Clinical Course, Antifungal Susceptibility, and Genomic Sequencing of Trichophyton indotineae.

Importance: Trichophyton indotineae is an emerging dermatophyte causing outbreaks of extensive tinea infections often unresponsive to terbinafine. This species has been detected worldwide and in multiple US states, yet detailed US data on infections with T indotineae are sparse and could improve treatment practices and medical understanding of transmission. Objective: To correlate clinical features of T indotineae infections with in vitro antifungal susceptibility testing results, squalene epoxidase gene sequence variations, and isolate relatedness using whole-genome sequencing. Design, Setting, and Participants: This retrospective cohort study of patients with T indotineae infections in New York City spanned May 2022 to May 2023. Patients with confirmed T indotineae infections were recruited from 6 New York City medical centers. Main Outcome and Measure: Improvement or resolution at the last follow-up assessment. Results: Among 11 patients with T indotineae (6 male and 5 female patients; median [range] age, 39 [10-65] years), 2 were pregnant; 1 had lymphoma; and the remainder were immunocompetent. Nine patients reported previous travel to Bangladesh. All had widespread lesions with variable scale and inflammation, topical antifungal monotherapy failure, and diagnostic delays (range, 3-42 months). Terbinafine treatment failed in 7 patients at standard doses (250 mg daily) for prolonged duration; these patients also had isolates with amino acid substitutions at positions 393 (L393S) or 397 (F397L) in squalene epoxidase that correlated with elevated terbinafine minimum inhibitory concentrations of 0.5 µg/mL or higher. Patients who were treated with fluconazole and griseofulvin improved in 2 of 4 and 2 of 5 instances, respectively, without correlation between outcomes and antifungal minimum inhibitory concentrations. Furthermore, 5 of 7 patients treated with itraconazole cleared or had improvement at the last follow-up, and 2 of 7 were lost to follow-up or stopped treatment. Based on whole-genome sequencing analysis, US isolates formed a cluster distinct from Indian isolates. Conclusion and Relevance: The results of this case series suggest that disease severity, diagnostic delays, and lack of response to typically used doses and durations of antifungals for tinea were common in this primarily immunocompetent patient cohort with T indotineae, consistent with published data. Itraconazole was generally effective, and the acquisition of infection was likely in Bangladesh.

Simple quantitative planimetric measurement of nigrosome-1 for clinical settings.

INTRODUCTION: Loss of MRI hyperintense signal in nigrosome-1 (assessed with susceptibility-weighted imaging) is a biomarker for Parkinson's disease (PD). Current clinical practice involves subjectively rating the appearance of nigrosome-1 which is challenging. The study aimed to test and compare a simple method for quantifying nigrosome-1 with the current subjective rating method. METHODS: Two experienced neuroradiologists measured area of hyperintense signal in nigrosome-1 (quantitative method) and rated nigrosome-1 appearance (as normal, attenuated, or absent; subjective method) in 42 patients encompassing the full spectrum of nigrosome-1 integrity (21 patients aged 55.5 ± 20.9 years with Essential tremor (ET) and a subset of 21 patients aged 69.6 ± 8.6 years with PD). Neuroradiologists were blinded to each other's measurements, clinical notes, and patient group. RESULTS: Both methods yielded a significant difference between the groups (PD vs ET; p < 0.001). Pooled (across sides) area of nigrosome-1 hyperintense signal was significantly smaller in the PD group (median = 2.1 mm2, range = 0-15.8 mm2) than ET group (median = 8.3 mm2, range = 0-15.7 mm2; p < 0.001). Inter-rater reliability was high to very high for both methods (subjective: weighted kappa = 0.640, p < 0.001; quantitative: W = 0.733, p = 0.004). Our primary hypothesis that area of nigrosome-1 hyperintense signal exhibits higher inter-rater reliability than subjective rating of nigrosome-1 appearance was not supported. CONCLUSION: The simple quantitative method, used with subjectively rated nigrosome-1 appearance, may improve confidence in longitudinal clinical reporting, when nigrosome-1 is attenuated. However, further work on the incremental diagnostic value of planimetry and bias, repeatability and reproducibility are needed before it can be recommended in clinical practice.

Unpacking and validating the "physiological adaptation" core concept of physiology.

