Effectiveness of human T-lymphotropic virus (HTLV) recipient tracing (lookback) and the current HTLV-I and -II confirmatory algorithm, 1999 to 2004.

BACKGROUND: This study reports on the efficacy of an investigational human T-lymphotropic virus (HTLV)-I and -II lookback program in the context of differing confirmatory testing algorithms. STUDY DESIGN AND METHODS: The results of testing approximately 35 million donations for anti-HTLV-I and -II were evaluated for two recent periods reflecting the use of two different confirmatory algorithms. The number of seroconverting donors was established for the entire period, and the results of lookback on their prior donations were investigated. RESULTS: The dual enzyme immunoassay (EIA) strategy was used throughout both study periods and resulted in a 57 to 76 percent reduction in the number of samples requiring confirmatory testing. From May 2000 to February 2002, a total of 9138 samples were repeatedly reactive by the primary screening test; of the concordant EIA-reactive samples, 461 (12%) were confirmed by Western blot, whereas 3083 (79%) were indeterminate. From March 2002 to December 2004, a total of 21,291 samples were repeatedly reactive; of the concordant EIA-reactive samples, 1099 (22%) were confirmed by the State of California's reference laboratory and only 273 (5%) were equivocal. Overall, 38 or 1 in 921,000 donations were from a seroconverting donor with 32 prior donations within the lookback period. Of those 32, components from only 11 were transfused to recipients who survived; of these, 4 were tested and all were nonreactive for HTLV-I and -II antibodies. CONCLUSION: Use of creative algorithms can increase the efficacy of anti-HTLV-I and -II confirmatory testing and reduce the number of indeterminate results. Currently, lookback for HTLV-I and -II has a very low yield, and its public health benefit is questionable.

Cell-cell contact and membrane spreading in an ultrasound trap.

An ultrasonic standing wave trap [Langmuir 19 (2003) 3635] in which the morphologies of 2-D latex-microparticle aggregates, forming a pressure node plane, were characterised has been applied here to different cell suspensions with increasing order of specificity of cross-linking molecule, i.e. polylysine with chondrocytes; wheat germ agglutinin (WGA) with erythrocytes and surface receptors on neural cells. The outcome of initial cell-cell contact, i.e. whether the cells stuck at the point of contact (collision efficiency = 1) or rolled around each other (collision efficiency = 0), was monitored in situ by video-microscopy. The perimeter fractal dimensions (FD) of 2-D hexagonally symmetric, closely packed aggregates of control erythrocytes and chondrocytes were 1.16 and 1.18, respectively while those for the dendrititc aggregates formed initially by erythrocytes in 0.5microg/ml WGA and chondrocytes in 20 microg/ml polylysine were 1.49 and 1.66. The FDs for control and molecularly cross-linked cells were typical of reaction-limited aggregation (RLA) and transport diffusion-limited aggregation (DLA), respectively. The FDs of the aggregates of cross-linked cells decreased with time to give more closely packed aggregates without clear hexagonal symmetry. Suspensions of neural cells formed dendritic aggregates. Spreading of inter-cellular membrane contact area occurred over 15 min for both erythrocyte and neural cell dendritic aggregates. The potential of the technique to characterise and control the progression of cell adhesion in suspension away from solid substrata is discussed.

Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis?

