Development of predictive nomograms for clinical use to quantify the risk of isolating resistance prone organisms in patients with infected foot ulcers.

Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) have been considered prevalent pathogens in foot infections. However, whether empiric therapy directed against these organisms is necessary, and in whom to consider treatment, is rather unclear. The aim of this study was to develop predictive algorithms for forecasting the probability of isolating these organisms in the infected wounds of patients in a population where the prevalence of resistant pathogens is low. This was a retrospective study of regression model-based risk factor analysis that included 140 patients who presented with infected, culture positive foot ulcers to two urban hospitals. A total of 307 bacteria were identified, most frequently MRSA (11.1%). P. aeruginosa prevalence was 6.5%. In the multivariable analysis, amputation (odds ratio (OR) 5.75, 95% confidence interval (CI) 1.48-27.63), renal disease (OR 5.46, 95% CI 1.43-25.16) and gangrene (OR 2.78, 95% CI 0.82-9.59) were identified as risk factors associated with higher while diabetes (OR 0.07, 95% CI 0.01-0.34) and Infectious Diseases Society of America infection severity >3 (OR 0.18, 95% CI 0.03-0.65) were associated with lower odds of P. aeruginosa isolation (C statistic 0.81). Similar analysis for MRSA showed that amputation was associated with significantly lower (OR 0.29, 95% CI 0.09-0.79) risk, while history of MRSA infection (OR 5.63, 95% CI 1.56-20.63) and osteomyelitis (OR 2.523, 95% CI 1.00-6.79) was associated with higher odds of isolation (C statistic 0.69). We developed two predictive nomograms with reasonable to strong ability to discriminate between patients who were likely of being infected with P. aeruginosa or MRSA and those who were not. These analyses confirm the association of some, but also question the significance of other frequently described risk factors in predicting the isolation of these organisms.

Improving the quality of systematic reviews of neurological conditions: an assessment of current practice and the development and validation of six new search strategies.

BACKGROUND AND PURPOSE: Our aim was to study the quality of the literature search strategies used in recent systematic reviews and to develop and assess the diagnostic accuracy of six new search strategies (i.e. hedges). METHODS: Six neurological conditions were studied: migraine, stroke, dementia, epileptic seizures, Parkinson's disease and multiple sclerosis. Two reviewers independently assessed the quality of the search strategies used in systematic reviews published in 2015-2016. Complex hedges pertaining to the six conditions for use in Ovid MEDLINE were developed. Their diagnostic accuracy was compared to simple, single-term keyword searches. RESULTS: Almost 60% of quality criteria for the overall literature search strategy used in 182 systematic reviews were not respected. Over 30% of search strategies relied on a single keyword to identify the neurological condition. The sensitivities of our complex hedges amongst 10 311 articles were between 83% and 95%, significantly higher than the simple keyword searches (as low as 48%). The specificities were greater than 97%. CONCLUSIONS: There is great room for improvement in the search strategies used in systematic reviews of neurological conditions. Complex hedges were developed and validated to improve the accuracy of such searches. It is expected that this will lead to higher quality systematic reviews and meta-analyses.

Hydrogen-poor superluminous stellar explosions.

Supernovae are stellar explosions driven by gravitational or thermonuclear energy that is observed as electromagnetic radiation emitted over weeks or more. In all known supernovae, this radiation comes from internal energy deposited in the outflowing ejecta by one or more of the following processes: radioactive decay of freshly synthesized elements (typically (56)Ni), the explosion shock in the envelope of a supergiant star, and interaction between the debris and slowly moving, hydrogen-rich circumstellar material. Here we report observations of a class of luminous supernovae whose properties cannot be explained by any of these processes. The class includes four new supernovae that we have discovered and two previously unexplained events (SN 2005ap and SCP 06F6) that we can now identify as members of the same class. These supernovae are all about ten times brighter than most type Ia supernova, do not show any trace of hydrogen, emit significant ultraviolet flux for extended periods of time and have late-time decay rates that are inconsistent with radioactivity. Our data require that the observed radiation be emitted by hydrogen-free material distributed over a large radius (∼10(15) centimetres) and expanding at high speeds (>10(4) kilometres per second). These long-lived, ultraviolet-luminous events can be observed out to redshifts z > 4.

Population pharmacokinetic analysis of lanicemine (AZD6765), an NMDA channel blocker, in healthy subjects and patients with major depressive disorder.