A national Task Force of 25 Australian physiology educators used the Delphi protocol to develop seven physiology core concepts that were agreed to nationally. The aim of the current study was to unpack the "physiological adaptation" core concept with the descriptor "organisms adjust and adapt to acute and chronic changes in the internal and external environments across the lifespan." This core concept was unpacked by three Task Force members and a facilitator into four themes and nine subthemes that encompass the role of stressors and disturbed homeostasis in adaptation and the capacity for, and the nature of, the physiological adaptation. Twenty-two Task Force members then provided feedback and rated the themes and subthemes for level of importance and difficulty for students to learn via an online survey using a five-point Likert scale. Seventeen respondents completed all survey questions. For all themes/subthemes, importance was typically rated 1 (Essential) or 2 (Important) (n = 17, means ±SD ranged from 1.1 ± 0.3 to 2.2 ± 0.9), and difficulty was typically rated 3 (Moderately Difficult) (n = 17, means ranged from 2.9 ± 0.7 to 3.4 ± 0.9). Subtle differences in the proportion of importance scores (n = 17, Fisher's exact: P = 0.004, ANOVA: F12,220 = 2.630, P = 0.003; n = 22, Fisher's exact: P = 0.002, ANOVA: F12,281 = 2.743, P < 0.001), but not difficulty scores, were observed between themes/subthemes, and free-text feedback was minor. The results suggest successful unpacking of the physiological adaptation core concept. The themes and subthemes can inform the design of learning outcomes, assessment, and teaching and learning activities that have commonality and consistency across curricula.NEW & NOTEWORTHY An Australian Task Force of physiology educators identified physiological adaptation as a core concept of physiology. It was subsequently unpacked into four themes and nine subthemes. These were rated, by the Task Force, Essential or Important and Moderately Difficult for students to learn. The themes and subthemes can inform the design of learning outcomes, assessments, and teaching and learning activities that have commonality and consistency across curricula.

Neuronal glutamate transporters control reciprocal inhibition and gain modulation in D1 medium spiny neurons.

Understanding the function of glutamate transporters has broad implications for explaining how neurons integrate information and relay it through complex neuronal circuits. Most of what is currently known about glutamate transporters, specifically their ability to maintain glutamate homeostasis and limit glutamate diffusion away from the synaptic cleft, is based on studies of glial glutamate transporters. By contrast, little is known about the functional implications of neuronal glutamate transporters. The neuronal glutamate transporter EAAC1 is widely expressed throughout the brain, particularly in the striatum, the primary input nucleus of the basal ganglia, a region implicated with movement execution and reward. Here, we show that EAAC1 limits synaptic excitation onto a population of striatal medium spiny neurons identified for their expression of D1 dopamine receptors (D1-MSNs). In these cells, EAAC1 also contributes to strengthen lateral inhibition from other D1-MSNs. Together, these effects contribute to reduce the gain of the input-output relationship and increase the offset at increasing levels of synaptic inhibition in D1-MSNs. By reducing the sensitivity and dynamic range of action potential firing in D1-MSNs, EAAC1 limits the propensity of mice to rapidly switch between behaviors associated with different reward probabilities. Together, these findings shed light on some important molecular and cellular mechanisms implicated with behavior flexibility in mice.

Establishing consensus for the core concepts of physiology in the Australian higher education context using the Delphi method.

A set of core concepts ("big ideas") integral to the discipline of physiology are important for students to understand and demonstrate their capacity to apply. We found poor alignment of learning outcomes in programs with physiology majors (or equivalent) from 17 Australian universities and the 15 core concepts developed by a team in the United States. The objective of this project was to reach Australia-wide consensus on a set of core concepts for physiology, which can be embedded in curricula across Australian universities. A four-phase Delphi method was employed, starting with the assembling of a Task Force of physiology educators with extensive teaching and curriculum development expertise from 25 Australian universities. After two online meetings and a survey, the Task Force reached agreement on seven core concepts of physiology and their descriptors, which were then sent out to the physiology educator community across Australia for agreement. The seven core concepts and their associated descriptions were endorsed through this process (n = 138). In addition, embedding the core concepts across the curriculum was supported by both Task Force members (85.7%) and educators (82.1%). The seven adopted core concepts of human physiology were Cell Membrane, Cell-Cell Communication, Movement of Substances, Structure and Function, Homeostasis, Integration, and Physiological Adaptation. The core concepts were subsequently unpacked into themes and subthemes. If adopted, these core concepts will result in consistency across curricula in undergraduate physiology programs and allow for future benchmarking.NEW & NOTEWORTHY This is the first time Australia-wide agreement has been reached on the core concepts of physiology with the Delphi method. Embedding of the core concepts will result in consistency in physiology curricula, improvements to teaching and learning, and benchmarking across Australian universities.

