Species selection determines carbon allocation and turnover in Miscanthus crops: Implications for biomass production and C sequestration.

Growing Miscanthus species and hybrids has received strong scientific and commercial support, with the majority of the carbon (C) modelling predictions having focused on the high-yield, sterile and noninvasive hybrid Miscanthus × giganteus. However, the potential of other species with contrasting phenotypic and physiological traits has been seldom explored. To better understand the mechanisms underlying C allocation dynamics in these bioenergy crops, we pulse-labelled (13CO2) intact plant-soil systems of Miscanthus × giganteus (GIG), Miscanthus sinensis (SIN) and Miscanthus lutarioriparius (LUT) and regularly analysed soil respiration, leaves, stems, rhizomes, roots and soils for up to 190 days until leaf senescence. A rapid isotopic enrichment of all three species was observed after 4 h, with the amount of 13C fixed into plant biomass being inversely related to their respective standing biomass prior to pulse-labelling (i.e., GIG < SIN < LUT). However, both GIG and LUT allocated more photoassimilates in the aboveground biomass (leaves+stems = 78 % and 74 %, respectively) than SIN, which transferred 30% of fixed 13C in its belowground biomass (rhizomes+roots). Although less fixed 13C was recovered from the soils (<1 %), both rhizospheric and bulk soils were signficantly more enriched under SIN and LUT than under GIG. Importantly, the soils under SIN emitted less CO2, which suggests it could be the best choice for reaching C neutrality. These results from this unique large-scale study indicate that careful species selection may hold the success for reaching net GHG mitigation.

Can we evidence-base injury prevention and management in women's football? A scoping review.

This review aimed, as part of a larger FIFA project aiming to steer women's football research, to scope literature on any level of competitive football for women, to understand the current quantity of research on women's football injuries. The study reviewed all injury-related papers scoped by a recent scoping review mapping all published women's football research with an updated search performed on 23 February 2021. Eligibility criteria assessment followed the recent scoping review with injury-specific research focus. A total of 497 studies were scoped. Most studies contained an epidemiological (N = 226; 45%) or risk factors assessment (N = 105; 21%). Less assessed areas included financial burden (N = 1; <1%) and injury awareness (N = 5; 1%). 159 studies (32%) assessed injuries of the whole body. The most common single location assessed in the literature was the knee (N = 134, 27%), followed by head/face (N =108, 22%). These numbers were, however, substantially lowered, when subdivided by playing level and age-group. The volume of research focuses especially on descriptive research and specific body locations (head/face and knee). Although information can be taken from studies in other sports, more football-specific studies to support management and prevention of injuries are warranted.

Osteoarthritic changes in the knees of recently retired male professional footballers: a pilot study.

Background: Knee osteoarthritis (OA) is common amongst retired male professional footballers. There is limited understanding with respect to the interplay between imaging findings, clinical presentation and patient-reported outcome measures (PROMs) in retired professional footballers with knee OA. Objectives: This pilot study aimed to evaluate the extent of radiological and clinical knee OA in a cohort of retired male professional footballers, and to explore the relationship between these findings and knee-related PROMs. Methods: Fifteen retired male professional footballers underwent knee radiographs and were surveyed on their history of clinical OA, severe knee injury and previous knee surgery. The Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS) and the Patient-Reported Outcomes Measurement Information System Global Health (PROMIS-GH) were used to assess health outcomes, such as level of function and pain. Results: Radiological knee OA was diagnosed in six out of 15 participants. Seven of the participants had a clinical diagnosis of knee OA. Evidence of clinical and radiological OA was present amongst four participants. Radiological knee OA and clinical OA was significantly associated with a history of severe knee injury and previous knee surgery. Low correlations (ρ<-0.40) were found between knee OA severity and knee-related PROMs. Moderate correlation (ρ=-0.65) was found between clinical knee OA and KOOS-SP. Conclusion: Clinical knee OA correlates with PROMs amongst retired professional footballers but radiological OA does not. Further studies are required to understand the relationship between imaging findings, clinical presentation and PROMs amongst retired professional footballers with knee OA.

