Machine learning algorithms predict experimental output of chaotic lasers.

We apply an artificial neural network (ANN) of 20 hidden layers and backpropagation regression to the forecast of experimental time series from a Kerr lens mode locking (KLM) Ti:sapphire laser and a Nd:vanadate with modulation losses. In both cases the neural network is able to predict up to 10 steps ahead. In the Ti:sapphire laser the prediction in pulse amplitude is accurate even when the pulse is an extreme event. In the Nd:vanadate laser we forecast both pulse amplitude and pulse-to-pulse time separation. In both cases the prediction goes beyond the Lyapunov prediction horizon.

Hidden instabilities in the Ti:sapphire Kerr lens mode-locked laser.

It is experimentally shown that pulse-to-pulse instabilities in the output of Kerr lens mode-locked Ti:sapphire lasers are usual and that they can affect some of the pulse variables (e.g., the spot size) and not others (e.g., pulse duration and energy). These instabilities are not detectable in the averaged signals (such as the autocorrelation of the pulse) that are customarily used for controlling the laser. But, if they are present but are disregarded, these instabilities have undesirable consequences in almost any application. A simple way to detect and eliminate the instabilities is described.

A randomized phase II study of BB-10010: a variant of human macrophage inflammatory protein-1alpha for patients receiving high-dose etoposide and cyclophosphamide for malignant lymphoma and breast cancer.

Macrophage inflammatory protein-1alpha (MIP-1alpha) is a chemokine that can inhibit the cell cycle progression of both primitive haemopoietic and epidermal progenitor cells. This property could potentially be exploited to attenuate both the myelosuppressive effects of chemotherapy as well as mucositis. We evaluated both the biological and clinical effects of BB-10010, a genetically engineered variant of MIP-1alpha, in patients with malignant lymphoma or breast cancer receiving high-dose etoposide (VP 3.6 g/m2) and cyclophosphamide (Cy 200 mg/kg). 52 patients were randomized to one of three cohorts. Cohort A received no BB-10010; cohorts B and C received 10 microg/kg and 100 microg/kg of BB-10010, respectively. All patients received post-chemotherapy G-CSE BB-10010 was well tolerated. There were no significant differences between groups in recovery to an ANC > 0.5 x 10(9)/l, 1 x 10(9)/l or 1.5 x 10(9)/l, the number of days with an ANC < 0.5 x 10(9)/l, days to a platelet count > 50 x 10(9)/l or 100 x 10(9)/l, or the incidence and severity of mucositis. There was no evidence of any effect of BB-10010 on colony-forming cell (CFC) or long-term culture-initiating cell (LTC-IC) mobilization, cycling activity in the marrow or on chemotherapy-induced changes in CFC or LTC-IC number both of which were in the normal range by 22 d after completion of the chemotherapy. To our knowledge this is the first report of a myelointensive regimen having no apparent long-term effect on the LTC-IC compartment. In summary, BB-10010 is safe when used in patients receiving high-dose therapy but has no effect on reducing the toxicity of such therapy.

Hypotensive effect of an M2-selective muscarinic antagonist in anaesthetized guinea-pigs.

1. In order to determine an involvement of muscarinic M2 receptors in the regulation of systemic arterial blood pressure, we investigated the cardiovascular effects of the M2-selective antagonist methoctramine and other agents in anaesthetized guinea-pigs. 2. Intravenous injection of methoctramine, atropine, pirenzepine (an M1-selective muscarinic antagonist) or 4-DAMP (an M3-selective muscarinic antagonist) each significantly increased heart rate in comparison to vehicle controls. 3. Methoctramine produced significant, dose-dependent decreases in mean arterial blood pressure, with an ED50 of 0.1 mg kg-1. Atropine decreased blood pressure only at high doses. Pirenzepine and 4-DAMP did not alter blood pressure, indicating that M1 or M3 receptor antagonism was not responsible for the cardiovascular effects of methoctramine. 4. The hypotensive effect of methoctramine was unaltered by indomethacin pretreatment, ruling out an alteration in arachidonic acid metabolism as the mechanism of action. 5. In contrast to methoctramine, mecamylamine (a nicotinic ganglionic receptor antagonist) greatly decreased heart rate and slightly decreased blood pressure, suggesting that ganglionic blockade was not the mechanism for the cardiovascular effects of methoctramine. 6. Methoctramine (0.3 mg kg-1) pretreatment did not alter the hypertensive effect of intravenous noradrenaline, demonstrating that methoctramine did not directly inhibit vascular reactivity and indicating an indirect hypotensive of action of methoctramine. 7. In summary, the results suggest that the hypotensive action of methoctramine resulted from selective M2 receptor antagonism. Therefore, muscarinic M2 receptors appear to play a role in the regulation of systemic arterial blood pressure in guinea-pigs. However, the anatomical site(s) of action of methoctramine remains to be determined.