WHAT IS KNOWN AND OBJECTIVE: Lanicemine (AZD6765) is a low-trapping N-methyl-d-aspartate receptor channel blocker that has demonstrated antidepressant efficacy in three of four clinical studies. The aim of this study was to develop a population pharmacokinetic model describing the concentration vs time profile of intravenously administered lanicemine in healthy subjects and patients with major depressive disorder (MDD) and to use the model to evaluate the impact of demographic and clinical factors and concomitant medication on the pharmacokinetics of lanicemine. METHODS: Data were derived from four studies: two Phase I trials in healthy subjects (studies 8 [NCT01069822] and 13 [NCT00785915]) and two Phase II trials in patients with MDD (studies 1 [NCT00491686] and 9 [NCT00781742]). Population pharmacokinetic analysis was performed by nonlinear mixed-effects modelling. The covariates evaluated within the model included sex, race, age and body weight parameters, clinically relevant laboratory measures, and use of concomitant medications. Goodness-of-fit plots, bootstrap and visual predictive checks were conducted to confirm concordance with observed data. RESULTS AND DISCUSSION: A total of 2531 plasma lanicemine concentrations were available for analysis from 191 healthy subjects and patients with MDD. The pharmacokinetics of lanicemine following intravenous infusion was best described by a two-compartment model with zero-order input and first-order elimination. Mean systemic clearance (CL) was estimated at 9.43 L/h (90% CI 9.12-9.77), central compartment volume of distribution (V1) was 106 L (90% CI 93.7-115), peripheral volume of distribution (V2) was 47.3 (95% CI 39.6-56.6), and intercompartmental clearance (Q) was 75.7 (90% CI 51.8-127). Lean body mass and body surface area had a statistically significant effect on CL and V1, respectively. WHAT IS NEW AND CONCLUSIONS: The population pharmacokinetic model developed adequately described the clinical observation of lanicemine in patients with MDD and healthy volunteers. Lean body mass and body surface area were identified as covariates that significantly influence the pharmacokinetics of lanicemine.

Molecular detection, risk factors, and phylogenetic analysis of tick-borne pathogens in dogs from northern Vietnam.

In tropical regions, numerous tick-borne pathogens (TBPs) play a crucial role as causative agents of infectious diseases in humans and animals. Recently, the population of companion and pet dogs has significantly increased in Vietnam; however, information on the occurrence of TBPs is still limited. The objectives of this investigation were to determine the occurrence rate, risk factors, and phylogenetic characteristics of TBPs in dogs from northern Vietnam. Of 341 blood samples tested by PCR, the total infection of TBPs was 73.9% (252/341). Babesia vogeli (18SrRNA gene - 30.5%) was detected most frequently in studied dogs followed by Rickettsia spp. (OmpA gene - 27%), Anaplasma platys (groEL gene - 22%), Bartonella spp. (16SrRNA - 18.8%), Mycoplasma haemocanis (16SrRNA - 9.4%) and Hepatozoon canis (18SrRNA gene - 1.2%), respectively. All samples were negative for Ehrlichia canis and Anaplasma phagocytophylum. Co-infection was detected in 31.4% of the samples (107/341) of which, A. platys/Bartonella spp. (34/94,10%), Rickettsia spp./B. vogeli (19/94, 5.6%), and M. haemocanis/B. vogeli (19/94, 5.6%) were recorded as the three most frequent two species of co-infection types. Statistical analysis revealed a significant correlation between TBP infection and several host variables regarding age, breed, and living area in the current study. The recent findings reported herein, for the first time in Vietnam, are essential for local veterinarians when considering the appropriate approaches for diagnosing these diseases. Furthermore, this data can be used to establish control measures for future surveillance and prevention strategies against canine TBPs in Vietnam.

The effects of different types of statins on proliferation and migration of HGF-induced Human Umbilical Vein Endothelial Cells (HUVECs).