PURPOSE: To determine if the location of deep vein thrombosis is a predictor of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. METHODS: The study population consisted of 1,149 consecutive patients with symptomatic proximal deep vein thrombosis. In all patients, deep vein thrombosis was confirmed by Duplex ultrasound or venography and was classified as popliteal, femoral, or iliofemoral. Patients received initial treatment with unfractionated heparin, enoxaparin, or reviparin for least 4 days, as well as a coumarin derivative, with a target international normalized ratio of 2.0 to 3.0, starting on the 1st or 2nd day of treatment. All patients were followed for 3 months, and all episodes of recurrent venous thromboembolism were confirmed with objective diagnostic tests. RESULTS: The overall rate of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy was 5.5% (63/1,149). The rate of recurrence in patients with popliteal vein thrombosis was 5.1% (23/453); in patients with femoral vein thrombosis, it was 5.3% (34/645); and in patients with iliofemoral vein thrombosis, it was 11.8% (6/51). Two clinical risk factors were associated with an increased risk of recurrent venous thromboembolism: iliofemoral vein thrombosis (odds ratio [OR] = 2.4; 95% confidence interval [CI]: 0.95, 5.9), and cancer (OR = 2.6; 95% CI: 1.5, 4.4). CONCLUSIONS: Patients with extensive iliofemoral vein thrombosis who receive conventional anticoagulant therapy have a greater than twofold higher risk of developing recurrent venous thromboembolism than patients without iliac vein involvement (i.e., 11.8% vs. 5.2%). Prospective studies are needed to determine whether alternative antithrombotic strategies are warranted in such patients.

Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy.

BACKGROUND: In patients with venous thromboembolism (VTE), identifying clinical risk factors for recurrence during the initial 3 months of anticoagulant therapy and knowledge of the time course of recurrence may help clinicians decide about the frequency of clinical surveillance and the appropriateness of outpatient treatment. METHODS: Analysis of a randomized controlled trial database involving 1021 patients with VTE (750 with deep vein thrombosis [DVT] and 271 with pulmonary embolism [PE]) who were followed up for 3 months after the start of anticoagulant therapy. All patients received initial treatment with unfractionated heparin or a low-molecular-weight heparin (reviparin) and a coumarin derivative starting the first or second day of treatment, with a target international normalized ratio of 2.0 to 3.0. RESULTS: Four independent clinical risk factors for recurrent VTE were identified: (1) cancer (odds ratio [OR], 2.72; 95% confidence interval [CI], 1. 39-5.32), (2) chronic cardiovascular disease (OR, 2.27; 95% CI, 1. 08-4.97), (3) chronic respiratory disease (OR, 1.91; 95% CI, 0.85-4. 26), and (4) other clinically significant medical disease (OR, 1.79; 95% CI, 1.00-3.21). Older age was associated with a decreased risk for recurrent VTE (OR, 0.76; 95% CI, 0.64-0.92). Previous VTE, sex, and idiopathic VTE were not risk factors for recurrence. In patients with DVT or PE, there was no significant difference in the rates of recurrent nonfatal VTE (4.8% vs 4.1%; P =.62), major bleeding (2.9% vs 2.2%; P =.53), and non-VTE death (6.4% vs 7.8%; P =.45), but recurrent fatal PE was more frequent in patients with PE than DVT (2. 2% vs 0%; P<.01). There was a clustering of recurrent VTE episodes during the initial 2 to 3 weeks after the start of treatment. CONCLUSIONS: During the initial 3 months of anticoagulant therapy, recurrent VTE is more likely to occur in patients with cancer, chronic cardiovascular disease, chronic respiratory disease, or other clinically significant medical disease. Patients with PE are as likely to develop recurrent VTE as those with DVT; however, recurrence is more likely to be fatal in patients who initially present with PE. Arch Intern Med. 2000;160:3431-3436.

Prelabor rupture of the membranes at term: expectant management at home or in hospital? The TermPROM Study Group.

OBJECTIVE: To determine whether adverse effects of expectant management for premature rupture of membranes (PROM) at term and patient satisfaction were greater if women were managed at home rather than in a hospital. METHODS: We undertook a secondary analysis of data from the International TermPROM Study for women managed expectantly at home or in a hospital. Using multiple logistic regression analyses, we determined the effect of home and hospital management and controlled for differences in baseline characteristics, in measures of maternal and neonatal infections and rates of cesarean. RESULTS: Six hundred fifty-three women (39.1%) were managed at home, and 1017 (60.9%) in a hospital. Management at home, compared with in a hospital, increased risk of nulliparas needing antibiotics before delivery (odds ratio [OR] 1.52 95% confidence interval [CI] 1.04, 2.24, P =.03), those not colonized with group B streptococcus having cesareans (OR 1.48 95% CI 1.03, 2. 14, P =.04), and neonatal infections (OR 1.97 95% CI 1.00, 3.90, P =. 05). More multiparas managed at home said they would participate in the study again (OR 1.80 95% CI 1.27, 2.54, P <.001). CONCLUSION: Expectant management at home, rather than in a hospital, might increase the likelihood of some adverse outcomes.

