Cortical inexcitability defines an adverse clinical profile in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis, studies using threshold-tracking transcranial magnetic stimulation (TMS) have identified corticomotoneuronal dysfunction as a key pathogenic mechanism. Some patients, however, display no motor response at maximal TMS intensities, termed here an 'inexcitable' motor cortex. The extent to which this cortical difference impacts clinical outcomes remains unclear. The aim of this study was to determine the clinical profile of patients with inexcitability to TMS. METHODS: Motor cortex excitability was evaluated using TMS. Patients in whom a motor evoked potential could not be recorded in one or more limbs at maximal TMS intensities were classified as four-limb or partially inexcitable. Demographic information, clinical variables and survival data were analysed. RESULTS: From 133 patients, 40 were identified with inexcitability. Patients with four-limb inexcitability were younger (P = 0.03) and had lower-limb disease onset (64%), greater functional disability (P < 0.001) and faster disease progression (P = 0.02), particularly if inexcitability developed within 1 year of symptoms (P < 0.01). Patients with partial inexcitability had higher resting motor thresholds compared to the excitable cohort (P < 0.01), but averaged short-interval intracortical inhibition was similar (P = 0.5). Mean survival was reduced if inexcitability involved all limbs within 12 months of symptom onset (P = 0.04). CONCLUSION: Amyotrophic lateral sclerosis patients with inexcitability of all four limbs to TMS have a distinct clinical profile of younger age and lower-limb onset. Importantly, these patients display a more malignant disease trajectory, with faster progression, greater functional disability and reduced survival when occurring in early disease. This measure may provide an important prognostic marker in amyotrophic lateral sclerosis.

Sonographic assessment of nerve blood flow in diabetic neuropathy.

AIMS: To undertake sonographic assessment of nerve blood flow in people with Type 2 diabetes and correlate the findings with neuropathy severity scores and electrophysiological measurements. METHODS: Median and tibial nerve ultrasound scans were undertaken in 75 people with diabetes and 30 aged-matched controls without diabetes, using a high-resolution linear probe at non-entrapment sites. Nerve blood flow was quantified using power Doppler techniques to obtain the vessel score and the maximum perfusion intensity. Neuropathy severity was assessed using a total neuropathy score. RESULTS: Diabetic nerves had higher rates of nerve blood flow detection (28%) compared to the control group (P < 0.0001). Significant correlations were found between nerve blood flow measurements and nerve size (P <0.001), reported sensory symptoms (P < 0.05) and neuropathy severity scores (P < 0.001). The cohort with diabetes had significantly larger median (8.5 ± 0.3 mm2 vs 7.2 ± 0.1 mm2 ; P < 0.05) and tibial nerves (18.0 ± 0.9 mm2 vs 12.8 ± 0.5 mm2 ; P < 0.05) compared with controls. CONCLUSION: Peripheral nerve hypervascularity is detectable by ultrasonography in moderate to severe diabetic neuropathy with prominent sensory dysfunction.

Motor neuron disease: current management and future prospects.

Motor neuron disease (MND) is characterised by progressive neurological deterioration and coexistence of upper and lower motor neuron signs. Over the past decade, evidence has emerged of unique pathophysiological processes, including glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the recently discovered C9orf72 gene, have radically changed the pathological mindset, from MND being classified as a neuromuscular disease to one that MND forms a continuum with other primary neurodegenerative disorders, including frontotemporal dementia. The present review will highlight the improvements that have occurred in clinical care, in conjunction with recent scientific developments.

Common peroneal neuropathy and cancer.

Common peroneal neuropathy (CPN) may develop unexpectedly in patients with underlying cancer. To clarify the underlying pathophysiology, clinical and neurophysiological data were prospectively collected from 10 oncology clinic patients referred for neurological assessment after the onset of foot weakness. In all patients, the CPN occurred in the setting of advanced systemic malignancy frequently associated with marked weight loss at the time of foot weakness. Neurophysiological studies localised the CPN to the fibular head in 80% of cases. Findings from this study, combined with recent experimental evidence, support the hypothesis that clinically evident CPN develops after rapid weight loss, perhaps reflecting a relative metabolic deficiency within the nerve, which exposes anatomical susceptibility and possible subclinical pre-existing nerve injury.

Switching pathways: room-temperature neutral solvolysis and substitution of amides.