BACKGROUND AND AIM: Statins are HMG-CoA reductase inhibitors within the framework of cholesterol biosynthesis and used to lower the low-density lipoprotein (LDL). There are other aspects of statins can deploy a protective effect, even without the LDL's lowering. The aim of this study is to investigate the effects of different type of statins on proliferative and migrative behaviors of Hepatocyte Growth Factor (HGF) induced human umbilical vein endothelial cells (HUVECs). MATERIALS AND METHODS: Human umbilical vein endothelial cells were isolated and cultured. Groups were designed in order to observe the effects of every individual substance. HUVECs were stimulated with HGF, statins and farnesylpyrophosphat ammonium salt (FPP) or geranylgeranyl-pyrophosphate (GGPP), respectively. Cell proliferations were counted 48 hours after initial stimuli and distances between migration fronts were used in migration analyses. RESULTS: All types of statins showed significant anti-migrative and anti-proliferative characters. Simvastatin and fluvastatin but not cerivastatin, were able to inhibit the HGF-depending migration and showed a significant effect on the inhibition of the isoprenylation (GGPP). Only simvastatin influenced the HGF-depending migration via inhibiting the isoprenylation process through GGPP. Cerivastatin significantly decreased the proliferation and Fluvastatin significantly enhanced the migration behaviors of HUVECs when they were co-incubated with methyl-8-cyclodextrin (MCD). CONCLUSIONS: Statins countermand the proproliferative and as well as the promigrative effect of HGF on HUVECs. The mechanisms which provoke this effect are dependent on the type of statin. Direct interactions of statins with lipid rafts play a significant role in the endothelial cell mechanisms.

Molecular architecture of the ciliary tip revealed by cryo-electron tomography.

Cilia are essential organelles that protrude from the cell body. Cilia are made of a microtubule-based structure called the axoneme. In most types of cilia, the ciliary tip is distinct from the rest of the cilium. Here, we used cryo-electron tomography and subtomogram averaging to obtain the structure of the ciliary tip of the ciliate Tetrahymena thermophila. We show the microtubules in the tip are highly cross-linked with each other and stabilised by luminal proteins, plugs and cap proteins at the plus ends. In the tip region, the central pair lacks the typical projections and twists significantly. By analysing cells lacking a ciliary tip-enriched protein CEP104/FAP256 by cryo-electron tomography and proteomics, we discovered candidates for the central pair cap complex and explain potential functions of CEP104/FAP256. These data provide new insights into the function of the ciliary tip and inform about the mechanisms of ciliary assembly and length regulation.

Preclinical pharmacology of AZD2327: a highly selective agonist of the δ-opioid receptor.

In the present article, we summarize the preclinical pharmacology of 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327), a highly potent and selective agonist of the δ-opioid receptor. AZD2327 binds with sub-nanomolar affinity to the human opioid receptor (K(i) = 0.49 and 0.75 nM at the C27 and F27 isoforms, respectively) and is highly selective (>1000-fold) over the human µ- and κ-opioid receptor subtypes as well as >130 other receptors and channels. In functional assays, AZD2327 shows full agonism at human δ-opioid receptors ([(35)S]GTPγ EC(50) = 24 and 9.2 nM at C27 and F27 isoforms, respectively) and also at the rat and mouse δ-opioid receptors. AZD2327 is active in a wide range of models predictive of anxiolytic activity, including a modified Geller-Seifter conflict test and social interaction test, as well as in antidepressant models, including learned helplessness. In animals implanted with microdialysis probes and then given an acute stressor by pairing electric shock delivery with a flashing light, there is an increase in norepinephrine release into the prefrontal cortex associated with this acute anxiety state. Both the benzodiazepine anxiolytic standard diazepam and AZD2327 blocked this norepinephrine release equally well, and there was no evidence of tolerance to these effects of AZD2327. Overall, these data support the role of the δ-opioid receptor in the regulation of mood, and data suggest that AZD2327 may possess unique antidepressant and anxiolytic activities that could make a novel contribution to the pharmacotherapy of psychiatric disorders.

Investigating gradients of gene expression involved in early human cortical development.

The division of the neocortex into functional areas (the cortical map) differs little between individuals, although brain lesions in development can lead to substantial re-organization of regional identity. We are studying how the cortical map is established in the human brain as a first step towards understanding this plasticity. Previous work on rodent development has identified certain transcription factors (e.g. Pax6, Emx2) expressed in gradients across the neocortex that appear to control regional expression of cell adhesion molecules and organization of area-specific thalamocortical afferent projections. Although mechanisms may be shared, the human neocortex is composed of different and more complex local area identities. Using Affymetrix gene chips of human foetal brain tissue from 8 to 12.5 post-conceptional weeks [PCW, equivalent to Carnegie stage (CS) 23, to Foetal stage (F) 4], human material obtained from the MRC-Wellcome Trust Human Developmental Biology Resource (http://www.hdbr.org), we have identified a number of genes that exhibit gradients along the anterior-posterior axis of the neocortex. Gene probe sets that were found to be upregulated posteriorally compared to anteriorally, included EMX2, COUPTFI and FGF receptor 3, and those upregulated anteriorally included cell adhesion molecules such as cadherins and protocadherins, as well as potential motor cortex markers and frontal markers (e.g. CNTNAP2, PCDH17, ROBO1, and CTIP2). Confirmation of graded expression for a subset of these genes was carried out using real-time PCR. Furthermore, we have established a dissociation cell culture model utilizing tissue dissected from anteriorally or posteriorally derived developing human neocortex that exhibits similar gradients of expression of these genes for at least 72 h in culture.

