Model of global spontaneous activity and local structured activity during delay periods in the cerebral cortex

We investigate self-sustaining stable states (attractors) in networks of integrate-and-fire neurons. First, we study the stability of spontaneous activity in an unstructured network. It is shown that the stochastic background activity, of 1-5 spikes/s, is unstable if all neurons are excitatory. On the other hand, spontaneous activity becomes self-stabilizing in presence of local inhibition, given reasonable values of the parameters of the network. Second, in a network sustaining physiological spontaneous rates, we study the effect of learning in a local module, expressed in synaptic modifications in specific populations of synapses. We find that if the average synaptic potentiation (LTP) is too low, no stimulus specific activity manifests itself in the delay period. Instead, following the presentation and removal of any stimulus there is, in the local module, a delay activity in which all neurons selective (responding visually) to any of the stimuli presented for learning have rates which gradually increase with the amplitude of synaptic potentiation. When the average LTP increases beyond a critical value, specific local attractors (stable states) appear abruptly against the background of the global uniform spontaneous attractor. In this case the local module has two available types of collective delay activity: if the stimulus is unfamiliar, the activity is spontaneous; if it is similar to a learned stimulus, delay activity is selective. These new attractors reflect the synaptic structure developed during learning. In each of them a small population of neurons have elevated rates, which depend on the strength of LTP. The remaining neurons of the module have their activity at spontaneous rates. The predictions made in this paper could be checked by single unit recordings in delayed response experiments.      

DIURNAL EFFECTS OF FLUOXETINE AND NALOXONE ON THE HUMAN HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

1. Central serotonergic pathways are hypothesized to be involved in the stimulation of hypothalamic adrenocorticotropic hormone (ACTH) secretagogue release by both circadian- and stress-induced mechanisms. We aimed to investigate this hypothesis by measuring the effect of the highly specific serotonin re-uptake inhibitor fluoxetine (FX) on ACTH and Cortisol release in the morning and in the afternoon in humans, both by itself and in combination with the opioid antagonist naloxone (Nal). Naloxone causes ACTH release in humans by removing an endogenous inhibitory opioid tone on central noradrenergic pathways stimulatory to hypothalamic corticotropin-releasing hormone (CRH) secretion. Serotonergic agents may act directly or indirectly through these central noradrenergic pathways and, if so, would be expected to be additive to or synergistic with Nal in causing ACTH and Cortisol release. 2. Oral FX (40 mg) was given at approximately 07.00 or 11.00 h, either alone or with intravenous Nal 3 h later, to normal human volunteers. Plasma ACTH and Cortisol levels were measured for 5 h after FX dosing. 3. Fluoxetine produced a small but non-significant increase in Nal-stiimilated ACTH and Cortisol release in both morning and afternoon studies. Naloxone alone did not cause different ACTH and Cortisol responses in the morning and afternoon. 4. These results suggest that serotonergic pathways are not major regulators of the hypothalamic-pituitary-adrenal axis in humans or that FX has counteracting acute inhibitory effects on the axis, such as inhibition of hypothalamic arginine vasopressin secretion, which has been demonstrated in chronic animal studies.     

Tackling rugby injury: Iessons learned from the implementation of a five-year sports injury prevention program

Rugby Union football is a very popular sport in New Zealand but of all the major sports played in that country, it has the highest reported incidence of injury. In 1995, a national rugby injury prevention program was instigated to address this problem. Known as Tackling Rugby Injury, this multifaceted program was implemented over a five-year period. The program was based on the results of a prospective cohort study of rugby injury, known as the Rugby Injury and Performance Project (RIPP), and was organised around seven themes, five relating to the prevention of injury: coaching, fitness, injury management, tackling, and foul play, and two relating to the implementation and evaluation of the program. The purpose of this paper is to describe the lessons learned from the implementation of Tackling Rugby Injury. Qualitative research methods were used to describe the process of implementation, including informant interviews, participant observation, and the scrutiny of written, visual and archival material. Among the lessons learned were the importance of basing injury prevention strategies on scientific evidence rather than popular belief, the difficulty in implementing complex interventions, the advantages of a formal agreement between partners in the implementation of a program, the central role played by coaches in promoting injury prevention strategies, and the value of describing the process of implementation as well as monitoring injury outcomes and changes in knowledge, attitudes and behaviour. It is hoped that other sports wishing to develop injury prevention programs can learn from this experience.     