Genetic regulatory elements introduced into neural stem and progenitor cell populations.

The genetic manipulation of neural cells has advantage in both basic biology and medicine. Its utility has provided a clearer understanding of how the survival, connectivity, and chemical phenotype of neurones is regulated during, and after, embryogenesis. Much of this achievement has come from the recent generation by genetic means of reproducible and representative supplies of precursor cells which can then be analyzed in a variety of paradigms. Furthermore, advances made in the clinical use of transplantation for neurodegenerative disease have created a demand for an abundant, efficacious and safe supply of neural cells for grafting. This review describes how genetic methods, in juxtaposition to epigenetic means, have been used advantageously to achieve this goal. In particular, we detail how gene transfer techniques have been developed to enable cell immortalization, manipulation of cell differentiation and commitment, and the controlled selection of cells for purification or safety purposes. In addition, it is now also possible to genetically modify antigen presentation on cell surfaces. Finally, there is detailed the transfer of therapeutic products to discrete parts of the central nervous system (CNS), using neural cells as elegant and sophisticated delivery vehicles. In conclusion, once the epigenetic and genetic controls over neural cell production, differentiation and death have been more fully determined, providing a mixture of hard-wired elements and more flexibly expressed characteristics becomes feasible. Optimization of the contributions and interactions of these two controlling systems should lead to improved cell supplies for neurotransplantation.

Predictors of cesarean delivery after prelabor rupture of membranes at term.

OBJECTIVE: To identify the significant predictors of cesarean delivery after prelabor rupture of membranes (PROM) at term. METHODS: In a multicenter study involving 72 institutions in six countries, 5041 women were randomized to induction of labor with oxytocin or prostaglandins or to expectant management. We did univariate and multivariate logistic regression analyses to determine the statistically significant independent predictors of cesarean delivery (P < .05). RESULTS: The following variables were found to be significantly associated with cesarean delivery: delivery in Israel, versus Canada (odds ratio [OR] 0.34); delivery in Australia, versus Canada (OR 1.93); nulliparity (OR 2.81); labor lasting more than 12 hours, versus less than 6 hours (OR 2.78); labor lasting 6-12 hours, versus less than 6 hours (OR 1.66); previous cesarean delivery (OR 2.75); epidural anesthesia (OR 2.66); clinical chorioamnionitis (OR 2.42); internal fetal heart rate monitoring (OR 2.19); birth weight of at least 4000 g (OR 2.07); use of oxytocin (OR 1.97); maternal age of at least 35 years (OR 1.44); latent period of at least 12 hours (OR 1.41); and meconium staining (OR 1.41). CONCLUSION: Strong predictors of cesarean delivery after PROM at term were country of birth, nulliparity, long labor, previous cesarean delivery, and epidural anesthesia.

Ionic mechanisms underlying excitatory effects of serotonin on embryonic rat motoneurons in long-term culture.

The actions of serotonin were investigated on motoneurons isolated from embryonic day 14 rat spinal cord and enriched by metrizamide density gradient centrifugation. Trophic support was provided by a spinal cord glial monolayer, ciliary neurotrophic factor and heat-inactivated serum. Cultures were maintained for 17-83 days and investigated using whole-cell patch-clamp recording. Serotonin evoked slow depolarizations (6.2+/-0.7 or 9.3+/-1.3 mV in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione and strychnine, EC50 8.2 nM), which were reversibly blocked by 0.1 microM ketanserin. Serotonin generated synaptic potentials in motoneurons, lowered the threshold for repetitive firing and changed the slope of the current intensity-firing frequency relationship. The inward current evoked by serotonin (-147+/-15.2 pA) was ascribed to a complex ionic mechanism, which varied amongst neurons in the sampled population. It was due to closure of barium-sensitive potassium channels, effects on Ih and increase in a separate mixed cation current which comprised both transient voltage-sensitive and sustained components. We conclude that serotonergic responses develop in motoneurons cultured under these conditions in the absence of serotonergic input, sensory neurons or many interneurons.

