Salience attribution and its relationship to cannabis-induced psychotic symptoms.

BACKGROUND: Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity. METHOD: We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test, a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory. Dopamine synthesis capacity, indexed as the influx rate constant K i cer , was measured in 10 users and six controls with 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine positron emission tomography. RESULTS: There was no significant difference in aberrant salience between the groups [F 1,32 = 1.12, p = 0.30 (implicit); F 1,32 = 1.09, p = 0.30 (explicit)]. Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r = 0.61, p = 0.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F 1,15 = 5.8, p = 0.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r = -0.91, p = 0.01), whereas this relationship was non-significant within users (difference between correlations: Z = -2.05, p = 0.04). CONCLUSIONS: Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use.

The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories.

3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a recreational drug. Preliminary work has supported the potential of MDMA in psychotherapy for post-traumatic stress disorder (PTSD). The neurobiological mechanisms underlying its putative efficacy are, however, poorly understood. Psychotherapy for PTSD usually requires that patients revisit traumatic memories, and it has been argued that this is easier to do under MDMA. Functional magnetic resonance imaging (fMRI) was used to investigate the effect of MDMA on recollection of favourite and worst autobiographical memories (AMs). Nineteen participants (five females) with previous experience with MDMA performed a blocked AM recollection (AMR) paradigm after ingestion of 100 mg of MDMA-HCl or ascorbic acid (placebo) in a double-blind, repeated-measures design. Memory cues describing participants' AMs were read by them in the scanner. Favourite memories were rated as significantly more vivid, emotionally intense and positive after MDMA than placebo and worst memories were rated as less negative. Functional MRI data from 17 participants showed robust activations to AMs in regions known to be involved in AMR. There was also a significant effect of memory valence: hippocampal regions showed preferential activations to favourite memories and executive regions to worst memories. MDMA augmented activations to favourite memories in the bilateral fusiform gyrus and somatosensory cortex and attenuated activations to worst memories in the left anterior temporal cortex. These findings are consistent with a positive emotional-bias likely mediated by MDMA's pro-monoaminergic pharmacology.

Drug cue induced overshadowing: selective disruption of natural reward processing by cigarette cues amongst abstinent but not satiated smokers.

BACKGROUND: Addicts show both reward processing deficits and increased salience attribution to drug cues. However, no study to date has demonstrated that salience attribution to drug cues can directly modulate inferences of reward value to non-drug cues. Associative learning depends on salience: a more salient predictor of an outcome will 'overshadow' a less salient predictor of the same outcome. Similarly, blocking, a demonstration that learning depends on prediction error, can be influenced by the salience of the cues employed. METHOD: This study investigated whether salient drug cues might interact with neutral cues predicting financial reward in an associative learning task indexing blocking and overshadowing in satiated smokers (n=24), abstaining smokers (n=24) and non-smoking controls (n=24). Attentional bias towards drug cues, craving and expired CO were also indexed. RESULTS: Abstaining smokers showed drug cue induced overshadowing, attributing higher reward value to drug cues than to neutral cues that were equally predictive of reward. Overshadowing was positively correlated with expired CO levels, which, in turn, were correlated with craving in abstainers. An automatic attentional bias towards cigarette cues was found in abstainers only. CONCLUSIONS: These findings provide the first evidence that drug cues interact with reward processing in a drug dependent population.

Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being.

BACKGROUND: Cannabis varies considerably in levels of its two major constituent cannabinoids - (delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Recently, we found evidence that those who smoked cannabis containing detectable levels of CBD had fewer psychotic-like symptoms than those whose cannabis had no CBD. The present study aimed, first, to replicate those findings and, second, to determine whether protective effects of CBD may extend to other harms of cannabis, such as memory impairment and reduced psychological well-being. METHOD: A total of 120 current cannabis smokers, 66 daily users and 54 recreational users were classified into groups according to whether analysis of their hair revealed the presence or absence of CBD and high versus low levels of THC. All were assessed on measures of psychosis-like symptoms, memory (prose recall; source memory) and depression/anxiety. RESULTS: Lower psychosis-like symptoms were found in those whose hair had CBD compared with those without. However, this was seen only in recreational users, who had higher levels of THC in their hair. Higher THC levels in hair were associated with increased depression and anxiety. Prose recall and source memory were poorer in daily users with high THC levels in hair while recognition memory was better in individuals with CBD present in hair. CONCLUSIONS: CBD attenuates the psychotic-like effects of cannabis over time in recreational users. Higher THC negatively impacts on memory and psychological well-being. These findings raise concerns for the harms stemming from use of varieties such as 'skunk' (sensimillia), which lack any CBD but currently dominate the supply of cannabis in many countries.

