Parkinson's and motoneuron disease morbidity in the Twin Cities metropolitan area: 1979-1984

To better characterize the morbidity from Parkinson's disease and motoneuron disease, we examined hospital discharge diagnosis data for all acute care facilities (except for the Veterans Administration Medical Center) in the Minneapolis-St. Paul area in each year from 1979 to 1984 for persons aged 30-74 years. For each person in whom the discharge diagnosis included either Parkinson's disease or motoneuron disease, the age, gender, and year of admission were recorded. Annual age-gender-specific and age-adjusted gender-specific hospital discharge diagnosis rates were calculated. For Parkinson's disease, for both, men and women, the age-adjusted hospital discharge diagnosis rate declined by 26-27%. Component age-specific data for Parkinson's disease showed more variable temporal changes. For motoneuron disease, no temporal changes were observed, although the number of observations was small. These data suggest that Parkinson's disease is declining in prevalence in the hospitalized population. The implications for motoneuron disease are less clear. Further studies in this area are needed.     

AUR Memorial Award 1991. Immunogenicity of gadolinium-based contrast agents for magnetic resonance imaging. Induction and characterization of antibodies in animals.

To evaluate the immunogenic potential of gadolinium-based magnetic resonance imaging (MRI) contrast agents, Sprague-Dawley rats were sensitized with gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) dimeglumine and with Gd-DTPA covalently linked to either human serum albumin, dextran, or polylysine. IgG antibodies directed against Gd-DTPA were detected in immune sera by an enzyme-linked immunosorbent assay (ELISA), and were confirmed by competitive inhibition of antibody binding using free Gd-DTPA dimeglumine. Antiserum induced by immunization with human serum albumin-(Gd-DTPA) was characterized by a monophasic competition curve with 50% inhibition (IC50) = 5.5 x 10(-4) M when Gd-DTPA dimeglumine was used as both the well-coating and the displacing agent in a competition ELISA. Antiserum induced by Gd-DTPA dimeglumine alone was characterized by a biphasic competition curve with IC50 = 6.5 x 10(-7) M and 7.9 x 10(-4) M. Antisera obtained after exposure to either dextran-(Gd-DTPA) or polylysine-(Gd-DTPA) were of insufficient titer for characterization. The detection of antibodies specific for Gd-DTPA suggests in vivo protein binding with formation of hapten-carrier conjugates. This hypothesis is supported by increased relaxivity values observed when Gd-DTPA dimeglumine is incubated in serum rather than in water. Gd-DTPA dimeglumine and albumin-(Gd-DTPA) are immunogenic in rats under idealized experimental conditions. Additional studies will be necessary to determine the potential for immunologic response in humans to gadolinium chelates under conditions of exposure inherent in clinical use.     

Veterans Helping Veterans: a NSW Example

World War II veterans are now in their seventies and eighties. Health problems that were experienced during the years of conflict have a lasting effect on this unique section of the community. Through VWAWC, a nucleus of veterans and the widows of veterans on the Central Coast of New South Wales have developed successful strategies of support for the wider veteran community, to help them accomplish healthier, happier ageing.     

Cell death by apoptosis in acute leukaemia

We have previously demonstrated that when freshly isolated childhood T-cell acute lymphoblastic leukaemia cells are incubated in growth medium after isolation from blood, chromatin is rapidly cleaved into nucleosomal sized fragments that are multiples of 200 bp. The fragmentation is similar to that observed in other types of cells undergoing apoptosis or programmed cell death. In this study we describe a more comprehensive approach to the study of DNA fragmentation in leukaemia. Fragmentation was observed in freshly isolated cells from patients with T-cell acute lymphoblastic leukaemia and in one with common acute lymphoblastic leukaemia. Frozen samples of T-cell acute lymphoblastic leukaemia, common acute lymphoblastic leukaemia, and acute myeloid leukaemia cells also showed fragmentation of DNA. However, no fragmentation was evident in normal leukocytes treated under the same conditions. Ultrastructural studies on the isolated leukaemia cells demonstrate that the chromatin cleavage observed biochemically is associated with morphological changes characteristic of apoptosis.     

