed a reduction in pre-existing higher order aberrations, ranging between 1% and 48%. Spherical aberration was reduced most (mean 38% reduction), coma was reduced by a mean 14%, and all other terms were reduced by a mean 17% compared to preoperative values. Subjectively, all patients noticed a reduction in their pre-existing visual symptoms and reported visual performance comparable to their fellow asymptomatic eye. Overall, the treatment was considered very satisfactory by patients in terms of visual quality gain. CONCLUSION: Wavefront-guided custom ablation with Alcon's LADARVision4000 was effective in reducing higher order aberrations and related visual symptoms in this preliminary small series. Longer follow-up on more eyes is necessary to assess the accuracy of the algorithm in the correction of defocus, which resulted in a slight overcorrection in this study.     

Optimal requirements for high affinity and use-dependent block of skeletal muscle sodium channel by N-benzyl analogs of tocainide-like compounds

Newly synthesized tocainide analogs were tested for their state-dependent affinity and use-dependent behavior on sodium currents (INa) of adult skeletal muscle fibers by means of the Vaseline-gap voltage clamp method. The drugs had the pharmacophore amino group constrained in position alpha [N-(2,6-dimethylphenyl)pyrrolidine-2-carboxamide (To5)] or beta [N-(2,6-dimethylphenyl)pyrrolidine-3-carboxamide (To9)] in a proline-like cycle and/or linked to a lipophilic benzyl moiety as in N-benzyl-tocainide (Benzyl-Toc), 1-benzyl-To5 (Benzyl-To5), and 1-benzyl-To9 (Benzyl-To9). INa were elicited with pulses to -20 mV from different holding potentials (-140, -100, and -70 mV) and stimulation frequencies (2 and 10 Hz). All compounds were voltage-dependent and use-dependent channel blockers. The presence of a proline-like cycle increased the potency; i.e., To5 was 3- and 10-fold more effective than Toc in blocking INa at the holding potential of -140 and -70 mV, respectively. The benzyl group on the amine further enhanced drug effectiveness with the following scale: Benzyl-To9 >/= Benzyl-Toc > Benzyl-To5. At a holding potential of -100 mV and 10-Hz stimulation, Benzyl-To9 blocked INa with a half-maximal concentration of 0.5 microM, being 60 and 400 times more potent than To9 and Toc, respectively. The similar effectiveness of Benzyl-Toc and Benzyl-To9 was paralleled by a similar spatial arrangement by equilibrium geometry modeling. In addition, the latter had a higher pKa value that probably contributed to a slow kinetic during its high use-dependent behavior. Benzyl-To5 had its lowest energy level at a more folded conformation that justifies the less favorable profile among the N-benzylated analogs. The new compounds are the most potent tocainide-like sodium channel blockers so far described and have high therapeutic potentials.     

Different ability of clenbuterol and salbutamol to block sodium channels predicts their therapeutic use in muscle excitability disorders

Activation of muscle beta(2)-adrenergic receptors successfully counteracted sarcolemma inexcitability in patients suffering from hyperkalemic periodic paralysis (HPP), a hereditary disease caused by mutations in the gene encoding the skeletal muscle sodium channel. Looking for potential modulation of these channels by beta(2)-adrenergic pathway using patch-clamp technique, we found that clenbuterol blocked sodium currents (I(Na)) in rat skeletal muscle fibers and in tsA201 cells transfected with the human channel isoform, whereas salbutamol did not. The effects of clenbuterol were independent of beta-adrenoceptor stimulation. Instead, clenbuterol structure and physicochemical characteristics as well as I(Na) blocking properties resembled those of local anesthetics, suggesting direct binding to the channels. Similar experiments with the chemically similar beta-antagonists propranolol and nadolol, suggested the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. Importantly, clenbuterol use-dependently inhibited action potential firing in rat skeletal muscle fibers, owing to beta-adrenoceptor-independent I(Na) block. From a clinical point of view, our study defines the rationale for the safe use of salbutamol in HPP patients, whereas clenbuterol may be more indicated in patients suffering from myotonic syndromes, a condition characterized by sarcolemmal overexcitability, because use-dependent I(Na) block can inhibit abnormal runs of action potentials.     

Effect of the gadolinium ion on body fluid regulation

Both osmoreception and baroreception are thought to involve ion channels that are sensitive to changes in membrane stretch. We investigated the effect of a blocker of stretch-activated ion channels, the Gd3+ ion, on osmoregulatory and cardiovascular responses in the intact rat. Intracerebroventricular injection of 50-100 nmol Gd3+ reduced thirst induced by various treatments. Similar doses also reduced intake of saline induced by various treatments. Intracerebroventricular injection of 100 nmol Gd3+ transiently increased arterial pressure and reduced the pressor response to intracerebroventricular angiotensin II (Ang II). Systemic administration of Gd3+ failed to alter thirst, except for a high dose (270 micromol/kg) that induced illness. This high dose failed to prevent urinary hypertonicity and excretion of a load of hypertonic NaCl. Intravenous infusion of 270 micromol/kg of Gd3+ reduced blood pressure and pressure responses to intravenous phenylephrine, but did not reduce the baroreceptor reflex control of heart rate. We conclude that the effects of Gd3+ on thirst and on the cardiovascular system are probably not due to a direct effect of the drug on stretch-sensitive ion channels. Instead, many of the effects of Gd3+ were compatible with blockade of voltage-gated Ca2+ channels.     