Neurocognitive function and schizophrenia-proneness in individuals dependent on ketamine, on high potency cannabis ('skunk') or on cocaine.

BACKGROUND: Ketamine, psychostimulants and cannabis have all been associated with psychotic phenomena but no study has directly compared users of these drugs. AIMS: The aim of this study was to assess schizophrenia proneness and neurocognitive function in individuals dependent upon ketamine, cannabis and cocaine. METHOD: 130 volunteers - 29 'skunk' users, 22 cocaine users, 21 ketamine users, along with 28 'recreational' poly-drug users and 30 drug-naïve controls - were assessed on the Schizophrenia Proneness Instrument, Adult version (SPI-A). They were specifically asked to rate symptoms when not under the acute influence of a psychoactive drug. RESULTS: Ketamine and skunk users manifested the greatest attentional and cognitive disturbances. The symptom profile of the dependent ketamine users was very similar to that of prodromal individuals who transitioned to psychosis. CONCLUSIONS: Given the recent rapid rise in use of high potency cannabis and of ketamine, these findings are important and clinicians should be careful to rule out the effects of persistent drug use, especially in users of ketamine or skunk, when assessing an individual's risk of psychosis. A longitudinal study is needed to differentiate which basic symptoms persist following abstention from ketamine and skunk.

Modeling lesion counts in multiple sclerosis when patients have been selected for baseline activity.

The number of new gadolinium-enhancing lesions discovered via magnetic resonance imaging is a well-established outcome for multiple sclerosis studies, especially Phase II Studies. Due to the high cost of magnetic resonance imaging scans, many investigators select participants for the presence of lesions. While this selection procedure is thought to improve the power of inferences, the effect of screening for baseline activity on parameter estimation and interval coverage has not yet been examined. The objective of this study was to investigate the performance of the negative binomial distribution for modeling lesion count data in multiple sclerosis when patients have been selected for activity on a baseline scan. We performed computer simulations to investigate the influence of the screening process on inferences made using a negative binomial model about treatment effects in two independent samples. We also demonstrate how the statistical properties of screening can be incorporated into trial design. We demonstrate that when the negative binomial distribution is used to model lesion counts, while screening for baseline activity improves point estimation, this practice also has the potential to decrease interval coverage and inflate the Type I error rate. For data that is to be modeled using a negative binomial distribution, screening for baseline activity can create a trade-off between cost effectiveness and a higher than desired false positive rate that must be carefully considered in planning Phase II trials.

Impact of an enhanced recovery program for cesarean delivery on postoperative opioid use.

BACKGROUND: Cesarean delivery is one of the most common surgeries performed worldwide and the adoption of enhanced recovery programs for cesarean delivery is gaining popularity. We tested the hypothesis that implementation of an enhanced recovery program for cesarean delivery would be associated with a decrease in postoperative opioid consumption. METHODS: We compared a retrospective cohort of women delivered by elective cesarean delivery (January 1, 2017 to June 30, 2018) to a prospective cohort exposed to the enhanced recovery protocol (July 1, 2018 to December 31, 2018). The primary outcome was inpatient maternal opioid use, measured as total oral morphine equivalents. Secondary outcomes included postoperative 0-10 pain scores, length of stay, 30-day postoperative complication rates, and hospital re-admissions. RESULTS: Data from 541 patients were analyzed. The enhanced recovery cohort used significantly less oral morphine equivalents compared with the pre-enhanced recovery cohort (60.3 mg vs 104.3 mg, P <0.001). The number of patients who required opioid medication within 24 h of discharge was significantly reduced in the enhanced recovery cohort (41.1% vs 74.6%, P <0.001). There were no significant differences in average pain scores (1.6 vs 1.9, P=0.037). CONCLUSIONS: The implementation of an enhanced recovery program for cesarean delivery was associated with a significant reduction in postoperative opioid consumption throughout hospitalization, with average pain scores remaining <2. Implementation of this program was also associated with an increase in the number of patients who were opioid-free 24 h prior to discharge.

Acute cannabis use causes increased psychotomimetic experiences in individuals prone to psychosis.