Modulatory effects of serotonin, FMRFamide, and myomodulin on the duration of action potentials, excitability, and membrane currents in tail sensory neurons of Aplysia.

1. The electrophysiological properties of sensory neurons that mediate withdrawal reflexes of Aplysia can be modulated by a variety of neurotransmitters. We compared the known excitatory actions of serotonin (5-HT) with the actions of FMRFamide (Phe-Met-Arg-Phe-NH2) and myomodulin (Pro-Met-Ser-Met-Leu-Arg-Leu-NH2) on the durations of action potentials and excitability. In addition, with the use of voltage-clamp and pharmacological separation techniques, we characterized the membrane currents that were modulated by each of the three agents. 2. Application of 5-HT produced an increase in the duration of action potentials and an enhancement of excitability in somata of the tail sensory neurons. FMRFamide and myomodulin reversed these excitatory effects and decreased the duration of action potentials and excitability. These results indicated that FMRFamide and myomodulin exerted inhibitory effects on the electrophysiological properties of the sensory neurons. properties of the sensory neurons. 3. FMRFamide appeared to modulate three K+ currents. The first current, which was increased by FMRFamide, had properties closely resembling those of the S-K+ current (IK,S). These properties include slow activation, little inactivation, and relative insensitivity to the K+ channel blockers 4-aminopyridine (4-AP) and tetraethylammonium (TEA). The second current, which was reduced by FMRFamide, had kinetic and pharmacological properties similar to those of a component of the Ca(2+)-activated K+ current (IK,Ca). Finally, at large depolarizations, FMRFamide appeared to increase a third current that was attenuated by 4-AP, suggesting that FMRFamide also modulated the delayed or voltage-dependent K+ current (IK,V). 4. Myomodulin appeared to modulate two of the currents modulated by FMRFamide, because it increased both IK,S and IK,V. Unlike FMRFamide, however, myomodulin did not appear to modulate IK,Ca. 5. Arachidonic acid mimicked the modulation of IK,S, IK,Ca, and IK,V by FMRFamide. Because myomodulin did not modulate IK,Ca, it appears that a second messenger other than arachidonic acid or its metabolites mediates the modulatory effects of myomodulin. 6. These results indicate that both FMRFamide and myomodulin can inhibit the tail sensory neurons by increasing IK,S. FMRFamide, but not myomodulin, also reduces IK,Ca, which suggests that under some conditions FMRFamide may also have excitatory actions. Finally, these results suggest that the effects of FMRFamide and myomodulin may be mediated by different second-messenger systems.     

Serotonergic modulation of two potassium currents in the pleural sensory neurons of Aplysia

1. The properties of membrane currents that were modulated by serotonin (5-HT) were investigated with two-electrode voltage-clamp techniques in sensory neuron somata isolated from the pleural ganglion of Aplysia californica. The modulatory effects of 5-HT were revealed by computer subtraction of current responses elicited in the presence of 5-HT from current responses elicited prior to the application of 5-HT. The complexities of the resulting 5-HT difference currents (I5-HT) suggested that 5-HT modulated more than one component of membrane current. 2. The 5-HT difference currents appeared to have at least two distinct components. One component was clearly evident at membrane potentials more negative than -10 mV was relatively voltage independent and did not inactivate. A second component was activated at membrane potentials more positive than -10 mV, had complex kinetics, and was highly voltage dependent. In an attempt to identify the membrane currents that were modulated by 5-HT, we compared the pharmacologic sensitivity of I5-HT to that of previously described K+ currents. 3. The two components of I5-HT had different sensitivities to agents that block K+ currents. The relatively voltage-independent component of I5-HT was not blocked by 2 mM 4-aminopyridine (4-AP) and was relatively insensitive to tetraethylammonium (TEA) (estimated Kd of 92 mM). In contrast, the voltage-dependent component of I5-HT was blocked by 4-AP (2 mM) and moderate concentrations of TEA (estimated Kd of 5 mM). 4. The K+ current blockers that were used to examine I5-HT were also used to examine voltage-activated membrane currents. Externally applied TEA blocked the delayed or voltage-dependent K+ current (IK.V) with an estimated dissociation constant (Kd) of 8 mM and a membrane current similar to the Ca2+-activated K+ current (IK.Ca) with an estimated Kd of 0.4 mM. In addition, externally applied 4-AP (2 mM) blocked IK.V. Thus TEA and 4-AP were equipotent in blocking both IK.V and the voltage-dependent component of I5-HT. 5. The suggestion that I5-HT contained multiple components was supported further by examining the modulatory effects of adenosine 3',5'-cyclic monophosphate (cAMP) that mediates some actions of 5-HT on membrane currents in these cells. cAMP difference currents (IcAMP) were similar to the relatively voltage-independent component of I5-HT. The subsequent addition of 5-HT to solutions already containing cAMP resulted in 5-HT difference currents similar to the voltage-dependent component of I5-HT.(ABSTRACT TRUNCATED AT 400 WORDS)     