Pattern Formation by Staphylococcus epidermidis via Droplet Evaporation on Micropillars Arrays at a Surface.

We evaluate the effect of epoxy surface structuring on the evaporation of water droplets containing Staphylococcus epidermidis (S. epidermidis). During evaporation, droplets with S. epidermidis cells yield to complex wetting patterns such as the zipping-wetting1-3 and the coffee-stain effects. Depending on the height of the microstructure, the wetting fronts propagate circularly or in a stepwise manner, leading to the formation of octagonal or square-shaped deposition patterns.4,5 We observed that the shape of the dried droplets has considerable influence on the local spatial distribution of S. epidermidis deposited between micropillars. These changes are attributed to an unexplored interplay between the zipping-wetting1 and the coffee-stain6 effects in polygonally shaped droplets containing S. epidermidis. Induced capillary flows during evaporation of S. epidermidis are modeled with polystyrene particles. Bacterial viability measurements for S. epidermidis show high viability of planktonic cells, but low biomass deposition on the microstructured surfaces. Our findings provide insights into design criteria for the development of microstructured surfaces on which bacterial propagation could be controlled, limiting the use of biocides.

Can illness beliefs, from the common-sense model, prospectively predict adherence to self-management behaviours? A systematic review and meta-analysis.

OBJECTIVE: To determine whether people's beliefs about their illness, conceptualised by the common sense model (CSM), can prospectively predict adherence to self-management behaviours (including, attendance, medication, diet and exercise) in adults with acute and chronic physical illnesses. DESIGN AND MAIN OUTCOME MEASURES: Electronic databases were searched in September 2014, for papers specifying the use of the 'CSM' in relation to 'self-management', 'rehabilitation' and 'adherence' in the context of physical illness. Six hundred abstracts emerged. Data from 52 relevant studies were extracted. Twenty-one studies were meta-analysed, using correlation coefficients in random effects models. The remainder were descriptively synthesised. RESULTS: The effect sizes for individual illness belief domains and adherence to self-management behaviours ranged from .04 to .13, indicating very weak, predictive relationships. Further analysis revealed that predictive relationships did not differ by the: type of self-management behaviour; acute or chronic illness; or duration of follow-up. CONCLUSION: Individual illness belief domains, outlined by the CSM, did not predict adherence to self-management behaviours in adults with physical illnesses. Prospective relationships, controlling for past behaviour, also did not emerge. Other factors, including patients' treatment beliefs and inter-relationships between individual illness beliefs domains, may have influenced potential associations with adherence to self-management behaviours.

Survey of the UK veterinary profession 2: sources of information used by veterinarians.

Access to the most up-to-date evidence is an important cornerstone for veterinarians attempting to practice in an evidence-based manner; therefore, an understanding of what and how information is accessed is vital. The aim of this study was to identify what resources the UK veterinary profession access and regard as most useful. Based on questionnaires received from veterinarians, the Veterinary Times was nominated as most often read journal or magazine by respondents (n=3572, 79 per cent). In Practice (n=3224, 82 per cent) and the Veterinary Record (n=165, 34 per cent) were seen as most useful by clinicians, and non-clinicians, respectively. Google was the most often nominated electronic resource by all respondents (n=3076, 71 per cent), with Google (n=459, 23 per cent) and PubMed (n=60, 17 per cent) seen as most useful by clinicians and non-clinicians, respectively. The abstract and conclusion sections were the most read parts of scientific manuscripts nominated by all respondents. When looking for assistance with difficult cases, colleagues were the common information choice for clinicians. Different sections of the veterinary profession access information, and deem resources useful, in different ways. Access to good quality evidence is important for the practice of evidence-based veterinary medicine, and therefore, researchers should think about disseminating their findings in a targeted way for optimal use by the profession.