A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling.

A conserved domain in the extracellular region of the 60- and 80-kilodalton tumor necrosis factor receptors (TNFRs) was identified that mediates specific ligand-independent assembly of receptor trimers. This pre-ligand-binding assembly domain (PLAD) is physically distinct from the domain that forms the major contacts with ligand, but is necessary and sufficient for the assembly of TNFR complexes that bind TNF-alpha and mediate signaling. Other members of the TNFR superfamily, including TRAIL receptor 1 and CD40, show similar homotypic association. Thus, TNFRs and related receptors appear to function as preformed complexes rather than as individual receptor subunits that oligomerize after ligand binding.

Pharmacometric Modeling of Naloxegol Efficacy and Safety: Impact on Dose and Label.

Naloxegol is a peripherally acting µ-opioid receptor antagonist that was developed for the treatment of opioid-induced constipation. Modeling and simulation of naloxegol efficacy and tolerability informed selection of doses for phase III studies and provided comprehensive dosage recommendations for the naloxegol US package insert.

Simulation and Prediction of the Drug-Drug Interaction Potential of Naloxegol by Physiologically Based Pharmacokinetic Modeling.

Naloxegol, a peripherally acting µ-opioid receptor antagonist for the treatment of opioid-induced constipation, is a substrate for cytochrome P450 (CYP) 3A4/3A5 and the P-glycoprotein (P-gp) transporter. By integrating in silico, preclinical, and clinical pharmacokinetic (PK) findings, minimal and full physiologically based pharmacokinetic (PBPK) models were developed to predict the drug-drug interaction (DDI) potential for naloxegol. The models reasonably predicted the observed changes in naloxegol exposure with ketoconazole (increase of 13.1-fold predicted vs. 12.9-fold observed), diltiazem (increase of 2.8-fold predicted vs. 3.4-fold observed), rifampin (reduction of 76% predicted vs. 89% observed), and quinidine (increase of 1.2-fold predicted vs. 1.4-fold observed). The moderate CYP3A4 inducer efavirenz was predicted to reduce naloxegol exposure by ∼50%, whereas weak CYP3A inhibitors were predicted to minimally affect exposure. In summary, the PBPK models reasonably estimated interactions with various CYP3A modulators and can be used to guide dosing in clinical practice when naloxegol is coadministered with such agents.

Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children.

Predictive performance of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models of drugs predominantly eliminated through kidney in the pediatric population was evaluated. After optimization using adult clinical data, the verified PBPK models can predict 33 of 34 drug clearance within twofold of the observed values in children 1 month and older. More specifically, 10 of 11 of predicted clearance values were within 1.5-fold of those observed in children between 1 month and 2 years old. The PopPK approach also predicted 19 of 21 drug clearance within twofold of the observed values in children. In summary, our analysis demonstrated both PBPK and PopPK adult models, after verification with additional adult pharmacokinetic (PK) studies and incorporation of known ontogeny of renal filtration, could be applied for dosing regimen recommendation in children 1 month and older for renally eliminated drugs in a first-in-pediatric study.

Detection of Germline Mutation in Hereditary Breast and/or Ovarian Cancers by Next-Generation Sequencing on a Four-Gene Panel.