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Estimating the glutamate transporter surface density in distinct sub-cellular compartments of mouse hippocampal astrocytes.

Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft.

Adults with a history of recreational cannabis use have altered speech production.

Stereotypical depictions of speech in cannabis users often suggest slow, laboured output, yet objective evidence supporting this assumption is extremely limited. We know that depressants or hallucinogenic drugs such as cannabis can cause acute changes in communication and speech rate, but the long-lasting effects of cannabis use on speech are not well described. The aim of this study was to investigate speech in individuals with a history of recreational cannabis use compared to non-drug-using healthy controls. Speech samples were collected from a carefully described cohort of 31 adults with a history of cannabis use (but not use of illicit stimulant drugs) and 40 non-drug-using controls. Subjects completed simple and complex speech tasks including a monologue, a sustained vowel, saying the days of the week, and reading a phonetically balanced passage. Audio samples were analysed objectively using acoustic analysis for measures of timing, vocal control, and quality. Subtle differences in speech timing, vocal effort, and voice quality may exist between cannabis and control groups, however data remain equivocal. After controlling for lifetime alcohol and tobacco use and applying a false discovery rate, only spectral tilt (vocal effort and intensity) differed between groups and appeared to change in line with duration of abstinence from cannabis use. Differences between groups may reflect longer term changes to the underlying neural control of speech. Our digital analysis of speech shows there may be a signal differentiating individuals with a history of recreational cannabis use from healthy controls, in line with similar findings from gait and hand function studies.

Measurement of the adult human midbrain with transcranial ultrasound.

BACKGROUND: Transcranial sonography is increasingly used to aid clinical diagnoses of movement disorders, for example, to identify an enlarged area of substantia nigra echogenicity in patients with Parkinson's disease. OBJECTIVE: The current study investigated characteristics of the midbrain at the anatomical plane for quantification of substantia nigra echogenicity. METHODS: Area of substantia nigra echogenicity, cross-sectional area of the midbrain, and interpeduncular angle were quantified in two groups of adults aged 18-50 years: 47 healthy non-drug-using controls (control group) and 22 individuals with a history of methamphetamine use (methamphetamine group), a cohort with a high prevalence of enlarged substantia nigra echogenicity and thus risk of Parkinson's disease. RESULTS: In the control group, cross-sectional area of the midbrain (4.47±0.44 cm2) and interpeduncular angle were unaffected by age, sex, or image acquisition side. In the methamphetamine group, cross-sectional midbrain area (4.72±0.60 cm2) and area of substantia nigra echogenicity were enlarged compared to the control group, and the enlargement was sex-dependent (larger in males than females). Whole midbrain area and interpeduncular angle were found to be weak predictors of area of substantia nigra echogenicity after accounting for group and sex. CONCLUSIONS: History of methamphetamine use is associated with an enlarged midbrain and area of substantia nigra echogenicity, and the abnormality is more pronounced in males than females. Thus, males may be more susceptible to methamphetamine-induced changes to the brainstem, and risk of Parkinson's disease, than females.

Circadian Modulation of Neurons and Astrocytes Controls Synaptic Plasticity in Hippocampal Area CA1.

Most animal species operate according to a 24-h period set by the suprachiasmatic nucleus (SCN) of the hypothalamus. The rhythmic activity of the SCN modulates hippocampal-dependent memory, but the molecular and cellular mechanisms that account for this effect remain largely unknown. Here, we identify cell-type-specific structural and functional changes that occur with circadian rhythmicity in neurons and astrocytes in hippocampal area CA1. Pyramidal neurons change the surface expression of NMDA receptors. Astrocytes change their proximity to synapses. Together, these phenomena alter glutamate clearance, receptor activation, and integration of temporally clustered excitatory synaptic inputs, ultimately shaping hippocampal-dependent learning in vivo. We identify corticosterone as a key contributor to changes in synaptic strength. These findings highlight important mechanisms through which neurons and astrocytes modify the molecular composition and structure of the synaptic environment, contribute to the local storage of information in the hippocampus, and alter the temporal dynamics of cognitive processing.

Diagnostic accuracy of the appearance of Nigrosome-1 on magnetic resonance imaging in Parkinson's disease: A systematic review and meta-analysis.