Stick or twist: By introducing steric hindrance at the nitrogen atom, stable linear amides bearing an electron-withdrawing α-substituent (Z = Ar, PhSO(2), P(O)(OR)(2), CN, or CO(2)R) can be induced to undergo solvolysis and substitution reactions through an elimination-addition mechanism (see picture). Key to this process is a low barrier to rotation around the amide bond and the α-substituent Z.

Mapping the properties of bidentate ligands with calculated descriptors (LKB-bid).

We have extended the Ligand Knowledge Base (LKB) approach to consider a broad range of bidentate ligands, varying donors, substituents and backbones, which gives rise to a diverse set of 224 ligands in a new database, LKB-bid. Using a subset of steric and electronic parameters described previously for bidentate P,P-donor ligands (LKB-PP), here this approach has been applied to a wider set of bidentate ligands, to explore how these modifications affect the properties of organometallic complexes. The resulting database has been processed with Principal Component Analysis (PCA), generating a "map" of ligand space which highlights the contribution of donor atoms and bridge length to the variation in ligand properties. This mapping of bidentate ligand space with DFT-calculated steric and electronic parameters has demonstrated that the properties of ligands with different donor atoms can be captured within a single computational approach, providing both an overview of ligand space and scope for the more detailed investigation and comparison of different ligand classes.

Prenatal exposure to prednisone in humans and animals retards intrauterine growth.

Prednisone treatment for infertility and subsequent pregnancy maintenance in humans resulted in a significant decrease in the birth weight of full-term infants and a marked increase in the percentage of newborn infants weighing 2500 grams or less, that is, "light for dates" in comparison to control offspring. A parallel experiment with mice indicated that the reduction of birth weight was caused by exposure to corticosteroids rather than to maternal disease or malfunction.

Room-temperature palladium-catalyzed C-H activation: ortho-carbonylation of aniline derivatives.

Pd and CO--ureally got me! The title reaction proceeds efficiently at 18 degrees C under CO (1 atm) with 5 % [Pd(OTs)(2)(MeCN)(2)] as precatalyst. Depending on the solvents used, either anthranilates or cyclic imides can be obtained in high yields (see picture, BQ = benzoquinone, Ts = 4-toluenesulfonyl).

Quantitative muscle ultrasound as a biomarker in Charcot-Marie-Tooth neuropathy.

OBJECTIVE: The utility of quantitative muscle ultrasound as a marker of disease severity in Charcot-Marie-Tooth (CMT) disease subtypes was investigated. METHODS: Muscle ultrasound was prospectively performed on 252 individual muscles from 21 CMT patients (9 CMT1A, 8 CMTX1, 4 CMT2A) and compared to 120 muscles from 10 age and gender-matched controls. Muscle ultrasound recorded echogenicity and thickness in representative muscles including first dorsal interosseus (FDI) and tibialis anterior (TA). RESULTS: Muscle volume of FDI and thickness of TA correlated with MRC strength. Muscle echogenicity was significantly increased in FDI (65.05 vs 47.09; p<0.0001) and TA (89.45 vs 66.30; p<0.0001) of CMT patients. In TA, there was significantly higher muscle thickness (23 vs 18 vs 16mm; p<0.0001) and lower muscle echogenicity (80 vs 95 vs 108; p<0.0001) in CMT1A compared to CMTX1 and CMT2A. This corresponded to disease severity based on muscle strength (MRC grading CMT1A vs CMTX1 vs CMT2A: 59 vs 48 vs 44; p=0.002). CONCLUSION: In CMT, quantitative muscle ultrasound of FDI and TA is a useful marker of disease severity. SIGNIFICANCE: The current findings suggest that quantitative muscle ultrasound has potential as a surrogate marker of disease progression in future interventional trials in CMT.

Testosterone and its metabolites modulate 5HT1A and 5HT1B agonist effects on intermale aggression.