Occupational asthma (OA) with sensitization to diphenylmethane diisocyanate (MDI) presenting at the onset like a reactive airways dysfunction syndrome (RADS)

BACKGROUND: Two types of OA are distinguished: immunological (OA with sensitization) and non-immunological, i.e., irritant induced asthma or reactive airways dysfunction syndrome (RADS). METHODS: We describe the case of a worker who developed respiratory symptoms after a spill of diphenylmethane diisocyanate (MDI) at the workplace. RADS was initially diagnosed and the worker resumed working. The progressive worsening of symptoms and the appearance of symptoms-work relationship one year later, when concentrations of isocyanates were no longer "irritant," suggested immunological OA. RESULTS: The diagnosis was confirmed by specific inhalation challenge test, followed by removal from exposure and complete recovery. CONCLUSIONS: In the case of RADS due to an agent with both irritant and sensitizing properties, history should be repeatedly assessed for a possible symptom-work relationship. If this is found, further investigations should be carried out, including specific inhalation challenges, to confirm the possibility of immunological OA.     

Sertoli cell-induced adult rat islet beta-cell mitogenesis: causative pathways

We have previously observed that in vitro co-incubation of rat pre-pubertal Sertoli cells (SC), or their dialyzed/concentrated secretory products with homologous islets, resulted in significant stimulation of the islet beta-cell mitotic index. Aim of the present work was to assess both the specificity and nature of the mechanisms underlying this phenomenon. For this purpose, first we tested astrocytes (AA), separated and purified from the rat brain cortex, where they are known to release a number of growth factors and neurotrophic cytokines, for co-incubation with the islets. However, under the same experimental conditions used for SC, AA did not induce any changes in the beta-cell life cycle, thereby confirming specificity of SC, with respect to induction of beta-cell mitogenicity. For the second purpose, we examined the products of PD-1, a gene located in the cytoplasm of SC, where it promotes spermatogenesis. By blocking the protein encoded by PD-1, under appropriate culture conditions, we observed that the SC-induced increase in beta-cell mitotic activity lost its statistical significance, which suggested a role of PD-1 with respect to SC-related mitogenic properties on beta-cells. These findings corroborate the idea that SC, by either direct contact, or by means of their secretory products, clearly affect the islet beta-cell mitotic rate. Preliminarily, PD-1 gene, located in the cytoplasm of SC, might be one of the factors involved with the induction of beta-cell mitotic activity. In conclusion, SC-induced beta-cell mitotic activity is specific, seemingly mediated by humoral factors whose acting mechanisms have started being unfolded.     

Portal vein thrombosis following splenectomy: identification of risk factors

Portal vein thrombosis (PVT) following splenectomy is a potentially life-threatening complication, and the true incidence of PVT in splenectomized patients is unknown. The objective of this study was to determine the incidence of symptomatic PVT after splenectomy. The hospital database was searched to identify cases of PVT associated with splenectomy from January 1990 to May 2002. Six hundred eighty-eight patients underwent splenectomy during this period, 321 of them for hematologic diseases. Eleven of the 688 patients had PVT associated with splenectomy, and the charts of these patients were reviewed. Six patients developed PVT after splenectomy. Five had hematologic diseases. Symptoms were abdominal pain (6), ileus (5), fever (3), or diarrhea (2). Diagnosis was confirmed by computed tomography (CT) (4), duplex ultrasonography (1), and magnetic resonance imaging (1). The indications for splenectomy included hemolytic anemia (3), thalassemia (1), and myelofibrosis (1). One patient had an incidental splenectomy during gastrectomy. There were four laparoscopic and two open splenectomies. The median interval between splenectomy and diagnosis of PVT was 40 days (range, 13-741). One patient died of pulmonary embolism. Five of six patients with postsplenectomy PVT had splenomegaly and hemolysis. We conclude that the risk of PVT is higher in patients with hematologic conditions associated with splenomegaly and hemolysis.     

Postinfarction ventricular septal defect in a patient without coronary lesions

A 46-year-old man with polycystic kidney disease was referred to our institution for ventricular septal defect complicating myocardial infarction. Cardiac catheterization disclosed normal coronary arteries and absence of myocardial bridging. None of the more frequent causes of thrombosis were present, and histopathology proved negative for acute myocarditis. The surgical procedure was successful and the 11-month follow-up uneventful.