The role of lattice parameter in water adsorption and wetting of a solid surface.

Ice formation is a complex cooperative process that is almost invariably catalysed by the presence of an interface on which ice crystals nucleate. As yet there is no clear picture of what factors make a surface particularly good at nucleating ice, but the importance of having a template with a suitable lattice parameter has often been proposed. Here we report the contrasting wetting behaviour of a series of pseudomorphic surfaces, designed to form an ordered template that matches the arrangement of water in a bulk ice Ih(0001) bilayer. The close-packed M(111) surfaces (M = Pt, Pd, Rh, Cu and Ni) form a (√3 × âˆš3) R30° Sn substitutional alloy surface, with Sn atoms occupying sites that match the symmetry of an ice bilayer. The lattice constant of the alloy changes from 4% smaller to 7% greater than the lateral spacing of ice across the series. We show that only the PtSn surface, with a lattice parameter some 7% greater than that of a bulk ice layer, forms a stable water layer, all the other surfaces being non-wetting and instead forming multilayer ice clusters. This observation is consistent with the idea that the repeat spacing of the surface should ideally match the O-O spacing in ice, rather than the bulk ice lattice parameter, in order to form a continuous commensurate water monolayer. We discuss the role of the lattice parameter in stabilising the first layer of water and the factors that lead to formation of a simple commensurate structure rather than an incommensurate or large unit cell water network. We argue that lattice match is not a good criteria for a material to give low energy nucleation sites for bulk ice, and that considerations such as binding energy and mobility of the surface layer are more relevant.

Survey of the UK veterinary profession: common species and conditions nominated by veterinarians in practice.

The practice of evidence-based veterinary medicine involves the utilisation of scientific evidence for clinical decision making. To enable this, research topics pertinent to clinical practice need to be identified, and veterinary clinicians are best placed to do this. The main aim of this study was to describe the veterinary population, the common species and conditions veterinary clinicians nominated they saw in practice and how much information clinicians perceived was available in the literature for these. A questionnaire was distributed to all Royal College of Veterinary Surgeons registered veterinarians agreeing to be contacted for research purposes (n=14,532). A useable response rate of 33 per cent (4842/14,532) was achieved. The most commonly seen species reported by vets were dogs, cats and rabbits followed by equines and cattle. Overall, skin conditions were most commonly mentioned for small animals, musculoskeletal conditions for equines and reproduction conditions for production animals. Veterinary clinicians perceived there was a higher level of information available in the literature for conditions in dogs, cattle and equines and lower levels for rabbits and guinea pigs. The results from this study can be used to help define the research needs of the profession to aid the incorporation of evidence in veterinary practice.

Somatodendritic 5-hydroxytryptamine1A (5-HT1A) autoreceptor function in major depression as assessed using the shift in electroencephalographic frequency spectrum with buspirone.

BACKGROUND: Positron emission tomography and post-mortem studies of the number of somatodendritic 5-hydroxytryptamine(1A) (5-HT(1A)) autoreceptors in raphé nuclei have found both increases and decreases in depression. However, recent genetic studies suggest they may be increased in number and/or function. The current study examined the effect of buspirone on the electroencephalographic (EEG) centroid frequency, a putative index of somatodendritic 5-HT(1A) receptor functional status, in a cohort of medication-free depressed patients and controls. METHOD: A total of 15 depressed patients (nine male) and intelligence quotient (IQ)-, gender- and age-matched healthy controls had resting EEG recorded from 29 scalp electrodes prior to and 30, 60 and 90 min after oral buspirone (30 mg) administration. The effect of buspirone on somatodendritic 5-HT(1A) receptors was assessed by calculating the EEG centroid frequency between 6 and 10.5 Hz. The effect of buspirone on postsynaptic 5-HT(1A) receptors was assessed by measuring plasma growth hormone, prolactin and cortisol concentrations. RESULTS: Analysis of variance revealed a significantly greater effect of buspirone on the EEG centroid frequency in patients compared with controls (F1,28 = 6.55, p = 0.016). There was no significant difference in the neuroendocrine responses between the two groups. CONCLUSIONS: These findings are consistent with an increase in the functional status of somatodendritic, but not postsynaptic, 5-HT1A autoreceptors, in medication-free depressed patients in line with hypotheses based on genetic data. This increase in functional status would be hypothesized to lead to an increase in serotonergic negative feedback, and hence decreased release of 5-HT at raphé projection sites, in depressed patients.