Monocytes and macrophages synthesize and secrete thrombospondin

Thrombospondin, one of the major glycoproteins released from alpha- granules of thrombin-stimulated platelets, is a disulfide-linked trimer of 160,000-dalton subunits. Cultured human monocytes secreted thrombospondin (determined by an enzyme-linked immunosorbent assay) into the culture medium in a time-dependent manner (1.45 micrograms/10(6) cells/24 hr); secretion was totally blocked by cycloheximide (1 microgram/mL). 35S-thrombospondin was isolated from 35S-methionine-labeled human monocyte postculture medium with rabbit polyclonal anti-thrombospondin coupled to protein A-Sepharose. The immunoisolated 35S-thrombospondin migrated in sodium dodecyl sulfate- polyacrylamide gels after reduction with a molecular weight of 159,000. Similar results were obtained using mouse resident peritoneal macrophages. Elicited peritoneal macrophages harvested from mice pretreated with endotoxin, casein, or thioglycollate secreted much less thrombospondin than did resident macrophages harvested from control mice. Thus, monocytes and macrophages from two different species synthesize and secrete thrombospondin, and the rate of synthesis of thrombospondin appears to depend on the state of activation of the cells.     

Determinants of participation in family and recreational activities of young children with cerebral palsy

Purpose: To test a model of child, family and service determinants of participation in family and recreational activities for young children with cerebral palsy (CP).

Methods: Participants were a convenience sample of 429 children (242 males) with CP, aged 18 to 60 months, representing all levels of the Gross Motor Function Classification System (GMFCS). Children were divided into two groups by GMFCS levels, levels I to II and levels III to V. Data on impairments and gross motor function were collected by therapists; parents provided information about children’s health conditions and adaptive behaviour. Seven months later, parents reported on family life and services received. One year after the beginning of the study, parents reported their children’s participation. Data from the two groups of children were analysed separately using structural equation modelling.

Results: The model explained 35% and 40% of the variance of frequency of participation in family and recreation and 28% and 38% of enjoyment in participation, for the two groups of children, respectively. Children’s adaptive behaviour, family ecology, and number of community recreational programs were associated with the frequency of participation for both groups. Gross motor function was only associated with the frequency of participation for children in levels III–V. Adaptive behaviour was associated with enjoyment for both groups. The extent services met children’s needs was associated with enjoyment for children in levels I to II and family ecology was a determinant of enjoyment for children in levels III to V.

Conclusion: Supporting children’s adaptive behaviour, family ecology, and access to community recreational programmes may foster participation in family and recreational activities for young children with CP.

• Implications for Rehabilitation

• Participation in family and recreational activities for young children with CP is complex and influenced by child, family and environmental factors.

• Practitioners are encouraged to support children’s adaptive behaviour and access to community programs and family relationships, involvement in community activities and expectations of their children.

• Optimizing gross motor function for children who have limitations in self-mobility may enhance their participation in family and recreational activities.

• For children with a good prognosis for walking, providing services perceived by parents to meet their children’s needs may enhance children’s enjoyment of participation.

     

Effects of Treatments by Calcium and Sex Hormones on Vertebral Fracturing in Osteoporosis

Lateral radiographs of the thoracic and lumbar spine were takenperiodically in 49 patients with osteoporosis. Thirty patientswere postmenopausal, and 19 nonmenopausal with osteoporosisdue to steroids, male hypogonadism, alcoholism, thyrotoxicosisor unknown cause. Patients were studied before, during and aftertreatment with high calcium alone, or with combined calciumand sex steroids. Calcium was given as effervescent calciumlactate gluconate, and sex hormones as oestradiol valerate,testosterone oenanthate, or methenolone oenanthate. A totalof 964 films covering 409 patient-years were available for measurement.On each vertebra, deformity due to loss of anterior height wasmeasured and assigned to one of four grades. For the time intervalbetween each consecutive pair of films, a patient's vertebralfracture rate score was calculated and expressed per thousandpatient-years. In comparison with the corresponding pretreatment fracture ratescore, both the postmenopausal and the nonmenopausal groupswho had not received sex hormones previously, failed to showsignificant changes (p=0.144; p=0.017) on high calcium aloneduring mean periods of 4.3 and 2.8 years respectively. If thefirst 2 years on high calcium were excluded for the postmenopausalgroup, they still failed to show a reduction in fracture ratescore (observed for a mean period of 5.0 years; p=0.04). When treated with combined calcium and sex hormones, both postmenopausaland nonmenopausal groups showed a lower fracture rate scoreof 20 and 207 respectively when compared with the pretreatmentlevels of 1500 and 1697 (in mean treatment periods of 3.2 and4.4 years; p<0.001 in each case). When given high-dose calciumalone, but after treatment with sex hormones as well, the postmenopausalgroup showed no change in fracture rate score from pretreatment(in a mean of 3.1 years; p=0.069); however the nonmenopausalgroup still showed a significant reduction in fracture ratescore from 1697 to 42 over a mean period of 2.3 years (p=0.001).The postmenopausal group, after stopping all treatment, showeda higher fracture rate score of 1286 (in a mean of 2.6 years)than did those on combined calcium and sex hormones, in whomthe fracture rate score was 20 (in a mean of 3.2 years; p=0.008).A subgroup of 11 patients with osteoporosis of both the menopausaland nonmenopausal types, had data both before (in a mean of5.5 years) and during (for a mean of 2.5 years) treatment withcalcium alone; the fracture rate scores were 1473 and 918 (p=0.247).Data were available for nine patients both before (for meanof 5.5 years) and during (for a mean of 5.5 years) treatmentwith calcium and sex hormones; the fracture rate score fellfrom 1397 to 100 (p=0.001). It is concluded that in groups with both menopausal and nonmenopausalosteoporosis, vertebral fracturing was reduced by treatmentwith combined calcium and sex hormones, but no significant effectfrom calcium alone was shown. In both groups, cessation of therapywas associated with a return to near the pretreatment fracturerate score, strongly suggesting the need for lifelong treatment.     