Methoctramine induces nonspecific airway hyperresponsiveness in vivo.

We investigated the effects of subtype-selective muscarinic receptor antagonists upon aerosol antigen-induced bronchoconstriction in anesthetized guinea pigs. Neither pirenzepine (muscarinic M1 receptor-selective), 4-methylpiperidine methiodide (4-DAMP, muscarinic M3 receptor-selective), [N-iminomethyl-N'-[(2-hydroxy-2-phenyl-2-cyclohexyl)-ethyl] piperazine HCl (DAC-5945, muscarinic M3 receptor-selective), ipratropium or atropine inhibited bronchoconstriction, but methoctramine (muscarinic M2 receptor-selective) produced a dose-dependent increase in bronchoconstriction (up to 46%). Methoctramine also produced increases in bronchoconstriction induced by aerosols of histamine (up to 45%) and platelet activating factor (up to 118%), demonstrating nonspecific airway hyperresponsiveness. This effect of methoctramine was not inhibited by atropine, DAC-5945 or vagotomy and could not be attributed to altered arachidonic acid metabolism or beta-adrenergic antagonism. However, propranolol prevented methoctramine-induced airway hyperresponsiveness, suggesting that this effect resulted from the reported ganglionic blocking activity of methoctramine. In conclusion, muscarinic receptors do not appear to play an important role in antigen-induced bronchoconstriction in anesthetized guinea pigs. Furthermore, caution should be exercised in using methoctramine to characterize the roles of muscarinic receptors in airway inflammatory responses in vivo.

Pulmonary pharmacology of a novel, smooth muscle-selective muscarinic antagonist in vivo.

The need for a smooth muscle-selective muscarinic antagonist that could provide oral bronchodilator activity with minimal side effects has led to the discovery of 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (NPC-14695). Orally administered NPC-14695 was as potent as albuterol in the prevention of aerosolized carbachol-induced collapse in conscious guinea pigs. After s.c. administration in conscious guinea pigs challenged with aerosolized carbachol, NPC-14695 was more potent in the inhibition of collapse than in the inhibition of salivation or the production of mydriasis. Moreover, NPC-14695 exhibited a greater selectivity for the inhibition of collapse over salivary or pupillary effects than either ipratropium or oxybutynin. NPC-14695 was more M3/M2 selective than diphenyl-acetoxy-4-methylpiperidine methiodide (4-DAMP) in vivo, which was determined from the reversal of bronchoconstriction and bradycardia after i.v. administration in anesthetized guinea pigs infused with methacholine, but was less potent than ipratropium or 4-DAMP. At increasing equieffective bronchodilator doses of aerosolized ipratropium and intraduodenally administered NPC-14695 in anesthetized guinea pigs infused with methacholine, ipratropium reversed the bradycardia and then produced tachycardia whereas NPC-14695 did not alter the heart rate. At doses that produced 50% of the maximum bronchodilation, neither aerosolized ipratropium or intraduodenally administered NPC-14695 affected the pupillary diameter or salivation. At doses that produced a maximum bronchodilation, the two drugs produced an equivalent inhibition of salivation and NPC-14695 produced mydriasis. NPC-14695 did not inhibit the bronchoconstriction induced by three other agonists.(ABSTRACT TRUNCATED AT 250 WORDS)