Effect of labour induction on rates of stillbirth and cesarean section in post-term pregnancies.

BACKGROUND: Meta-analyses of randomized controlled trials suggest that elective induction of labour at 41 weeks' gestation, compared with expectant management with selective labour induction, is associated with fewer perinatal deaths and no increase in the cesarean section rate. The authors studied the changes over time in the rates of labour induction in post-term pregnancies in Canada and examined the effects on the rates of stillbirth and cesarean section. METHODS: Changes in the proportion of total births at 41 weeks' and at 42 or more weeks' gestation, and in the rate of stillbirths at 41 or more weeks' (versus 40 weeks') gestation in Canada between 1980 and 1995 were determined using data from Statistics Canada. Changes in the rates of labour induction and cesarean section were determined using data from hospital and provincial sources. RESULTS: There was a marked increase in the proportion of births at 41 weeks' gestation (from 11.9% in 1980 to 16.3% in 1995) and a marked decrease in the proportion at 42 or more weeks (from 7.1% in 1980 to 2.9% in 1995). The rate of stillbirths among deliveries at 41 or more weeks' gestation decreased significantly, from 2.8 per 1000 total births in 1980 to 0.9 per 1000 total births in 1995 (p < 0.001). The stillbirth rate also decreased significantly among births at 40 weeks' gestation, from 1.8 per 1000 total births in 1980 to 1.1 per 1000 total births in 1995 (p < 0.001). The magnitude of the decrease in the stillbirth rate at 41 or more weeks' gestation was greater than that at 40 weeks' gestation (p < 0.001). All hospital and provincial sources of data indicated that the rate of labour induction increased significantly between 1980 and 1995 among women delivering at 41 or more weeks' gestation. The associated changes in rates of cesarean section were variable. INTERPRETATION: Between 1980 and 1995 clinical practice for the management of post-term pregnancy changed in Canada. The increased rate of labour induction at 41 or more weeks' gestation may have contributed to the decreased stillbirth rate but it had no convincing influence either way on the cesarean section rate.

Synaptic activity, induced rhythmic discharge patterns, and receptor subtypes in enriched primary cultures of embryonic rat motoneurones.

Long-term cultures of ventral horn neurones from embryonic rat spinal cord were established, after enrichment using density gradient centrifugation, to give a high proportion of cells (> 82%) with motoneurone characteristics. Neurones were grown on spinal cord glial monolayers for 4-83 days and investigated using whole-cell patch clamp. Synaptic activity interrupted by periods of quiescence increased in frequency with culture age and was suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and strychnine. However, strychnine (10 microM) or bicuculline (10-30 microM) or removal of Mg2+ alone induced patterned rhythmic bursting. Glutamate (3-300 microM), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA, 0.3-30 microM), and kainate (1-300 microM) evoked inward currents, as did N-methyl-D-aspartic acid (NMDA, 100 microM) in the absence of Mg2+ and presence of glycine (3-10 microM). Inward currents carried by Cl- were elicited by glycine (10-300 microM) and GABA (1-300 microM), while adenosine (1-10 microM) and cyclopentyladenosine (10 nM-1 microM) evoked a K(+)-dependent hyperpolarization. 5-HT, GABAB, purine A, and metabotropic glutamate receptors modulated synaptic excitation of presumed motoneurones. The results suggest that long-term cultures, containing more than 82% developing motoneurones, are able to generate rhythmic bursting; they respond to many of the neurotransmitters that are likely to be released onto motoneurones developing in vivo.

Immortalization of human marrow stromal cells by retroviral transduction with a temperature sensitive oncogene: identification of bipotential precursor cells capable of directed differentiation to either an osteoblast or adipocyte phenotype.