U-500R and aspart insulin for the treatment of severe insulin resistance in pregnancy associated with pregestational diabetes.

Severe insulin resistance as a complication of diabetes in pregnancy is seen with increasing frequency. Treatment with large doses of insulin (>300 units perday) can be practically difficult. A woman with preexisting Type 2 diabetes mellitus and poor glycemic control presented in early pregnancy requiring over 1000 units of insulin daily. She was transitioned to subcutaneous U-500 (concentrated regular insulin) in combination with a rapid-acting insulin analog achieving good glycemic control and good maternal and fetal outcomes. U-500R insulin in conjunction with a rapid-acting insulin analog can be used safely in early pregnancy to improve glycemic control in severe insulin resistance due to pregestational diabetes.

Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I-II study.

BACKGROUND: To establish the recommended dose level (RDL) and to evaluate the efficacy and safety of gefitinib plus irinotecan in patients with advanced fluoropyrimidine-refractory colorectal cancer (CRC). PATIENTS AND METHODS: Patients with advanced CRC progressing on or within 12 weeks of fluoropyrimidine-based chemotherapy, irinotecan naive and performance status of two or less were recruited. During dose-finding phase, dose-limiting toxicity (DLT) was encountered at dose level 1, therefore subsequent dose de-escalation and pharmacokinetic (PK) studies were carried out. The RDL was then expanded in a multicentre setting to further evaluate safety and efficacy. RESULTS: From June 2002 to February 2005, 39 patients were treated in total with 27 at the RDL. The RDL was established at irinotecan 225 mg/m(2) every 3 weeks and gefitinib 250 mg daily. The DLTs were neutropenia and diarrhoea. For the patients treated at RDL, the objective tumour response rate was 11.1% (95% confidence interval 2.4% to 29.2%) and median survival was 9.3 months. PK studies indicated that the addition of irinotecan to gefitinib resulted in an average of 50% increase in exposure to gefitinib (P < 0.05), but gefitinib did not alter the PK profiles of irinotecan or SN-38. Grade 3-4 toxic effects in all patients included diarrhoea (35.9%), lethargy (15.4%), neutropenia (15.4%), febrile neutropenia (10.3%) and skin rash (7.7%). CONCLUSIONS: Irinotecan and gefitinib at this dose schedule was tolerable, but gefitinib did not appear to add substantial efficacy to irinotecan.

CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials.

In a multivariate analysis of 154 patients receiving chemotherapy, baseline CA19-9 was an independent prognostic factor for overall survival (OS) (HR 1.8; 95% CI: 1.3-2.5, P = 0.0004). The 1-year OS was 19 and 46%, respectively, for patients with a baseline CA19-9 above or below the median value. A fall of 20% in CA19-9 level from baseline was an independent prognostic factor for OS (HR 1.9; 95% CI: 1.1-3.4, P = 0.019).

Lack of effect of tryptophan depletion on the loudness dependency of auditory event related potentials in healthy volunteers.