INTRODUCTION: There is currently no definitive diagnostic test for Parkinson's disease (PD) and the current diagnostic procedure primarily relies on clinical manifestations. A hypointense appearance of nigrosome-1 (or absence of the "swallow tail" sign) on magnetic resonance imaging (MRI) has been proposed as a biomarker for PD. This meta-analysis examined the diagnostic accuracy of the appearance of nigrosome-1 on Magnetic Resonance Imaging (MRI) in differentiating idiopathic PD patients from healthy adults. METHODS: Databases (MEDLINE, Embase, Scopus) were searched from 2012 (first publication of nigrosome-1 MRI scans) up until September 2019. Two researchers independently screened all titles and abstracts to identify studies that met the inclusion criteria and extracted relevant articles in a uniform manner. Two authors independently extracted data and assessed the risk of bias using a customized QUADAS-2 tool. Pooled sensitivity and specificity were calculated using a hierarchical summary receiver operating characteristic approach, as were positive and negative likelihood ratios. RESULTS: Nineteen studies containing a total of 1508 participants (903 idiopathic PD patients and 605 healthy controls) were included. The overall sensitivity and specificity were 0.94 (95%CI, 0.93-0.96) and 0.90 (95%CI, 0.88-0.92), respectively. The likelihood ratios for positive and negative test results were 9.72 (95%CI, 5.58-16.04) and 0.08 (95%CI, 0.05-0.12). The pooled area under the receiver operating characteristics curve (AUC) in the diagnosis of idiopathic PD was 0.98. CONCLUSIONS: Visual assessment of the nigrosome-1 appearance, at 3 or 7T, yields excellent diagnostic accuracy for differentiating idiopathic PD from healthy adults.

Prevalence of self-reported movement dysfunction among young adults with a history of ecstasy and methamphetamine use.

BACKGROUND: Illicit stimulant use is associated with long-lasting changes in movement and movement-related brain regions. The aim of our study was to investigate the prevalence of movement dysfunction in this population. We hypothesized that prevalence of self-reported movement dysfunction is higher among stimulant users than non-stimulant users. METHODS: Three groups of adults completed a survey containing questions about demographics, health, drug use, and movement. The groups consisted of ecstasy users with no history of methamphetamine use (ecstasy group, n = 190, 20 ±â€¯3 yrs.), methamphetamine users (methamphetamine group, n = 331, 23 ±â€¯5 yrs.), and non-stimulant users (control group, n = 228, 25 ±â€¯8 yrs.). Movement data was analyzed with logistic regression. RESULTS: In the unadjusted logistic regression model, group had a significant effect on fine hand control, tremor, and voice/speech questions, but not on other movement domain questions. The prevalence of tremor and abnormal fine hand control was significantly higher in the ecstasy and methamphetamine groups than in the control group (p < 0.018), and changes in voice/speech was more prevalent in the ecstasy group than in the control group (p = 0.015). Age and use of cannabis and hallucinogens were confounding variables. However, inspection of chi-square tables suggests that the effect of these parameters on the movement data is likely to be minor. CONCLUSIONS: The prevalence of self-reported tremor and changes in fine hand control and voice/speech is significantly higher in stimulant users than in non-stimulant users. Inclusion of these common and noticeable changes in body function may aid public health campaigns that target prevention or harm minimization.

What is the effect of bodily illusions on corticomotoneuronal excitability? A systematic review.

BACKGROUND: This systematic review aimed to summarise and critically appraise the evidence for the effect of bodily illusions on corticomotoneuronal excitability. METHODS: Five databases were searched, with two independent reviewers completing study inclusion, risk of bias, transcranial magnetic stimulation (TMS) reporting quality, and data extraction. Included studies evaluated the effect of an illusion that altered perception of the body (and/or its movement) on excitability of motor circuitry in healthy, adult, human participants. Studies were required to: use TMS to measure excitability and/or inhibition; report quantitative outcomes (e.g., motor evoked potentials); compare the illusion to a control or active comparison condition; evaluate that an illusion had occurred (e.g., measured illusion strength/presence). RESULTS: Of 2,257 studies identified, 11 studies (14 experiments) were included, evaluating kinaesthetic illusions (n = 5), a rubber hand illusion (RHI) paradigm (n = 5), and a missing limb illusion (n = 1). Kinaesthetic illusions (induced via vision/tendon vibration) increased corticomotoneuronal excitability. Conflicting effects were found for traditional, visuotactile RHIs of a static hand. However, embodying a hand and then observing it move ("self-action") resulted in decreased corticomotoneuronal excitability and increased silent period duration (a measure of Gamma-Aminobutynic acid [GABA]B-mediated intracortical inhibition in motor cortex), with the opposite occurring (increased excitability, decreased inhibition) when the fake hand was not embodied prior to observing movement ("other-action"). Visuomotor illusions manipulating agency had conflicting results, but in the lower risk study, illusory agency over movement resulted in a relative decrease in corticomotoneuronal excitability. Last, an illusion of a missing limb reduced corticomotoneuronal excitability. CONCLUSION: While evidence for the effect of bodily illusions on corticomotoneuronal excitability was limited (only 14 experiments) and had a high risk of bias, kinaesthetic illusions and illusions of embodying a hand (and seeing it move), had consistent effects. Future investigations into the role of embodiment and the illusion strength on corticomotoneuronal excitability and inhibition are warranted.