Our understanding of the neurochemical and neuroendocrine systems' regulating the display of offensive intermale aggression has progressed substantially over the past twenty years. Pharmacological studies have shown that serotonin, via its action at 5HT1A and/or 5HT1B receptor sites, modulates the display of intermale aggressive behavior and that its effects serve to decrease behavioral expression. Neuroendocrine investigations, in turn, have demonstrated that male-typical aggression is testosterone-dependent and studies of genetic effects, metabolic function and steroid receptor binding have shown that facilitation of behavioral displays can occur via independent androgen-sensitive or estrogen-sensitive pathways. Remarkably, there have been virtually no studies that examined the interrelationship between these facilitative and inhibitory systems. As an initial step toward characterizing the interaction between the systems, studies were conducted that assessed hormonal modulation of serotonin function at 5HT1A and 5HT1B receptor sites. They demonstrated: (1) that the androgenic and estrogenic metabolites of testosterone differentially modulate the ability of systemically administered 8-OH-DPAT (a 5HT1A agonist) and CGS12066B (a 5HT1B agonist) to decrease offensive aggression; and (2) when microinjected into the lateral septum (LS) or medial preoptic area (MPO), the aggression-attenuating effects of 1A and 1B agonists differ regionally and vary with the steroidal milieu. In general, the results suggest that estrogens establish a restrictive environment for attenuation of T-dependent aggression by 8-OH-DPAT and CGS 12066B, while androgens either do not inhibit, or perhaps even facilitate, the ability of 5HT1A and 5HT1B agonists to reduce aggression. Potential mechanisms involved in the production of these steroidal effects are discussed and emerging issues that may impact on efforts to develop an integrative neurobiological model of offensive, intermale aggression are considered.

Androgen receptor in mouse brain: sex differences and similarities in autoregulation.

The androgen receptor (AR) is generally considered an autoregulated protein. However, studies in brain have produced mixed results regarding sex differences, which should be present given the higher endogenous levels of androgens in males, and the effects of gonadectomy, which presumably should lead to a loss of AR. Resolving these issues is a necessary step in developing a model of AR regulation in the central nervous system and, more broadly, in determining how regulation of this receptor may mediate neural target tissue responsiveness to androgen. To further investigate these issues, the distribution, density, and regulation of neural AR were compared among male and female mice that were intact, gonadectomized, or gonadectomized and given testosterone propionate (TP) through immunocytochemical and Western blot analyses. Four brain areas that have been linked to the regulation of male-typical behavior were evaluated: bed nucleus of the stria terminalis, posterior aspect, medial preoptic area, and dorsal and ventral aspects of the lateral septum. In the immunocytochemical study, integrated particle density, which reflects the average intensity of AR staining, was assessed among the six groups 24 h after surgery using PG-21, a peptide-based AR antiserum. Major findings included regional differences in the intensity of immunostaining; a robust sexual dimorphism in each region, with males exhibiting more intense staining than females; a loss of AR in both sexes after gonadectomy, with more dramatic changes evident in males; and significant up-regulation of AR in response to TP that was equivalent in both sexes. The Western blot analyses of AR in limbic system extracts prepared from the six groups showed a pattern of differences that mirrored the immunocytochemical results, indicating that PG-21 recognized both liganded and unliganded AR. In addition, a dose-response study, in which gonadectomized males and females were administered from 25-1000 microg TP, demonstrated a significant linear trend in up-regulation of AR in both males and females, with no sexual dimorphism in the response to hormone treatment. These results demonstrate that the regulation of AR in both male and female neural tissue is comparable and that the critical determinant of AR expression is the presence or absence of androgen.

Development and expression of hormonal systems regulating aggression.

There are multiple pathways involved in the regulation of male typical aggression by T, and the functional pathway is determined by genotype. Target-tissue sensitivity to the aggression-promoting properties of T and its estrogenic and androgenic metabolites is determined by a complex sequence of events in which steroid receptors play a critical role. To date, it appears that the relative density of AR may be an important factor in the biobehavioral effects of androgens. Regarding sensitivity to estrogens, characterization of ER-NM interactions, and understanding of the contribution of the two activating functions within ER, appears to be necessary to comprehensively describe the cellular basis for responsiveness to the aggression-promoting effect of this T metabolite. In broader terms, these observations indicate that understanding the relationship between T and the expression of aggression in humans will require models that incorporate cellular aspects of steroid hormone action, including metabolism, receptor function, and gene regulation.

Genetic differences in progestin sensitivity in CD-1 and SW female mice.

The lordotic behavior of ovariectomized CD1 and SW female mice was tested in response to estradiol benzoate(EB)+progesterone (P) or EB + 5 alpha-dihydroprogesterone (DHP) to determine (i) the role of progestin metabolism in the regulation of sexually receptive behavior, and (ii) strain differences in sensitivity to these progestins. A greater proportion of SW females resisted mounting attempts than CD-1 females, regardless of the progestin administered. However, the differences in mounting were not correlated with the expression of lordotic behavior. A greater proportion of SW females exhibited sexually receptive behavior when given EB+P in comparison to the CD-1 females. There were no genotypic differences in lordotic behavior in response to EB+DHP. The potential mechanisms mediating genotype-based differences in responsiveness are discussed, and the relationship of this report to previously described strain differences in progestin sensitivity are considered.