The etiology of osteoporosis is multifactorial, but there is evidence from both animal and human studies that the volume of marrow adipose tissue increases when bone volume is reduced in osteoporosis. The cell-related mechanism that may account for this inverse relationship between the volume of marrow adipose tissue and bone remains to be clarified, although it is known that both adipocytes and osteoblasts are derived from stromal cells precursors in bone marrow. We report that retroviral transduction with a temperature-sensitive oncogene (SV40 large T antigen) can generate bipotential cell lines from human marrow stroma that are capable of directed differentiation, in vitro, down either an osteogenic or adipocytic lineage pathway. One such clone, designated hOP 7, expresses type alpha 1(I) procollagen and has low alkaline phosphatase (AP) activity under basal culture conditions that is reminiscent of an osteoprogenitor cell. Exposure of hOP 7 cells to dexamethasone upregulates AP activity and enables the cells to mineralize their extracellular matrix. Also, treatment with calcitriol induces osteocalcin expression and both PTH and PGE2 induce/augment cAMP formation. Incubation with normal rabbit serum, however, causes the cells to become adipogenic as demonstrated by histological staining with Oil-red-O, expression of mRNA for the early and late adipocyte markers lipoprotein lipase and glycerol 3-phosphate dehydrogenase, respectively, and loss of type alpha 1(I) procollagen mRNA. The generation of homogeneous populations of these cells, as confirmed by Southern blot analysis, demonstrates the capacity of a human clonal cell line to differentiate in either an osteogenic or adipogenic direction.

Maternal colonization with group B Streptococcus and prelabor rupture of membranes at term: the role of induction of labor. TermPROM Study Group.

OBJECTIVES: Our purpose was to determine the effect of induction of labor on neonatal infection if mothers are group B streptococci positive and have prelabor rupture of membranes at term. STUDY DESIGN: In the TermPROM study 5041 women were randomized to induction with intravenous oxytocin, induction with vaginal prostaglandin E2 gel, or expectant management with induction, if needed. Of these, 4834 women had vaginal or introital swabs for group B streptococci taken at entry. We used logistic regression to test for effects of treatment within group B streptococci subgroups. RESULTS: Group B streptococci were predictive of neonatal infection for the induction with vaginal prostaglandin E2 gel and expectant groups but not for the induction with oxytocin group. For women positive for group B streptococci the rates of neonatal infection were 2.5% for the induction with oxytocin group and > 8% for all other groups. CONCLUSIONS: Induction of labor with intravenous oxytocin may be preferable for group B streptococci-positive women with prelabor rupture of membranes at term.

Identification of 5-HT receptor sub-types in a homogeneous population of presumptive serotoninergic neurones.

The expression of the known rat 5-HT receptor sub-types has been analyzed in a presumptive serotoninergic cell line derived from the rat raphé nuclei, using reverse transcription followed by polymerase chain reaction. By manipulating the activity of the oncogene (ts-SV40T) product used to immortalize the serotoninergic precursors, it has been possible to compare the expression of the 5-HT receptors in either replicative or differentiating cells. 5-HT1B, 5-HT1D, 5-HT3, 5-HT6 and 5-HT7 receptor gene expression were all observed in the replicating cells. However, under differentiation conditions, expression of all except the 5-HT1B receptor was lost. Only one novel amplification product appeared during early differentiation, in the 5-HT2B lane; its smaller than expected size was suggestive of a previously undescribed alternate splicing of the mRNA in brain. The curtailment of 5-HT receptor expression in differentiating neurones in vitro may reflect the normal ongoing restriction in the phenotypic potential during embryogenesis in vivo. The serotonin cells, therefore, constitute a pristine cell line in which to study the receptor pharmacology of one or more 5-HT receptor sub-types in isolation.

p53 protein expression in malignant, pre-malignant and non-malignant lesions of the lip.