BACKGROUND: Epidemiological evidence suggests a link between cannabis use and psychosis. A variety of factors have been proposed to mediate an individual's vulnerability to the harmful effects of the drug, one of which is their psychosis proneness. We hypothesized that highly psychosis-prone individuals would report more marked psychotic experiences under the acute influence of cannabis. METHOD: A group of cannabis users (n=140) completed the Psychotomimetic States Inventory (PSI) once while acutely intoxicated and again when free of cannabis. A control group (n=144) completed the PSI on two parallel test days. All participants also completed a drug history and the Schizotypal Personality Questionnaire (SPQ). Highly psychosis-prone individuals from both groups were then compared with individuals scoring low on psychosis proneness by taking those in each group scoring above and below the upper and lower quartiles using norms for the SPQ. RESULTS: Smoking cannabis in a naturalistic setting reliably induced marked increases in psychotomimetic symptoms. Consistent with predictions, highly psychosis-prone individuals experienced enhanced psychotomimetic states following acute cannabis use. CONCLUSIONS: These findings suggest that an individual's response to acute cannabis and their psychosis-proneness scores are related and both may be markers of vulnerability to the harmful effects of this drug.

Application of the Phenomenex EZ:faasttrade mark amino acid analysis kit for rapid gas-chromatographic determination of concentrations of plasma tryptophan and its brain uptake competitors.

The Phenomenex EZ:faast amino acid analysis kit is available for gas (GC) or liquid (LC) chromatographic analysis of amino acids (AA) using mass spectrometry (MS) and other GC detectors. We used it for rapid GC determination of plasma tryptophan, its brain uptake competitors (Val, Leu, Ile, Phe and Tyr) and many other amino acids. Based on solid-phase extraction, this fast method enables one person to process two plasma samples in 8-10 min and six samples in approximately 15 min up to GC injection and a 7-min GC run per plasma sample. Using a Perkin-Elmer Clarus 500 GC, a Total Chrome software, a flame-ionisation detector (FID) and norvaline as internal standard, we used this method to analyse approximately 1,000 plasma samples from normal subjects undergoing acute tryptophan depletion and loading tests. The limit of detection for most amino acids is 1 nmol/ml (1 microM) and in many cases less. With manual injection, coefficients of variation for the above six amino acids were 1.5-6.2% (intra-assay) and 3.8-9.7% (inter-assay). This simple, rapid and elegant method will be valuable to the amino acid analyst and researcher, as it can save much manpower time and meet urgent emergency requests and the demands of a high-throughput laboratory.

Journey through the K-hole: phenomenological aspects of ketamine use.

Although recreational use of the dissociative anaesthetic drug ketamine is currently increasing, little is known about the phenomenological aspects of its use. We therefore designed a structured interview to examine initiation experiences, positive and negative effects of ketamine use, and concerns about the drug and its long-term effects. Ninety participants (30 frequent users, 30 infrequent 'recreational' users and 30 ex-users who had abstained from use for at least 3 months) were interviewed and reported drug use was verified by hair sample analysis. The most appealing aspects of ketamine for two-thirds of users were "melting into the surrounding", "visual hallucinations", "out-of-body experiences" and "giggliness". Unappealing effects for half of users were "memory loss" and "decreased sociability". Frequent ketamine users expressed more concerns than other groups about long-term effects on physical health problems, especially K-cramps and cystitis, whereas ex-users were more concerned about mental health problems. Addictive/dependent patterns of behaviour were also a concern: the majority of frequent users reported using the drug without stopping until supplies ran out and the mean increase in dosage in this group was six-fold from initiation to current use. We have identified specific health issues which seem uniquely related to ketamine use. Additionally, the dependence on ketamine frequently reported by users may be a cause for concern as its popularity grows and substance misuse services should be made aware of this when clients present in the future.

Ketamine for the treatment of addiction: Evidence and potential mechanisms.

Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine's ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine's efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

The effects of cannabidiol on impulsivity and memory during abstinence in cigarette dependent smokers.

Acute nicotine abstinence in cigarette smokers results in deficits in performance on specific cognitive processes, including working memory and impulsivity which are important in relapse. Cannabidiol (CBD), the non-intoxicating cannabinoid found in cannabis, has shown pro-cognitive effects and preliminary evidence has indicated it can reduce the number of cigarettes smoked in dependent smokers. However, the effects of CBD on cognition have never been tested during acute nicotine withdrawal. The present study therefore aimed to investigate if CBD can improve memory and reduce impulsivity during acute tobacco abstinence. Thirty, non-treatment seeking, dependent, cigarette smokers attended two laboratory-based sessions after overnight abstinence, in which they received either 800 mg oral CBD or placebo (PBO), in a randomised order. Abstinence was biologically verified. Participants were assessed on go/no-go, delay discounting, prose recall and N-back (0-back, 1-back, 2-back) tasks. The effects of CBD on delay discounting, prose recall and the N-back (correct responses, maintenance or manipulation) were null, confirmed by a Bayesian analysis, which found evidence for the null hypothesis. Contrary to our predictions, CBD increased commission errors on the go/no-go task. In conclusion, a single 800 mg dose of CBD does not improve verbal or spatial working memory, or impulsivity during tobacco abstinence.