Use of illicit amphetamines is associated with long-lasting changes in hand circuitry and control.

OBJECTIVE: The study aim was to determine if use of illicit amphetamines or ecstasy is associated with abnormal excitability of the corticomotoneuronal pathway and manipulation of novel objects with the hand. METHODS: Three groups of adults aged 18-50 years were investigated: individuals with a history of illicit amphetamine use, individuals with a history of ecstasy use but minimal use of other stimulants, and non-drug users. Transcranial magnetic stimulation was delivered to the motor cortex and the electromyographic response (motor evoked potential; MEP) was recorded from a contralateral hand muscle. Participants also gripped and lifted a novel experimental object consisting of two strain gauges and an accelerometer. RESULTS: Resting MEP amplitude was larger in the amphetamine group (6M, 6F) than the non-drug and ecstasy groups (p < 0.005) in males but not females. Overestimation of grip force during manipulation of a novel object was observed in the amphetamine group (p = 0.020) but not the ecstasy group. CONCLUSIONS: History of illicit amphetamine use, in particular methamphetamine, is associated with abnormal motor cortical and/or corticomotoneuronal excitability in males and abnormal manipulation of novel objects in both males and females. SIGNIFICANCE: Abnormal excitability and hand function is evident months to years after cessation of illicit amphetamine use.

Discovery of Small-Molecule Antibiotics against a Unique tRNA-Mediated Regulation of Transcription in Gram-Positive Bacteria.

The emergence of multidrug-resistant bacteria necessitates the identification of unique targets of intervention and compounds that inhibit their function. Gram-positive bacteria use a well-conserved tRNA-responsive transcriptional regulatory element in mRNAs, known as the T-box, to regulate the transcription of multiple operons that control amino acid metabolism. T-box regulatory elements are found only in the 5'-untranslated region (UTR) of mRNAs of Gram-positive bacteria, not Gram-negative bacteria or the human host. Using the structure of the 5'UTR sequence of the Bacillus subtilis tyrosyl-tRNA synthetase mRNA T-box as a model, in silico docking of 305 000 small compounds initially yielded 700 as potential binders that could inhibit the binding of the tRNA ligand. A single family of compounds inhibited the growth of Gram-positive bacteria, but not Gram-negative bacteria, including drug-resistant clinical isolates at minimum inhibitory concentrations (MIC 16-64 µg mL-1 ). Resistance developed at an extremely low mutational frequency (1.21×10-10 ). At 4 µg mL-1 , the parent compound PKZ18 significantly inhibited in vivo transcription of glycyl-tRNA synthetase mRNA. PKZ18 also inhibited in vivo translation of the S. aureus threonyl-tRNA synthetase protein. PKZ18 bound to the Specifier Loop in vitro (Kd ≈24 µm). Its core chemistry necessary for antibacterial activity has been identified. These findings support the T-box regulatory mechanism as a new target for antibiotic discovery that may impede the emergence of resistance.

Upper limb function in children with attention-deficit/hyperactivity disorder (ADHD).