It has previously been suggested that auditory event related potentials (AEPs) are a potential marker of central serotonergic (5-HT) activity in man, with the slope of the AEP amplitude stimulus intensity function (ASF-slope) inversely correlating with 5-HT activity. However, two recent studies investigating this hypothesis in healthy subjects by rapidly lowering central 5-HT concentrations using the acute tryptophan depletion paradigm have found no effect on ASF-slope [Biological Psychology, 59 (2002) 121; Psychopharmacology (Berl), 146 (1999) 101]. These studies employed a 50g tryptophan depletion drink, which has been argued may not lower central 5-HT concentrations sufficiently. We here report the effect of tryptophan depletion on the AEP ASF-slope using 100g amino acid drinks with and without tryptophan in 14 healthy male subjects, employing a within subject, double blind, random, balanced order, cross-over design. No significant effect of tryptophan depletion was found on ASF-slope. These negative findings cast further doubt on the hypothesis that the ASF-slope is an indicator of central 5-HT function.

Gender and age effects on pulsatile ocular blood flow.

PURPOSE: To examine gender and age effects on pulsatile ocular blood flow (POBF). METHODS: Normal subjects, 152 females and 107 males, were separated into younger (40-50) and older (50-60) age groups. RESULTS: For younger women, mean POBF (15.3 +/- 3.7 microl/s) was significantly different (p < 0.01) than for older women (13.8 +/- 3.5 microl/s), younger men (13.2 +/- 3.3 microl/s), and older men (13.3 +/- 3.1 microl/s). The mean POBFs for each of the latter three groups were not significantly different (p > 0.41) from one another. The four groups showed no significant differences in intraocular pressure (p > 0.07) or refraction (p > 0.46). Pulse rate for younger women was significantly higher (p < 0.05) than for the older two groups, but there were no significant pulse rate differences (p > 0.08) between other groups. POBF was not correlated with IOP (r2 < 0.04), refraction (r2 < 0.009) or pulse rate (r2 < 0.04). CONCLUSION: Gender and age play an important role in POBF.

A phase I/II study of oral uracil/tegafur (UFT), leucovorin and irinotecan in patients with advanced colorectal cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD), toxicity profile and response rate of the oral 5-fluorouracil prodrug UFT (tegafur/uracil) and leucovorin (LV) in combination with irinotecan in patients with advanced or metastatic colorectal cancer. PATIENTS AND METHODS: Patients with histologically proven advanced or metastatic colorectal adenocarcinoma received first-line chemotherapy comprising UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1 to 14, with escalating doses of irinotecan (200-300 mg/m(2)) administered intravenously on day 1 of a three-weekly cycle. Eligibility criteria were standard. The MTD was defined as the dose at which >33% of six patients experienced a dose-limiting toxicity (DLT) during cycle 1. RESULTS: A total of 32 patients were studied. Initially, six patients were treated at each of the irinotecan dose levels (200, 250 and 300 mg/m(2)) combined with UFT 250 mg/m(2)/day and LV 90 mg/day. DLTs consisting of grade 3 or 4 diarrhoea and febrile neutropenia were observed in one of 20 patients at 250 mg/m(2) and three of six patients at the 300 mg/m(2) irinotecan dose level. Having defined the MTD, the 250 mg/m(2) dose level was established as the recommended dose (RD) and expanded to 20 patients in whom treatment was generally well tolerated. The overall response rate was 19%, with five patients having a partial response (PR) and 18 stable disease (SD) out of 32 response-evaluable patients. CONCLUSION: UFT and LV can be safely combined with irinotecan. The RDs for future studies are UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1-14, with irinotecan 250 mg/m(2) administered on day 1, every 3 weeks. This combination is well tolerated and active. Further investigation of UFT and LV in combination with irinotecan is warranted in patients with colorectal cancer.

A randomised study of protracted venous infusion of 5-fluorouracil (5-FU) with or without bolus mitomycin C (MMC) in patients with carcinoma of unknown primary.