Suitability of liquid-stored donor platelets in platelet compatibility testing

Current platelet crossmatch procedures to select compatible donors for alloimmunized thrombocytopenic patients are hampered by the lack of a convenient platelet storage method. This study examined the feasibility of using washed apheresis donor platelets stored for up to 1 year in a modified Hank's buffer solution at 4 degrees C as crossmatch reagents in an indirect IgG-enzyme immunoassay. Pooled and monospecific HLA and PlA1 antisera were used to determine the antigenic reactivity of donor platelets in relation to duration of storage. There were no significant differences between mean HLA and PlA1 antigen expression in fresh and stored platelets. HLA reactivity was detected on 12 of 13 donor platelet samples stored for 3 to 9 months and on 14 of 17 platelets stored for 12 to 14 months. PlA1 reactivity was maintained at 12 to 14 months for all 12 donor platelet samples tested. In addition, incompatibility remained in 23 of 24 paired fresh and stored platelet crossmatches using individual alloimmunized patient plasmas. These data indicate that both HLA and platelet-specific PlA1 antigen reactivity can be maintained adequately in liquid storage at 4 degrees C for up to 1 year. The availability of a convenient platelet storage method should facilitate the general application of platelet crossmatching procedures for alloimmunized patients.     

Transfusion and cytomegalovirus-associated AIDS-defining disease in hemophiliacs. Hemophilia Malignancy Study

BACKGROUND: Whether transfusion increases the risk of AIDS-defining cytomegalovirus (CMV) infection (CMV AIDS) in immunosuppressed patients is not known. Because of concerns about the risk of transfusion transmission of CMV and potential exposure to multiple strains of CMV through transfusion, the National Hemophilia Foundation recently recommended that CMV-negative blood be used in human immunodeficiency virus-positive hemophiliacs, regardless of their CMV serologic status. Although the multiple strains of CMV cause different CMV disease manifestations in transplant recipients, there are no data on CMV disease in human immunodeficiency virus-positive hemophiliacs. STUDY DESIGN AND METHODS: It was hypothesized that if the transmission of CMV through transfusion causes CMV disease in human immunodeficiency virus- positive hemophiliacs, then hemophiliacs with CMV AIDS would be more likely to have received transfusions than those with AIDS-defining disease not caused by CMV (non-CMV AIDS). The number and type of transfusions were evaluated in 334 hemophiliacs with AIDS (35 with CMV AIDS and 299 with non-CMV AIDS) enrolled in the multicenter Hemophilia Malignancy Study. RESULTS: There were no differences between hemophiliacs with CMV AIDS and those with non-CMV AIDS in age, type, and severity of hemophilia; the proportion receiving transfusions; or the mean number of units transfused. These findings persisted after correction for transfusion practice, (i.e., CMV-unscreened blood vs. CMV-negative and/or white cell-reduced blood). There was no difference between the groups in CMV lgG titers or in the proportion who were CMV seropositive, and there was no difference between these parameters in those who had received transfusion(s) and those who had not. CONCLUSION: Transfusion appears to have little, if any, effect on the development of CMV AIDS or CMV lgG seroprevalence in patients with hemophilia.