Defective transfer RNA-queuine modification in C3H10T1/2 murine fibroblasts transfected with oncogenic ras.

tRNA isoacceptors for aspartic acid, asparagine, histidine, and tyrosine are modified in the anticodon wobble position with the deazaguanine analogue queuine. Queuine modification is defective in many tumors and transformed cell lines, and the extent of hypomodification correlates with staging and outcome in numerous human tumors. The molecular role of queuine modification in normal cells and the mechanisms of queuine hypomodification in tumors are unknown. We have characterized nontransformed C3H10T1/2 murine fibroblasts (C3H) and their ras-transfected counterparts (RasC4) with respect to the causes and effects of queuine hypomodification. RasC4 cells are hypomodified for queuine compared with C3H cells, despite increase tRNA-guanine ribosyltansferase activity. Excess exogenous queuine can cause repletion of tRNA queuine levels in RasC4 cells. Queuine modification of both C3H and RasC4 cells can be decreased by treatment with 7-methylguanine. This treatment does not affect growth in monolayer culture but enhances anchorage-independent growth of RasC4 cells greatly. These cell lines may be useful systems for the study of queuine function in normal cells and the causes and consequences of hypomodification for queuine in tumors.

6-Thioguanine-induced growth arrest in 6-mercaptopurine-resistant human leukemia cells.

The thiopurines 6-thioguanine (6TG) and 6-mercaptopurine (6MP) are cytotoxic to proliferating cells by a mechanism involving incorporation into DNA via the purine salvage pathway, and resistance to these agents can be conferred by lack of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase. However, human and murine hypoxanthine-guanine phosphoribosyltransferase-deficient leukemia cell lines have been shown to respond to 6TG by growth arrest and differentiation by a mechanism apparently not involving incorporation of 6TG into DNA. If so, leukemia cells resistant to 6MP should still respond to 6TG by growth arrest via an undescribed epigenetic mechanism. To test this, polyclonal 6MP-resistant variants were produced from three human leukemia cell lines, HL-60, U937, and CCRF-CEM. Treatment of both sensitive and resistant cells with 6TG induced growth arrest. The effect of 6TG in the 6MP-sensitive HL-60 and U937 cells was associated with significant loss of viability and DNA fragmentation. In contrast, the 6TG-treated 6MP-resistant cells exhibited a slower decline in viability and no DNA fragmentation. To identify the mechanism by which 6TG may induce growth arrest, tRNA was isolated from 6MP-resistant cells cultured for 48 h with 6TG. 6TG was found to be incorporated into tRNAs normally containing queuine in the anticodon wobble position. These studies may provide a basis for the development of new therapeutic regimens for the treatment of leukemia.

AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers.

Smoking cannabis daily doubles an individual's risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual's acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis-which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content-and also ± 7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis.

Kidney dialysis-associated amyloidosis: a molecular role for copper in fiber formation.

In the US alone, more than 250,000 people have impaired renal function that necessitates treatment by dialysis. A debilitating complication of long-term treatment is the deposition of beta2-microglobulin (beta2m) as amyloid fibers within the joint space. However, the intrinsic propensity of isolated beta2m protein to initiate in vitro fiber formation is negligible under conditions matched to the neutral pH and ionic conditions of serum. Here, we present evidence for a novel interaction between beta2m and Cu(2+) at a concentration within institutionally recommended limits for this metal ion in dialysate solution. Mass spectrometry, using electrospray ionization from native conditions, demonstrates that the binding of Cu(2+) is specific over Ca(2+) or Zn(2+). Despite maintaining a native-like conformation upon Cu(2+) binding, the folded protein is unusually destabilized against thermal and urea denaturation. We further demonstrate that destabilization by Cu(2+) uniquely promotes de novo fiber formation at 37 degrees C and neutral pH. Since the incidence of amyloidosis is dramatically reduced upon elimination of copper from dialysis membranes, our results provide a molecular understanding for dialysis-associated amyloid formation by beta2m.

A compact monomeric intermediate identified by NMR in the denaturation of dimeric triose phosphate isomerase.