Mutation in BRCA1/BRCA2 genes accounts for 20% of familial breast cancers, 5% to 10% of which may be due to other less penetrant genes which are still incompletely studied. Herein, a four-gene panel was used to examine the prevalence of BRCA1, BRCA2, TP53, and PTEN in hereditary breast and ovarian cancers in Southern Chinese population. In this cohort, 948 high-risk breast and/or ovarian patients were recruited for genetic screening by next-generation sequencing (NGS). The performance of our NGS pipeline was evaluated with 80 Sanger-validated known mutations and eight negative cases. With appropriate bioinformatics analysis pipeline, the detection sensitivity of NGS is comparable with Sanger sequencing. The prevalence of BRCA1/BRCA2 germline mutations was 9.4% in our Chinese cohort, of which 48.8% of the mutations arose from hotspot mutations. With the use of a tailor-made algorithm, HomopolymerQZ, more mutations were detected compared with single mutation detection algorithm. The frequencies of PTEN and TP53 were 0.21% and 0.53%, respectively, in the Southern Chinese patients with breast and/or ovarian cancers. High-throughput NGS approach allows the incorporation of control cohort that provides an ethnicity-specific data for polymorphic variants. Our data suggest that hotspot mutations screening such as SNaPshot could be an effective preliminary screening alternative adopted in a standard clinical laboratory without NGS setup.

Bioequivalence of 20-mg once-daily tamoxifen relative to 10-mg twice-daily tamoxifen regimens for breast cancer.

PURPOSE: We studied the bioequivalence of a new once-daily regimen of tamoxifen citrate relative to the standard twice-daily regimen of tamoxifen citrate, an established antiestrogenic treatment for breast cancer. PATIENTS AND METHODS: Of 30 women with breast cancer, 27 completed this open, two-period, crossover randomized trial. During one 3-month period, patients took one standard 10-mg tamoxifen tablet twice daily; during the preceding or following 3-month period, patients took one of the new 20-mg tablets once daily. Pharmacokinetic profiles and safety parameters were assessed at the end of each 3-month treatment period. RESULTS: Overall, measured concentrations of tamoxifen and its principal active metabolite, N-desmethyltamoxifen, remained relatively constant over the 24-hour sampling periods at the end of each treatment sequence. For both compounds, the percentage differences of the geometric means for all pharmacokinetic parameters indicated bioequivalence of the once-daily regimen of tamoxifen relative to the standard twice-daily regimen. Both treatment sequences were well tolerated; reported adverse events occurred at similar frequencies with the two treatment regimens. CONCLUSION: The 20-mg tamoxifen tablet taken once daily was bioequivalent to the 10-mg tamoxifen tablet taken twice daily, with no difference in relative risk. The once-daily treatment is a simpler regimen and may facilitate compliance, which may enhance therapeutic outcomes during long-term treatment of breast cancer.

Decreased uptake of 3H-serotonin and endogenous content of serotonin in blood platelets in hypertensive patients.

The uptake and content of serotonin in blood platelets were studied in patients with essential hypertension and in five families in which at least one member was hypertensive. Blood was obtained from male and female normotensive volunteers and hypertensive patients who were free of medication. Lineweaver-Burk plots of 3H-serotonin uptake from both control subjects and hypertensive patients were linear, which suggested simple Michaelis-Menten uptake kinetics. The maximal uptake velocity (Vmax) in hypertensive patients was significantly lower than in control subjects (control = 41.7 +/- 3.3 pmol/min/10(8) platelets, n = 17; hypertensive = 26.6 +/- 3.0 pmol/min/10(8) platelets, n = 16; p less than 0.005). The affinity constant (Km) was slightly but significantly lower in hypertensive patients (control = 0.70 +/- 0.08 microM; hypertensive = 0.46 +/- 0.08 microM; p less than 0.05). The serotonin content in blood platelets determined by high pressure liquid chromatography with electrochemical detection was significantly lower in hypertensive patients (control = 165.0 +/- 12.9 nmol/10(11) platelets, n = 29; hypertensive = 105.9 +/- 10.4 nmol/10(11) platelets, n = 27; p less than 0.001). In the five families investigated, the lowered serotonin content was observed in some normotensive members. The reduced number of carriers of serotonin uptake and the slight decrease in the affinity constant observed in platelets of patients with essential hypertension suggest that serotonin metabolism is altered in essential hypertension and that blood platelets may be a useful model in studying the serotonergic modifications at the molecular level.

Plasma thromboxane and pulmonary artery pressure in neonates treated with extracorporeal membrane oxygenation.

