Excitatory Connections Between CA1 Pyramidal Cells Revealed by Spike Triggered Averaging in Slices of Rat Hippocampus are Partially NMDA Receptor Mediated

Spike triggered averaging was used to record local circuit connections between pairs of CA1 pyramidal neurons in isolated slices of rat hippocampus. Of 795 pairs of neurons tested, six were connected. These epsps were only partially blocked by 2-amino-5-phosphonovalerate (AP-5), which decreased the amplitude and half width of the epsp, but did not affect the early rising phase. In contrast, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocked all phases of the epsp and combinations of AP-5 and CNQX blocked the epsp almost entirely. These results indicate that these epsps were mediated by both N-methyl-d-aspartate (NMDA) and non-NMDA excitatory amino acid receptors. Moreover, they exhibited a voltage relation typical of neuronal responses to NMDA, increasing in amplitude and duration as the postsynaptic cell was depolarized. These epsps were brief (10 - 90% rise time < 5 ms, width at half amplitude < 20 ms), indicating a proximal location. Increasing presynaptic firing rate (1 - 4 spikes/s) reduced average epsp amplitude by almost 50%. When epsps were evoked by pairs of spikes (interval 3 - 25 ms), a large response to the first spike precluded a large response to the second. No evidence for selective enhancement of the NMDA receptor component by paired spike activation was found. It is concluded that a significant NMDA receptor mediated input to CA1 is provided by local circuit CA1 - CA1 connections and that these synapses can be demonstrated under control conditions.     

Comparative pharmacokinetics of co-trifamole and co-trimoxazole to `steady state' in normal subjects

1 The plasma and urine concentrations of trimethoprim (TMP) and sulphonamide obtained using co-trimoxazole and co-trifamole (TMP and sulphamoxole) were estimated in 10 patients in a two way cross-over study using the manufacturers' recommended dosage schedules.

2 The pharmacokinetics of TMP using either preparation were comparable with those reported elsewhere; as were the kinetics of sulphamethoxazole. The values obtained for sulphamoxole, not previously reported, were t_½ 8.0 ± 2.8 h, k_el 0.096 ± 0.031 h^-1, CL_s 0.9 ± 0.4 1h^-1 and V_d 9.4 ± 2.01.

3 Studies in plasma showed sulphamoxole to have a lower volume of distribution than sulphamethoxazole. The half-lives of the two did not differ significantly; steady state plasma concentrations were achieved more rapidly (25 h) for co-trifamole than for co-trimoxazole (49 h) as a result of the differences in recommended dosage schedule.

4 Differences in urinary concentration of TMP and sulphonamide obtained using the two preparations were a reflection of the dosage regimens rather than the pharmacokinetics of the individual drugs. Urinary concentrations of TMP greatly exceeded the MIC for sensitive organisms in all cases. Sulphonamide concentrations fell below the MIC for both drugs and in neither case were optimum synergistic ratios obtained in urine.

5 The figures obtained suggest that the use of sulphamoxole offers no advantage over sulphamethoxazole so far as the plasma and urinary concentrations are concerned, and suggest that in the treatment of urinary tract infections the necessity for combination therapy with TMP and a sulphonamide is open to question.

     

Observer variation in the interpretation of lower limb venograms.

After agreeing on diagnostic criteria and after a pilot study, two experienced radiologists twice independently reviewed 40 lower limb venograms performed by a standard technique in patients suspected or known to have venous thrombosis. The observers reviewed 20 examinations at a time, their analysis requiring separate identification of 11 major veins. At each site observers stated whether thrombus was "absent," "doubtful," "presumed," or "definite," or declared "no opinion possible." They then rediscussed criteria of diagnosis and, using the same experimental design, examined another 40 venograms. To correct for agreement expected by chance, data were analyzed by using the kappa statistic. In general, levels of agreement were higher than those reported for many other clinical and radiologic investigations, probably because of refinement of criteria after the pilot study. Nonetheless, observers disagreed about the probable presence or absence of thrombus at some site in the limb in about 10% of examinations. Observer variation should be considered when venography is used as a reference standard to evaluate other methods of diagnosing thrombi.     

Intermittent peritoneal dialysis in the treatment of end-stage renal failure.