The denaturation of triose phosphate isomerase (TIM) from Saccharomyces cerevisiae by guanidine hydrochlorids at pH 7.2 has been monitored by NMR spectroscopy in conjunction with optical spectroscopy. In the absence of denaturant, the hydrodynamic radius of 29.6(+/-0.25) A and the substantial chemical shift dispersion evident in the NMR spectrum are consistent with the highly structured dimeric native state of the protein. On the addition of 2. 2 M guanidine hydrochloride the effective hydrodynamic radius increases to 51.4(+/-0.43) A, consistent with that anticipated for the polypeptide chain in a highly unstructured random coil state. In 1.1 M guanidine hydrochloride, however, the effective hydrodynamic radius is 24.0(+/-0.25) A, a value substantially decreased relative to that of the native dimeric state but very close to that anticipated for a monomeric species with native-like compaction (23. 5 A). The lack of chemical shift dispersion indicates, however, that few tertiary interactions persist within this species. Far UV CD and intrinsic fluorescence measurements show that this compact intermediate retains significant secondary structure and that on average the fluorophores are partially excluded from solvent. Such a species could be important in the formation of dimeric TIM from its unfolded state.

The effects of nicotine dependence and acute abstinence on the processing of drug and non-drug rewards.

RATIONALE: Drug addiction may be characterised by a hypersensitivity to drug rewards and a hyposensitivity to non-drug rewards. This imbalance may become further polarised during acute abstinence. OBJECTIVES: (i) Examine the differences between dependent and occasional smokers in choices for, motivation for and self-reported wanting and liking of cigarette and non-drug rewards. (ii) Examine the effects of 12-h nicotine abstinence on these metrics. METHODS: Dependent (n = 20) and occasional, non-dependent smokers (n = 20) were tested after ad libitum smoking and ≥12-h of nicotine abstinence. A novel task was developed (Drug, Reward and Motivation-Choice (DReaM-Choice)) in which different rewards (cigarettes, music and chocolate) could be won. In each trial, participants chose between two rewards and then could earn the chosen reward via repeated button-pressing. Participants subsequently 'consumed' and rated subjective liking of the rewards they had won. RESULTS: Compared with occasional smokers, dependent smokers made more choices for (p < 0.001), pressed more for (p = 0.046) and reported more wanting (p = 0.007) and liking (p < 0.001) of cigarettes, and also made fewer choices for chocolate (p = 0.005). There were no differences between the groups on button-pressing for chocolate or music. However, the balance between drug and non-drug reward processing was different between the groups across all metrics. Twelve-hour nicotine abstinence led to more cigarette choices (p < 0.001) and fewer music choices (p = 0.042) in both groups. CONCLUSIONS: Nicotine dependence was associated with a hypersensitivity to cigarette rewards, but we found little evidence indicating a hyposensitivity to non-drug rewards. Our findings question the moderating influence of dependence on how acute nicotine abstinence affects reward processing.

Hydrogen exchange properties of proteins in native and denatured states monitored by mass spectrometry and NMR.

The extent of deuterium labeling of hen lysozyme, its three-disulfide derivative, and the homologous alpha-lactalbumins, has been measured by both mass spectrometry and NMR. Different conformational states of the proteins were produced by varying the solution conditions. Alternate protein conformers were found to contain different numbers of 2H atoms. Furthermore, measurement in the gas phase of the mass spectrometer or directly in solution by NMR gave consistent results. The unique ability of mass spectrometry to distinguish distributions of 2H atoms in protein molecules is exemplified using samples prepared to contain different populations of 2H-labeled protein. A comparison of the peak widths of bovine alpha-lactalbumin in alternate solution conformations but containing the same average number of 2H atoms showed dramatic differences due to different 2H distributions in the two protein conformers. Measurement of 2H distributions by ESI-MS enabled characterization of conformational averaging and structural heterogeneity. In addition, a time course for hydrogen exchange was examined and the variation in distributions of 2H atom compared with simulations for different hydrogen exchange models. The results clearly show that exchange from the native state of bovine alpha-lactalbumin at 15 degrees C is dominated by local unfolding events.

No early effects of electroconvulsive therapy on tryptophan metabolism and disposition in endogenous depression.

The possibility that a single electroconvulsive therapy (ECT) could increase tryptophan (Trp) availability to the brain for 5-hydroxytryptamine (5-HT, serotonin) synthesis was examined in 10 depressed patients before and during the 1st hour following an ECT and in 4 control (minor ear, nose, and throat surgical) subjects receiving similar premedication. Trp availability to the brain, expressed as the serum Trp: competing amino acid ratio, and related aspects of Trp disposition were not significantly altered by ECT any differently than from preoperative stress and premedication. We suggest that Trp availability to the brain and, hence, cerebral 5-HT synthesis are not altered in depressed patients early after a single ECT.