Upper limb function was investigated in children with ADHD using objective methods. We hypothesised that children with ADHD exhibit abnormal dexterity, force application during manipulation of a novel object, and movement rhythmicity. Two groups of age- and gender-matched children were investigated: 35 typically developing children (controls, 10.5 ± 0.4 years, 32M-3F) and 29 children (11.5 ± 0.5 years, 27M-2F) with formally diagnosed ADHD according to DSM-IV-TR criteria. Participants underwent a series of screening tests and tests of upper limb function while "off" medication. Objective quantification of upper limb function involved measurement of force during a grip and lift task, maximal finger tapping task, and maximal pinch grip. Acceleration at the index finger was also measured during rest, flexion and extension, and a postural task to quantify tremor. The Movement Assessment Battery for Children-2 (MABC-2) was also administered. Significant between-group differences were observed in movement rhythmicity, manipulation of a novel object, and performance of the MABC-2 dexterity and aiming and catching components. Children with ADHD lifted a novel object using a lower grip force (P = 0.036), and held the object with a more variable grip force (P = 0.003), than controls. Rhythmicity of finger tapping (P = 0.008) and performance on the dexterity (P = 0.007) and aiming and catching (P = 0.042) components of the MABC-2 were also significantly poorer in the ADHD group than controls. Movement speed, maximum pinch grip strength, and tremor were unaffected. The results of the study show for the first time that ADHD is associated with deficits in multiple, but not all domains of upper limb function.

History of cannabis use is associated with altered gait.

BACKGROUND: Despite evidence that cannabinoid receptors are located in movement-related brain regions (e.g., basal ganglia, cerebral cortex, and cerebellum), and that chronic cannabis use is associated with structural and functional brain changes, little is known about the long-term effect of cannabis use on human movement. The aim of the current study was to investigate balance and walking gait in adults with a history of cannabis use. We hypothesised that cannabis use is associated with subtle changes in gait and balance that are insufficient in magnitude for detection in a clinical setting. METHODS: Cannabis users (n=22, 24±6years) and non-drug using controls (n=22, 25±8years) completed screening tests, a gait and balance test (with a motion capture system and in-built force platforms), and a clinical neurological examination of movement. RESULTS: Compared to controls, cannabis users exhibited significantly greater peak angular velocity of the knee (396±30 versus 426±50°/second, P=0.039), greater peak elbow flexion (53±12 versus 57±7°, P=0.038) and elbow range of motion (33±13 versus 36±10°, P=0.044), and reduced shoulder flexion (41±19 versus 26±16°, P=0.007) during walking gait. However, balance and neurological parameters did not significantly differ between the groups. CONCLUSIONS: The results suggest that history of cannabis use is associated with long-lasting changes in open-chain elements of walking gait, but the magnitude of change is not clinically detectable. Further research is required to investigate if the subtle gait changes observed in this population become more apparent with aging and increased cannabis use.

Hyperechogenicity of the Substantia Nigra in Parkinson's Disease: Insights from Two Brothers with Markedly Different Disease Durations.

We present clinical features and substantia nigra morphology for two brothers with Parkinson's disease (PD) aged 60 and 59 years. The brothers were diagnosed at 41 and 50 years of age, respectively. Both patients exhibited an abnormally large area of substantia nigra echogenicity bilaterally when viewed with transcranial ultrasound. The abnormality was similar in both brothers despite one having a much longer disease duration than the other. These findings further highlight that transcranial ultrasound is not associated with severity of clinical symptoms, but it might assist in the diagnosis of PD provided that it is combined with other variables known to precede PD.

Inhibition of HIV-1 Gag-membrane interactions by specific RNAs.

HIV-1 particle assembly, which occurs at the plasma membrane (PM) of cells, is driven by the viral polyprotein Gag. Gag recognizes phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2], a PM-specific phospholipid, via the highly basic region (HBR) in its N-terminal matrix (MA) domain. The HBR is also known to bind to RNA. We have previously shown, using an in vitro liposome binding assay, that RNA inhibits Gag binding to membranes that lack PI(4,5)P2 If this RNA block is removed by RNase treatment, Gag can bind nonspecifically to other negatively charged membranes. In an effort to identify the RNA species that confer this inhibition of Gag membrane binding, we have tested the impact of purified RNAs on Gag interactions with negatively charged liposomes lacking PI(4,5)P2 We found that some tRNA species and RNAs containing stem-loop 1 of the psi region in the 5' untranslated region of the HIV-1 genome impose inhibition of Gag binding to membranes lacking PI(4,5)P2 In contrast, a specific subset of tRNAs, as well as an RNA sequence previously selected in vitro for MA binding, failed to suppress Gag-membrane interactions. Furthermore, switching the identity of charged residues in the HBR did not diminish the susceptibility of Gag-liposome binding for each of the RNAs tested, while deletion of most of the NC domain abrogates the inhibition of membrane binding mediated by the RNAs that are inhibitory to WT Gag-liposome binding. These results support a model in which NC facilitates binding of RNA to MA and thereby promotes RNA-based inhibition of Gag-membrane binding.