No standard regimen has been identified for patients with a carcinoma of unknown primary (CUP). This study compared protracted venous infusion 5-fluorouracil (PVI 5-FU) with or without mitomycin C (MMC) in patients with CUP in a multicentre, prospectively randomised study. 88 patients were randomised to PVI 5-FU (300 mg/m(2)/day for a maximum of 24 weeks) +/-MMC (7 mg/m(2) 6 weekly for four courses). The overall response rate was 11.6% for PVI 5-FU alone compared with 20.0% for PVI 5-FU plus MMC (P=0.29). Median failure-free survival (FFS) was 4.1 months for PVI 5-FU and 3.6 months for PVI 5-FU plus MMC (P=0.78) with an equivalent overall survival (OS) (6.6 versus 4.7 months, P=0.60). Symptomatic benefit was observed in most patients in each arm. PVI 5-FU is a well tolerated outpatient treatment regimen for patients with CUP, although the addition of MMC provides little extra benefit. PVI 5-FU may be a potential reference regimen in randomised trials with newer chemotherapy agents in patients with CUP.

Neoadjuvant systemic fluorouracil and mitomycin C prior to synchronous chemoradiation is an effective strategy in locally advanced rectal cancer.

This study was designed to evaluate the benefits of neoadjuvant chemotherapy prior to chemoradiation and surgery in patients with locally advanced rectal cancer. Patients with previously untreated primary rectal cancer, reviewed in a multidisciplinary meeting and considered to have locally advanced disease on the basis of physical examination and imaging (MRI+CT n=30, CT alone n=6), were recruited. Patients received protracted venous infusion 5-FU (300 mg m(-2) day(-1) for 12 weeks) with mitomycin C (MMC) (7 mg m(-2) i.v. bolus every 6 weeks). Starting on week 13, 5-FU was reduced to 200 mg m(-2) day(-1) and concomitant pelvic radiotherapy 45 Gy in 25 fractions was commenced followed by 5.4-9 Gy boost to tumour bed. Surgery was planned 6 weeks after chemoradiation. Postoperatively, patients received 12 weeks of MMC and 5-FU at the same preoperative doses. Between January 99 and August 01, 36 eligible patients were recruited. Median age was 63 years (range=40-85). Following neoadjuvant chemotherapy, radiological tumour response was 27.8% (one CR and nine PRs) and no patient had progressive disease. In addition, 65% of patients had a symptomatic response including improvement in diarrhoea/constipation (59%), reduced rectal bleeding (60%) and diminished pelvic pain/tenesmus (78%). Following chemoradiation, tumour regression occurred in 80.6% (six CRs and 23 PRs; 95% CI=64-91.8%) and only one patient still had an inoperable tumour. R0 resection was achieved in 28 patients (82%). When compared with initial clinical staging, the pathological downstaging rate in T and/or N stage was 73.5% and pathological CR was found in one patient. Neoadjuvant systemic chemotherapy as a prelude to synchronous chemoradiation can be administered with negligible risk of disease progression and produces considerable symptomatic response with associated tumour regression.

Effects of a single dose of cortisol on the neural correlates of episodic memory and error processing in healthy volunteers.

RATIONALE: Neuropsychological impairments seen in depression may be secondary to hypercortisolaemia. Repeated cortisol administration impairs episodic memory with an alteration in event-related potentials (ERPs) recorded during information retrieval. It is unclear whether such ERP effects are specific to episodic memory, or whether repeated cortisol administration is required. OBJECTIVE: To investigate the effect of a single dose of hydrocortisone on the neural correlates of episodic memory and error detection. METHODS: Twenty healthy subjects were treated with hydrocortisone (100 mg) or placebo orally, in a double-blind, two-way crossover study. ERPs were recorded during an episodic memory and a Stroop task, 1-3 h following the medication. RESULTS: Cortisol increased error rates during the Stroop task but had no effect on episodic memory. The magnitude of ERPs associated with incorrect response in the Stroop task between -250 ms and +500 ms post-response was increased by cortisol, with no effect on correct-response ERPs. There was no effect of cortisol on episodic memory-retrieval-dependent ERPs. CONCLUSIONS: Cortisol can impair not only episodic memory but also processes involved in error detection. In contrast to repeated cortisol administration, a single dose of cortisol does not alter the behavioural performance or the electrophysiological correlates of episodic memory. However, it increases error rates in a choice response task with associated quantitative changes in incorrect-response ERPs. This probably reflects an alteration in anterior cingulate cortex activity. Such changes may contribute to the neuropsychological impairment seen in depression. This study also demonstrates the utility of ERPs for investigating the effect of neuroendocrine manipulations on the neural correlates of neuropsychological function.