To examine whether neonates with persistent pulmonary hypertension are subject to a thromboxane-mediated exacerbation of their pulmonary hypertension during extracorporeal membrane oxygenator therapy (a form of partial cardiopulmonary bypass), we performed serial measurements of plasma thromboxane B2 and pulmonary artery pressure before, during, and after extracorporeal membrane oxygenation. Pulmonary artery pressure was high before extracorporeal membrane oxygenation, did not increase after the start of this therapy, but began to decrease after 48 hours of extracorporeal membrane oxygenation. During the course of extracorporeal membrane oxygenation, mean pulmonary artery pressure decreased by 50% and mean plasma thromboxane B2 levels decreased by 70%. In addition, serial plasma thromboxane B2 levels were significantly correlated with pulmonary artery pressures in individual infants with a primary diagnosis of meconium aspiration (r = 0.965 to 0.723). We speculate that the decrease in pulmonary artery pressure and plasma thromboxane B2 levels over time may reflect resolution of acute lung injury and that thromboxane B2 may play a role in regulating pulmonary artery pressure in infants with meconium aspiration.

Plasma prostanoids in neonatal extracorporeal membrane oxygenation. Influence of meconium aspiration.

Thromboxane B2 may be a mediator of neonatal persistent pulmonary hypertension. Elevated levels of plasma thromboxane and prostacyclin have been described previously in hypoxic newborn infants with neonatal pulmonary hypertension. We measured serial plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha (stable metabolite of prostacyclin) in 21 newborn infants with severe respiratory failure and pulmonary hypertension who required extracorporeal membrane oxygenation support. We sought to study (1) the evolution of plasma prostanoids in pulmonary hypertensive infants treated with extracorporeal membrane oxygenation and (2) whether different pulmonary hypertensive diagnostic subgroups have distinctive prostanoid profiles. Our data indicated that infants with meconium aspiration had significantly lower levels of plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha while receiving extracorporeal membrane oxygenation than did infants with persistent pulmonary hypertension but no meconium aspiration. Levels of all infants decreased progressively as extracorporeal membrane oxygenation support continued.

Plasma prostanoids in neonates with pulmonary hypertension treated with conventional therapy and with extracorporeal membrane oxygenation.

Thromboxane may be a mediator of pulmonary hypertension in the neonate. Acute thromboxane-mediated pulmonary hypertension has been described in sheep receiving extracorporeal membrane oxygenation, which raises concerns about a potential thromboxane-mediated exacerbation of pulmonary hypertension in human neonates with severe pulmonary hypertension who are treated with extracorporeal membrane oxygenation. We measured plasma levels of thromboxane, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in infants with pulmonary hypertension, some of whom were treated medically and some of whom were treated with extracorporeal membrane oxygenation. Plasma levels of all three prostanoids were elevated in infants with pulmonary hypertension and decreased with time, whether the neonates were treated with extracorporeal membrane oxygenation or with medical management alone. In infants treated with extracorporeal membrane oxygenation, we collected samples simultaneously from preoxygenator sites, postoxygenator sites, and umbilical artery catheter. We could demonstrate no significant difference in plasma prostanoid levels across the oxygenator. In two patients, plasma thromboxane and prostaglandin F2 alpha levels measured shortly after a platelet transfusion were distinctly higher in the umbilical artery catheter than in venous samples.

Short-term lithium administration to healthy volunteers produces long-lasting pronounced changes in platelet serotonin uptake but not imipramine binding.

Platelet [3H]-5HT uptake, [3H]-imipramine binding and endogenous 5HT levels were measured in healthy volunteers during short-term (20 days) administration of lithium, and following its withdrawal. The Vmax of [3H]-5HT uptake was significantly decreased during lithium treatment. Following lithium withdrawal, platelet [3H]-5HT uptake (Vmax) remained decreased and was followed by a pronounced rebound effect in some of the subjects for up to 3 months. The affinity constant (Km) of [3H]-5HT uptake was not modified. Binding of tritiated imipramine during the same period and platelet 5HT levels measured till 14 days after withdrawal was not affected by lithium treatment. As lithium is devoid of in vitro effects on both 5HT uptake and imipramine binding, it is concluded that the effects of lithium on the 5HT transporter do not reflect a direct effect on the transporter complex. Our results indicate that lithium-induced changes at the level of 5HT uptake in platelets are not correlated with concomitant variations in platelet 5HT content and can be dissociated from modifications at the level of imipramine binding sites within the macromolecular complex of the 5HT transporter. Moreover, platelet 5HT uptake is apparently modulated by lithium, with a similar pattern in healthy volunteers and in manic-depressive patients.