Randomized controlled trial of brief cognitive behaviour therapy versus treatment as usual in recurrent deliberate self-harm: the POPMACT study

BACKGROUND: We carried out a large randomized trial of a brief form of cognitive therapy, manual-assisted cognitive behaviour therapy (MACT) versus treatment as usual (TAU) for deliberate self-harm. METHOD: Patients presenting with recurrent deliberate self-harm in five centres were randomized to either MACT or (TAU) and followed up over 1 year. MACT patients received a booklet based on cognitive behaviour therapy (CBT) principles and were offered up to five plus two booster sessions of CBT from a therapist in the first 3 months of the study. Ratings of parasuicide risk, anxiety, depression, social functioning and global function, positive and negative thinking, and quality of life were measured at baseline and after 6 and 12 months. RESULTS: Four hundred and eighty patients were randomized. Sixty per cent of the MACT group had both the booklet and CBT sessions. There were seven suicides, five in the TAU group. The main outcome measure, the proportion of those repeating deliberate self-harm in the 12 months of the study, showed no significant difference between those treated with MACT (39%) and treatment as usual (46%) (OR 0.78, 95% CI 0.53 to 1.14, P=0.20). CONCLUSION: Brief cognitive behaviour therapy is of limited efficacy in reducing self-harm repetition, but the findings taken in conjunctin with the economic evaluation (Byford et al. 2003) indicate superiority of MACT over TAU in terms of cost and effectiveness combined.     

Comparison of the fertilizing capability of spermatozoa from ejaculates, epididymal aspirates and testicular biopsies using intracytoplasmic sperm injection

A prospective study was carried out to compare the fertilizing capability and pregnancy outcome following intracytoplasmic sperm injection (ICSI) using spermatozoa obtained from ejaculates, or surgically from epididymis or seminiferous tubules. A total of 77 ICSI cycles (one per patient) was included. In all, 28 patients had severe oligoasthenoteratozoospermia, 19 patients had obstructive azoospermia and 30 patients had non-obstructive azoospermia. The main outcome measures were fertilization rate per injected metaphase II oocyte and the clinical pregnancy rate per embryo transferred back to the female recipients. In patients with severe oligoasthenoteratozoospermia, the fertilization and pregnancy rates were 79 and 25 %. In patients with obstructive azoospermia, for whom epididymal spermatozoa were used, these were 75 and 28%, and in the non-obstructive group for which testicular spermatozoa were used for injection, they were 69 and 21% respectively. These rates were not significantly different in the three groups (P = 0.85 and P = 0.14 respectively), suggesting that spermatozoa from the ejaculates and epididymal or testicular biopsies are able to fertilize equally by using ICSI. Live birth per embryo transfer was significantly reduced in patients with non-obstructive azoospermia compared to the other two groups. The high abortion rate (50%) in the group in which testicular spermatozoa were used raises doubts about the developmental competence of such embryos.