Our experience of 54 patients with end-stage renal failure, who were treated with intermittent peritoneal dialysis and compared with patients maintained by haemodialysis over the years 1972 to 1978, has been reviewed. All patients received peritoneal dialysis for more than six weeks. The total experience was 32.8 patient dialysis-years, 48% as home dialysis. Peritoneal dialysis was used as an interim procedure in 19 patients who were waiting for haemodialysis. However, in 35 patients (particularly in the very young and elderly, and in situations of poor social support), recurrent peritoneal dialysis was chosen as the definitive dialysis therapy. Dialysis was assessed as "adequate" in all, but two, patients. The major complication of peritoneal dialysis was peritonitis, although its over-all incidence of 1.31 episodes per patient dialysis-year was low. An attack of peritonitis occurred every nine months of patient exposure, though the incidence of bacterial peritonitis averaged only once every 26 months. Fifty per cent of patients never had an episode of peritonitis. Intermittent peritoneal dialysis was associated with greater morbidity and mortality than haemodialysis, perhaps due, in part, to the older age of the peritoneal dialysis group. Intermittent peritoneal dialysis is a valuable adjunct to haemodialysis and transplantation in the treatment of end-stage renal failure.     

Acupuncture analgesia: an experimental investigation.

A study was designed to establish whether acupuncture has any analgesic properties beyond those of suggestion. In three one-hour experimental sessions the increases in detection thresholds and tolerances for thermal pain at six body locations on 12 subjects were compared. A control session (without needles) was followed by one session in which electrically stimulated needles were inserted in accord with Chinese practice, and another in which the needles were inserted to avoid all recognised acupuncture "points." Acupuncture was significantly more effective than suggestion in raising overall body pain thresholds but just below significance for tolerances. A significant disproportionate effect on the epigastrium, predicted by the choice of acupuncture points, was found for tolerances but not thresholds.     

Anti-tumour immunity in malignant melanoma assay by tube leucocyte adherence inhibition.

Tumour antigen-induced inhibition of leucocyte adherence was modified for use in glass test tubes (Tube LAI assay) for the study of cell-mediated anti-tumour immunity to human malignant melanoma. Peripheral blood leucocytes (PBL) of 20 out of 25 patients (80%) with active malignant melanoma responded to an extract of malignant melanoma with LAI, whereas only 4-5% of 475 control subjects showed a response. The malignant melanoma patients reacted to both allogeneic and autologous extracts of malignant melanoma which indicates a common cross-reacting antigen. Malignant melanoma patients did not respond to unrelated tumour extracts. The LAI was mediated by PBL (monocytes) "armed" with cytophilic anti-tumour antibody specific for the sensitizing tumour antigen. The anti-tumour response of the malignant melanoma patients was dependent on the stage of the cancer, and 11 out of 13 Stage I patients had a positive NAI, whereas patients with disseminated cancer had decreased response. The diminished LAI in patients with large tumour burdens appeared to be the result of release of tumour antigen systemically. Also, surgery and chemotherapy depressed LAI. Although LAI was depressed after surgical excision of the cutaneous melanoma, most patients showed LAI 1-3 months later. Tumour-free melanoma patients monitored for one year by the Tube LAI assay showed a decline in their anti-tumour immunity 5-6 months after surgery. The NAI was low or negative after the 8th post-surgical month in tumour-free patients. Patients with residual malignant melanoma showed persistent or recurrent LAI after the 8th post-surgical month. LAI reactivity monitored after "curative" surgery for malignant melanoma may assist in determining whether the patient is tumour-free or has a recurrence.     

The diets of preschool children in Newcastle upon Tyne, 1968-71.

1. Ninety-one families containing 140 children under 4 years of age at enrolment were studied. At 1-monthly intervals, the children were weighed and measured and qualitative information about feeding habits was obtained. Weighed dietary surveys for periods of 5 d were made at approximately 8 months, 3 years, and 5 years of age; there were forty-six failures in 260 surveys attempted. 2. At the four specified ages, mean energy intakes were 3-75, 5-03, 5-82 and 6-75 MJ (896, 1203, 1392 and 1613 kcal)/d respectively. At 8 months, milk products provided on average, 43% of the total energy intake, and commerical baby foods provided 17%. These values decreased to 21 and 2% respectively at 20 months and there was little further change therafter. 3. Average intake of energy and of most nutrients met recommended intakes (Department of Health and Social Security, 1969). Iron intakes were marginal, and vitamin D intakes were low. 4. The energy intake of boys was significantly higher than that of the girls at 3 years of age, but the boys were not significantly heavier. The energy intake of children from "manual-worker" families was higher than that from "non-manual" families. Similarly, the energy intake of children from larger families was higher than that of children from smaller families. 5. Energy intakes were correlated with body-weights and with rates of gain in weight. Irrespective of body-weight, "big eaters" at 20 months tended to be "big eaters" at 3 years also.     