AIM: To elucidate the role of the p53 tumour suppressor gene in the pathogenesis of lip cancer. METHODS: Expression of p53 was evaluated immunocytochemically in a retrospective study of formalin fixed, paraffin wax embedded tissue. Five cases each of four types of lip lesions were studied; these comprised squamous cell carcinoma (SCC), solar keratosis (SK), chronic hyperplastic candidosis (CHC), and lichen planus (LP). Five cases each of normal lip mucosa, SCC, and SK from sun exposed facial skin as well as LP, CHC, and SCC from buccal mucosa were also analysed. Immunolocalisation of p53 was scored semiquantitatively. The degree of apoptosis was also assessed in selected lesions by determining cell nuclear fragmentation. RESULTS: All SCCs from lip lesions were immunopositive for p53. All cases of SK and two of five CHC lip lesions were also p53 positive. Normal lip mucosa samples were p53 negative. Sun exposed skin lesions of SCC and SK were all positive for p53, but only three of five cases of SCC from the buccal mucosa had detectable levels of p53. p53 expression was not detected in CHC and LP lesions of the buccal mucosa. CONCLUSIONS: The aberrant expression of p53 is likely to occur early in the pathogenesis of lip cancer and may be related to exposure to the sun. The immunopositive p53 cells identified in the benign LP lesions do not necessarily correlate with commitment of cells within the lesion to programmed cell death. In light of the prior reports which indicate that p53 positive cells may progress to form malignant tumours, it is suggested that patients with p53 positive but otherwise benign lesions should be followed more closely.

Acquisition of conditioned inhibition in rats is impaired by ablation of serotoninergic pathways.

The effects of chronically ablating the serotoninergic inputs to various regions of the rat brain on the ability to solve a feature-negative discrimination was measured. After intracerebroventricular administration of the specific neurotoxin 5,7-dihydroxytryptamine, the rats exhibited an impaired capacity to solve such a discrimination, irrespective of whether auditory or visual stimuli were used. Further behavioural analysis revealed that this effect was not due to a reduced capacity to form excitatory associations, since both groups responded equally to reinforced stimuli. By contrast, the lesion more likely resulted in a failure to endow the non-reinforced stimuli with inhibitory properties. This suggestion was supported by the observation that, in a retardation test, the conditioned inhibitor aroused less inhibition in the lesioned group than in vehicle-injected controls. Furthermore, the conditioned inhibitor failed to pass a summation test in lesioned animals, again indicating that their hampered ability to master the discrimination was the result of an impairment in the formation of inhibitory associations. It is concluded that destruction of central 5-hydroxytryptamine-containing pathways impairs the functioning of brain areas underlying inhibitory associative learning.

Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma.

PURPOSE: To determine whether modifying the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) from full doses given every 3 weeks to one-third doses given weekly (chop) increases the received chemotherapy dose-intensity in elderly patients with advanced-stage intermediate-grade lymphoma. PATIENTS AND METHODS: Consenting patients, age > or = 65 years who had acceptable cardiac, renal, and liver function and an Eastern Cooperative Oncology Group (ECOG) performance status less than 4, were stratified by bone marrow and performance status and randomized to receive standard CHOP or weekly chop. Drug doses were attenuated or escalated according to a defined dose-modification schedule. The primary outcome was average relative received dose-intensity. Secondary outcomes included response, progression-free and overall survival, toxicity, and performance status. RESULTS: Nineteen patients were allocated to each group. No difference in received dose-intensity was seen. When dose-intensity was calculated for the first six cycles of therapy, average relative received dose-intensity was .92 with CHOP versus .89 with weekly chop (P = .5); when calculated for the first 18 weeks of therapy, values were .88 with CHOP versus .89 with weekly chop (P = .8). The complete response rate was 68% with CHOP versus 74% with weekly chop (P = .9). At 2 years, the progression-free survival rate was 57% with CHOP versus 46% with weekly chop (P = .16) and the survival rate was 74% with CHOP versus 51% with weekly chop (p = .05). More myelotoxicity was seen with CHOP. CONCLUSION: We conclude that CHOP can be given in sufficient doses to elderly patients and that weekly chop does not increase received dose-intensity. Progression-free and overall survival are unlikely to be superior with weekly chop, and may be worse. CHOP should remain the standard against which new therapies for elderly patients with intermediate-grade lymphoma are compared.

Action potential-dependent output of 5-hydroxytryptamine in the anaesthetized rat amygdalopiriform cortex is strongly inhibited by tonic 5-HT1B-receptor stimulation.