EEG effects of buspirone and pindolol: a method of examining 5-HT1A receptor function in humans.

RATIONALE: An involvement of 5-HT(1A) receptors is postulated in the pathophysiology of affective disorders and mechanism of action of antidepressants. Methods for studying their functional integrity in humans are, however, limited. Preliminary data suggests that activation of somatodendritic 5-HT(1A) receptors cause a negative shift in the EEG frequency spectrum. Animal research suggests that pindolol is an agonist at these receptors but an antagonist at postsynaptic 5-HT(1A) receptors. OBJECTIVE: We postulated that while pindolol would antagonise known postsynaptic mediated neuroendocrine responses to the 5-HT(1A) agonist buspirone, both drugs would have a similar effect on the EEG frequency spectrum. METHODS: Fourteen healthy men were administered placebo or pindolol (20 mg orally) 90 min before placebo or buspirone (30 mg orally) in a double blind cross-over study. Plasma prolactin and growth hormone were assayed and EEGs recorded before and after drug administration. RESULTS: A significant negative shift in the EEG frequency spectrum was found for both buspirone and pindolol, with the combination producing a similar effect to each drug alone. In contrast, the neuroendocrine response to buspirone was significantly attenuated by pindolol. CONCLUSIONS: The data obtained are consistent with the EEG effects of buspirone and pindolol being mediated by somatodendritic 5-HT(1A) receptors, in contrast to the neuroendocrine response, which is known to be mediated by postsynaptic receptors. The development of this novel method of assessing somatodendritic 5-HT(1A) receptors in humans is a potentially important advance which may allow the testing of hypotheses of its involvement in depression and response to antidepressants.

Biochemical and behavioral characterization of novel methylphenidate analogs.

As part of a project to develop treatment agents for cocaine abuse, (+/-)-threo-methylphenidate (TMP) and 11 analogs were characterized biochemically and behaviorally to assess their potential as anti-cocaine medications. The compounds contained aryl and/or nitrogen substitutions, and/or replacement of the ester function by an alcohol or ether. All of the analogs, except for the N-methyl-substituted compounds, showed increased inhibitory potency against (3)H-(-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate ([(3)H]WIN 35,428) ([(3)H]WIN) binding to the dopamine transporter, compared with TMP. In general, parallel results were obtained for inhibition of [(3)H]dopamine ([(3)H]DA) uptake. Although compounds with N-substitutions were proportionally less potent at blocking DA uptake than WIN binding (compared with the unsubstituted compounds), one such compound that was 6-fold more potent against [(3)H]WIN binding than [(3)H]DA uptake did not attenuate inhibition by cocaine of synaptosomal [(3)H]DA transport. The compounds were significantly less potent in displacing [(3)H]citalopram binding from the serotonin transporter. In cocaine discrimination studies in rats, all but two of the analogs (both N-substituted) completely generalized with the cocaine stimulus. Robust positive correlations were observed between potency in the drug discrimination assay and activity at the dopamine transporter, but not the serotonin transporter. When tested for their ability to alter cocaine discrimination, four of the analogs (three of which had N-substitutions and shallow dose-response curves as cocaine substitutes) actually enhanced cocaine discrimination, often at combined doses of cocaine and test compound that were inactive when given separately. Taken together, the results suggest that TMP analogs may have potential as substitution therapies for the treatment of cocaine abuse.