Therapeutic limitations of argon laser trabeculoplasty.

Sixty-one patients (82 eyes) were studied after argon laser trabeculoplasty (ALT) to determine the lasting efficacy of such treatment. This investigation, now in its fourth year, was prospective, and the information derived was analysed with the aid of a computer. Success was defined as intraocular pressure (IOP) below baseline (22 mmHg). The mean follow-up time was 24.5 months, when the success rate was 74% compared with 75% at three months. Success declined to 45% at 42 months. No significant difference was noted when (a) first lasered eyes of all patients and those fellow eyes treated were analysed separately, (b) when right and left eyes were analysed separately, nor (c) when patients were divided into two treatment groups, (I) 100 burns at 1 W, and (II) 65 burns at 850 mW. Eight of 11 eyes showed progressive postlaser field loss despite below-baseline intraocular pressures. ALT is an alternative to carbonic anhydrase inhibitor therapy, with a success rate of 66.7% at two years. However, repeat ALT was successful in only 25% of patients seven months after treatment.     

In vivo gene therapy for pyridoxine-induced neuropathy by herpes simplex virus-mediated gene transfer of neurotrophin-3.

Neurotrophic factors have been demonstrated to prevent the development of peripheral neuropathy in animal models, but the therapeutic use of these factors in human disease has been limited by the short serum half-life and dose-limiting side effects of these potent peptides. We used peripheral subcutaneous inoculation with a replication-incompetent, genomic herpes simplex virus-based vector containing the coding sequence for neurotrophin-3 to transduce sensory neurons of the rat dorsal root ganglion in vivo, and found that expression of neurotrophin-3 from the vector protected peripheral sensory axons from neuropathy induced by intoxication with pyridoxine assessed by electrophysiological (foot sensory response amplitude, and conduction velocity, and H-wave), histological (nerve morphology and morphometry), and behavioral measures of proprioceptive function. In vivo gene transfer using herpes simplex virus vectors provides a unique option for treatment of diseases of the sensory peripheral nervous system.     

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Inhibition of N-methyl-d-aspartate (NMDA) and l-glutamate-induced noradrenaline and acetylcholine release in the rat brain by ethanol

Summary The influence of ethanol on stimulation-evoked ³H-transmitter release was examined in slices of the rat brain cortex and corpus striatum preincubated with ³H-noradrenaline and ³H-choline, respectively. ³H-Transmitter release was stimulated by NMDA, l-glutamate, electrical impulses, reintroduction of Ca²⁺ ions (Ca²⁺-evoked release; after superfusion with Ca²⁺-free, K⁺-rich solution) or veratridine. In cortical slices preincubated with ³H-noradrenaline and superfused with Mg²⁺-free, otherwise physiologically composed salt solution, ethanol inhibited the NMDA- or l-glutamate-induced tritium overflow (IC₅₀ 45 and 37 mmol/l, respectively). In contrast, the tritium overflow in response to electrical stimulation, reintroduction of Ca²⁺ ions or veratridine was not affected by ethanol at concentrations up to 320 mmol/l; these experiments were carried out in cortical slices superfused with solution containing a physiological Mg²⁺ concentration. Ethanol also failed to inhibit Ca²⁺-evoked release in the absence of Mg2⁺ ions. In the presence of 1 mol/l veratridine, but not in its absence, NMDA induced tritium overflow even when cortical slices were superfused with salt solution containing a physiological Mg²⁺ concentration; again, ethanol inhibited this NMDA-evoked tritium overflow (IC₅₀ 73 mmol/l). In striatal slices preincubated with ³H-choline and superfused with Mg²⁺-free physiological salt solution, the NMDA-evoked tritium overflow was also, although at lower potency, inhibited by ethanol (IC₅₀ 192 mmol/l).In spite of the differences between the IC₅₀ values of ethanol determined for the inhibition of cortical noradrenaline and striatal acetylcholine release, it may be concluded that the NMDA receptor-ion channel complex is one of the sites of action underlying the ethanol-induced inhibition of neurotransmitter release. Since in the brain cortex the NMDA-induced ³H-noradrenaline release appears to be mediated by an excitatory interneurone activated by NMDA, this neuronal system may be involved in the cortical actions of ethanol.     

Second harmonic imaging of intrinsic signals in muscle fibers in situ

We use second harmonic generation (SHG) imaging to study and quantify a strong intrinsic SHG signal in skeletal muscle fiber preparations and single isolated myofibrils. The intrinsic signal follows the striation pattern of the muscle cells and is positioned at the sarcomeric location of the myosin filaments. Interestingly, the signal is enhanced at the region where the myosin heads are located on the myosin filaments. As the intrinsic signal reflects the subcellular structure in an accurate way, SHG can be used for noninvasive high resolution structural imaging without exogenous labels in living muscle cells. This may be very important for detecting changes in myofibrillar organization occurring under pathophysiological conditions, e.g., in cardiac and skeletal myopathies. Due to the strong dependency of SHG on orientation and symmetries of the tissue, it may allow the study of dynamic interactions between the contractile proteins actin and myosin during force production and muscle shortening. Furthermore, SHG imaging can be combined with other nonlinear microscopical techniques, such as laser scanning multiphoton fluorescence microscopy, to simultaneously measure other dynamic cellular processes, representing a complementary method and extending the range of nonlinear microscopical methods.     

Follow-up on mental illness in medical inpatients: health care use and self-rated health and physical fitness

Consecutively admitted internal medical inpatients (N=294) who were psychiatrically assessed with the Schedules for Clinical Assessment in Neuropsychiatry in a two-phase design were followed up in a review of public files on their use of medical care over 18 months. Self-rated outcome was assessed from health and fitness ratings at admission and after 1 year. ICD-10 mental disorders had a statistically significant impact on the risk (odds ratio) of high use (above the 80th percentile) of primary care, as did ICD-10 anxiety/depression, and worry about illness (as assessed by the Whiteley-7 Scale). The authors found a less-than-significant tendency for mental illness to influence the use of inpatient admissions and self-rated outcome.