The output of 5-hydroxytryptamine (5-HT) from the amygdalopirifrom cortex has been measured in anaesthetized rats using intracerebral microdialysis followed by HPLC analysis. Basal output overall of 5-HT was 2.558 +/- 0.351 fmol/20 min sampling period. Application of the 5-HT antagonist metergoline through the dialysis probe resulted in a greater than 10-fold increase in the overflow of 5-HT. The major portion of this increase occurred in the range 1-3 microM metergoline, and was completely attenuated by inclusion of tetrodotoxin. More specific 5-HT antagonists, such as cyanopindolol, also enhanced output, but to a lesser extent. The pharmacological profile of the receptors mediating the effect was similar to that of the 5-HT1B type, which are often found presynaptically on 5-HT-containing nerve terminals. Other drugs were also capable of altering the output of 5-HT; in particular, muscimol reduced dialysate 5-HT content, while propranolol increased it. The 5-HT uptake inhibitor citalopram significantly increased the overflow of 5-HT, but only by about 80% above basal levels. It is concluded that the release of 5-HT from the rat amygdalopiriform cortex in vivo is tightly restricted due to activation of 5-HT1B receptors. Small alterations in such activation, however, can lead to large changes in 5-HT output, suggesting a possible mechanism by which neurotransmission through the amygdalopiriform cortex may become unstably amplified. These results may be of significance to the generation of epileptic activity in the amygdala or piriform cortex.

Antimicrobial activity of ceftriaxone compared with cefotaxime in the presence of serum albumin.

The effect of serum albumin on the antimicrobial activity of ceftriaxone, cefotaxime, and a 1:1 ratio of cefotaxime and its desacetyl metabolite against nonpseudomonal Gram-negative bacilli was determined. Antimicrobial activity of drugs was evaluated by measuring minimum inhibitory (mic) and bactericidal (mbc) concentrations in broth with and without human serum albumin. The analysis of logarithmically transformed mean mics and mbcs showed that there was a highly significant interaction between drug and serum albumin (P<0.0001). The inhibitory and bactericidal activities were greatest for cefotaxime followed by cefotaxime/desacetylcefotaxime and ceftriaxone (P<0.01). Time-kill kinetics demonstrated that ceftriaxone was less bactericidal than cefotaxime in broth with albumin. On the basis of these results it was concluded that the in vitro antimicrobial activity of ceftriaxone compared with that of cefotaxime was significantly diminished in the presence of serum albumin.

Raphé neural cells immortalized with a temperature-sensitive oncogene: differentiation under basal conditions down an APUD cell lineage.

Dividing cells from the midline of the ventral rhombencephalon and medulla oblongata have been transduced with a modulatable oncogene, (ts)SV40-T, using retroviral gene transfer. At the permissive temperature of the oncogene (33 degrees C), cells replicated and were isolated as individual, homogeneous clones. The effects of simply raising the temperature to the oncogene's non-permissive value, namely 39 degrees C, were analyzed by immunohistochemical methods. In one clone in particular (921202-6), cells ceased replication and started to differentiate. Certain neuronal characteristics became apparent: neurone-specific enolase-like immunoreactivity developed, as did the ability to take up exogenously applied 5-hydroxytryptamine (5HT). In addition, the cells took up exogenous 5-hydroxytryptophan (5HTP), and subsequently decarboxylated it to 5HT. However, they were unable to synthesize immunohistochemically detectable amounts of 5HT using L-tryptophan as a precursor. No 5HT uptake was found either in mitotic cells of this clone held at 33 degrees C, or in several other neuronal clones differentiating at 39 degrees C. Neither the neuronal nor the serotoninergic characteristics of clone 921202-6 developed in the presence of retinoic acid. It is concluded that 921202-6 cells differentiate under basal conditions down a neuronal pathway typical of an APUD cell, and that the choice of this pathway is made prior to the end of cell cycling. Furthermore, predisposition of the precursor cells to the neuronal/APUD phenotype can be overridden by extraneous epigenetic factors.