Effectiveness of the boston brace in treatment of large curves in adolescent idiopathic scoliosis

STUDY DESIGN: This is a retrospective study of 50 patients with adolescent idiopathic scoliosis with curves measuring 35 degrees to 45 degrees who were treated with a Boston brace. OBJECTIVES: The purpose of this study was to determine whether the Boston brace could effectively halt long-term progression in skeletally immature adolescents with idiopathic scoliosis who had a curve between 35 degrees and 45 degrees. SUMMARY OF BACKGROUND DATA: The Boston brace has been shown to be effective in preventing curve progression in adolescent idiopathic scoliosis, but its efficacy in large curves has not been fully studied. METHODS: Fifty adolescents were treated with a Boston brace for idiopathic scoliosis curves of 35-45 degrees (mean, 38.55 degrees ). All were judged to be skeletally immature based on menarcheal status (mean, 2.6 months before menarche), Risser sign (mean, 0.90; range, 0-2), and chronologic age (mean, 13 +/- 1 years). Patients were recalled for long-term follow-up at a mean of 9.7 years (range, 6.23-13.22 years) after brace discontinuation. Three well-matched patient subsets were then identified based on compliance. Group 1 (n = 24) consisted of patients who were compliant with the brace program and wore the brace 18 or more hours per day, Group 2 (n = 14) contained patients who wore the brace 12-18 hours per day, and Group 3 (n = 12) contained patients who wore the brace 0-12 hours per day. RESULTS: There was a significant difference in the amount of initial correction seen in the brace between the groups: 49%, 45%, and 33% curve correction in the brace for Groups 1, 2, and 3, respectively (P < 0.05). At long-term follow-up there was a statistically significant difference between Groups 1, 2, and 3 in the percentage of patients in whom the curve had progressed to more than 45 degrees (P < 0.001), who had more than 5 degrees of curve progression (P < 0. 05), or who had undergone posterior spinal fusion (P < 0.001). CONCLUSIONS: These long-term data confirm that the Boston brace when used 18 or more hours per day is effective in preventing progression of large curves at a mean of 9.8 years after bracing is discontinued.     

Inhibition of the allograft response by donor specific blood transfusion: association with reduced local TH1 cytokines and nitric oxide but enhanced prostaglandin E2 production

BACKGROUND: Donor-specific blood transfusion (DST) may improve allograft survival in human and animal models, but the mechanisms for this graft protective effect are incompletely understood. The sponge matrix allograft model was used to determine if DST induces regulatory factors within the allograft. METHODS: C57BL/6 (H-2b) recipients received donor-specific (DBA/2J, H-2d) or syngeneic (C57BL/6) blood 7 days before sponge matrix allograft (DBA/2J) implantation. Fourteen days postgrafting, the sponge infiltrating cells (SIC) were examined for cytotoxic T cell (CTL) and natural killer (NK) activity, and sponge exudate fluid (SEF) was assessed for nitric oxide (.N=O) and prostaglandin E2 (PGE2) content. Interleukin- (IL) 2, IL-4, IL-10, and interferon-gamma (IFN-gamma) production by SIC was also determined. Recipient splenocytes were simultaneously assessed for anti-donor cytotoxic and proliferative responses and .N=O production. RESULTS: SIC from mice receiving syngeneic transfusions (ST) acquired both CTL and NK activity postgrafting, with maximal activity by day 14. DST suppressed both CTL and NK activity throughout the postgrafting period. Limiting dilution analysis (LDA) of SIC to determine precursor and native CTL frequency showed significantly lower responder cell frequency after DST compared with ST. SEF .N=O levels and SIC production of IL-2 and IFN-gamma in grafted DST mice were significantly lower than in grafted mice receiving ST. No significant amounts of IL-4 and very low levels of IL-10 were produced by SIC from grafted mice after either ST or DST. Conversely, PGE2 content of sponge fluid and serum from DST mice was higher than in mice receiving ST. Antigen stimulated splenocyte proliferation and CTL development assessed by LDA were also inhibited by DST. CONCLUSIONS: Reduction in local TH1 cytokines, absence of detectable TH2 cytokines, with enhanced PGE2 and depressed .N=O were observed in the local graft environment after DST. These data support the hypothesis that DST induces donor-specific intragraft suppressor factors, accompanied by reduced local and systemic immune activation.     

Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia.

PURPOSE: Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia. EXPERIMENTAL DESIGN: Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification. RESULTS: Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91-100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients. CONCLUSIONS: Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.