Genetic variation in hypothalamic methyltrienolone (R1881) binding in male mice.

Methyltrienolone (R1881) binding to androgen receptors (AR) from combined hypothalamic-preoptic-septal cytosol was examined in CF-1, CFW, and CD-1 male mice, strains that differ in their sensitivity to the aggression-promoting property of this hormone. Both the affinity of R1881-AR binding and the number of binding sites (Bmax) significantly differed among the genotypes. The dissociation constant (Kd) was lower in CF-1 males (6.7 nM), a behaviorally responsive strain, in comparison to the insensitive CFW and CD-1 males (3.0 nM and 2.0 nM, respectively). The number of binding sites was higher in CF-1 and CFW males (9.07 and 8.81 fmol/mg protein, respectively) than in CD-1 males (5.11 fmol). The results were basically consistent with studies of neural dihydrotestosterone (DHT) binding in these genotypes, and the implications and limits of these data for understanding the androgenic regulation of intermale aggression are discussed.

Activation of male-typical aggression by testosterone but not its metabolites in C57BL/6J female mice.

Ovariectomized adult C57BL/6J mice were exposed to androgens, estrogens, or combined androgen-estrogen treatments and tested for the display of male-typical aggressive behavior toward olfactory bulbectomized stimulus males. Among the androgenic treatments (testosterone, dihydrotestosterone, or methyltrienolone) only testosterone, which, in contrast to the other androgens, can be aromatized, activated fighting behavior. In the second experiment, estradiol benzoate (EB) was totally ineffective as an aggression-promoting compound. Lastly, combined EB+dihydrotestosterone also did not induce male-like aggression. These data suggest that T itself may be capable of promoting aggression without undergoing aromatization or 5 alpha-reduction.

Nonaromatizable androgens may stimulate a male mouse reproductive behavior by binding estrogen receptors.

Castrated DBA/2J male mice emitted 70 kHz vocalizations to female stimuli in response to 10 days of treatment with either testosterone (T, 300 micrograms/day), diethylstilbestrol (DES, 1 or 3 micrograms/day) or methyltrienolone (R1881, 900 micrograms/day). Lower dosages of R1881 (300 and 600 micrograms/day) and the oil vehicle were relatively ineffective in restoring vocalizations. The effects of these hormones on restoring seminal vesicle weight did not always parallel their effects upon behavior. In general T and R1881 (600 and 900 micrograms/day) were effective in restoring seminal vesicles while DES, the lowest dose of R1881 (300 micrograms/day), and the oil vehicle were ineffective. In receptor competition studies, R1881 pretreatment significantly reduced estrogen binding in hypothalamic-preoptic cytosol. In fact the most effective dose for restoring vocalizations (900 micrograms/day) reduced available estrogen binding sites by 91%. We propose that the male-typical vocalizations of mice may normally be stimulated through the activation of estrogen receptors following androgen aromatization and that the ability of a pharmacological dosage of R1881 (900 micrograms/day) to restore behavior may be due to interaction with estrogen receptors in the brain.

Timing of neonatal testosterone exposure in the differentiation of estrogenic regulatory systems for aggression.

Neonatal female CF-1 mice were exposed to testosterone (T) or oil vehicle on Days 1-3, 4-6, or 7-9 postpartum and were tested for the display of male-like aggressive behavior in response to diethylstilbestrol (DES) after ovariectomy during adulthood. The results showed that only the Day 1-3 T treatment established the capacity to exhibit fighting behavior following estrogen administration. These data suggest that sexual differentiation of an estrogen-responsive regulatory system for aggressive behavior occurs during a highly restricted period early in life.

Prenatal exposure to testosterone and its precursors influences morphology and later behavioral responsiveness to testosterone of female mice.

Prenatal exposure to testosterone (T), dehydroepiandrosterone or progesterone significantly increased ano-genital distance of female mice. In addition, prenatal exposure to T or pregnenolone significantly reduced the duration of T exposure during adult life required to induce intraspecific fighting behavior. However, the most masculinized females, those exposed to T prenatally, still had significantly shorter ano-genital distances and required a longer exposure period to T in order to establish fighting than did prenatally oil-exposed male mice. Additional experiments revealed that pregnenolone augments later responsiveness to the aggression-promoting property of T only if it is administered during the prenatal period of development.