Taxon-selective venom variation in adult and neonate Daboia russelii (Russell's Viper), and antivenom efficacy.

Major variations in venom composition can occur between juvenile and adult venomous snakes. However, due to logistical constraints, antivenoms are produced using adult venoms in immunising mixtures, possibly resulting in limited neutralisation of juvenile snake venoms. Daboia russelii is one of the leading causes of snakebite death across South Asia. Its venom is potently procoagulant, causing stroke in prey animals but causing in humans consumptive coagulopathy-a net anticoagulant state-and sometimes death resulting from hemorrhage. In this in vitro study, we compared the venom activity of-and antivenom efficacy against-six 2-week-old D. russelii relative to that of their parents. Using a coagulation analyser, we quantified the relative coagulotoxicity of these venoms in human, avian, and amphibian plasma. The overall potency on human plasma was similar across all adult and neonate venoms, and SII (Serum Institute of India) antivenom was equipotent in neutralising these coagulotoxic effects. In addition, all venoms were also similar in their action upon avian plasma. In contrast, the neonate venoms were more potent on amphibian plasma, suggesting amphibians make up a larger proportion of neonate diet than adult diet. A similar venom potency in human and avian plasmas but varying selectivity for amphibian plasma suggests ontogenetic differences in toxin isoforms within the factor X or factor V activating classes, thereby providing a testable hypothesis for future transcriptomics work. By providing insights into the functional venom differences between adult and neonate D. russelii venoms, we hope to inform clinical treatment of patients envenomated by this deadly species and to shed new light on the natural history of these extremely medically important snakes.

Midterm response with latanoprost therapy in german ocular hypertension patients.

PURPOSE: The purpose of this prospective observational trial was to report the analysis of the midterm efficacy, safety, and discontinuation rates of a cohort of ocular hypertensive patients treated with latanoprost in Germany. METHODS: A subanalysis of patients with ocular hypertension who were previously treated on latanoprost monotherapy and continued within the study on this same medication for at least 6 months. RESULTS: 353 patients with ocular hypertension were included and treated with latanoprost monotherapy historically (1.4 +/- 1.3 years) and within the observational period of the study for a mean of 2.2 +/- 1.1 years. On latanoprost only, the average intraocular pressure at study entry was 18.4 +/- 2.7 mm Hg, and at 6 months the intraocular pressure was 18.3 +/- 2.3 mmHg (p = 0.54). During the observational period, the most common ocular side effect was conjunctival hyperemia (20.7%), and the most common systemic side effect was fatigue (3.1%). Nineteen patients (5.4%) discontinued latanoprost with the most common reason being insufficient efficacy (3.1%). Physician assessments of latanoprost monotherapy were "very good" to "excellent" for patient efficacy (75.2%), tolerability (83.8%), and patient satisfaction (82.1%). CONCLUSIONS: The study suggests that patients with ocular hypertension already treated with latanoprost monotherapy will continue to have, on average, at least midterm stable pressures, low incidence of side effects and discontinuations, as well as "very good" to "excellent" physician ratings of efficacy, tolerability, and patient satisfaction.

Watching the Photo-Oxidation of a Single Aromatic Hydrocarbon Molecule.

The photooxidation of single dye molecules can be followed by confocal fluorescence microscopy. The self-sensitized reaction with singlet oxygen leads to a suite of products, which may be differentiated spectrally. Tentative structures for certain photoproducts have been obtained from quantum-chemical calculations.

Identity of adenylyl cyclase isoform determines the G protein mediating chronic opioid-induced adenylyl cyclase supersensitivity.

To determine the intracellular signal transduction pathway responsible for the development of tolerance/dependence, the ability of Gzalpha to substitute for pertussis toxin (PTX)-sensitive G proteins in mediating adenylyl cyclase (AC) supersensitivity was examined in the presence of defined AC isoforms. In transiently micro-opioid receptor (OR) transfected COS-7 cells (endogenous inhibitory G proteins: Gialpha2, Gialpha3 and Gzalpha), neither acute (1 micro mol/L) nor chronic morphine treatment (1 micromol/L; 18 h) influenced intracellular cAMP production. Coexpression of the micro -OR together with AC type V and VI fully restored the ability of morphine to acutely inhibit cAMP generation. Chronic morphine treatment further resulted in the development of tolerance/dependence, as assessed by desensitization of the acute inhibitory opioid effect (tolerance) as well as the induction of AC supersensitivity after drug withdrawal (dependence). Specific direction of micro -OR signalling via Gzalpha by both PTX treatment and Gzalpha over-expression had no effect on chronic morphine regulation of AC type V, but completely abolished the development of tolerance/dependence with AC type VI. Similar results were obtained in stably micro -OR-expressing HEK293 cells transiently cotransfected with Gzalpha and either AC type V or VI. Coprecipitation studies further verified that Gzalpha specifically binds to AC type V but not type VI. Taken together, these results demonstrate that in principle each of the OR-activated G proteins per se is able to mediate AC supersensitivity. However, they also indicate that it is the molecular nature of AC isoform that selects and determines the OR-activated G protein mediating tolerance/dependence.

Coherent electronic coupling versus localization in individual molecular dimers.

We have investigated electronic excitation transfer in individual molecular dimers by time and spectrally resolved confocal fluorescence microscopy. The single molecule measurements allow for directly probing the distribution of the electronic coupling strengths due to static disorder in the polymer host. We find dimers where the excitation is delocalized (superradiant emission) while for others emission originates from a localized state. Transitions between delocalized and localized states as observed for a given dimer are attributed to structural fluctuations of the guest-host system.