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Antibodies directed against glutamic acid decarboxylase (GAD) are present in many patients with stiff person syndrome and increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia. The classic clinical features of stiff person syndrome include muscular stiffness with superimposed painful muscular spasms. Gait is often impaired. Other CNS disorders associated with GAD antibodies include progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and even epilepsy. Glutamic acid decarboxylase is the rate-limiting enzyme in the production of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter. Presumably, antibodies directed against GAD impair GABA production, but the precise pathogenic mechanism of GAD-antibody-related neurologic disorders is uncertain. Many patients respond to treatment with immunomodulating therapy. Symptomatic treatment with agents that enhance GABA activity, such as benzodiazepines and baclofen, is also helpful for many patients.

The present study tested the hypothesis that a minimum frequency of testosterone pulses is required to exert negative feedback control of luteinizing hormone (LH). Effect of gonadal steroids on endogenous LH release in rams was investigated after injecting ovine LH (NIADDK-oLH-26, i.v.; 5 μg 100kg−1 BW) to induce testosterone pulses while rams were undergoing windows of LH suppression during the influence of a LH releasing hormone (LHRH) antagonist (SB-75; Bajusz et al., 1988, Int. J. Peptide Protein Res., 32: 425–435). Patterns of LH release were characterized as rams recovered from LH inhibition. Rams were exposed to artificial photoperiods of 12 weeks of long days (16L:8D) followed by short days (8L:16D) to initiate reproductive activity. The study began during Week 5 of short days. Serial plasma samples were collected from six postpubertal rams (five Suffolks and one Hampshire) at 15-min intervals for 69.5 h. All rams were given LHRH antagonist (10 μg kg−1 BW, s.c.) at Hour 24 during each of three collection periods which took place on alternating weeks in a Latin square design. Rams were given a different exogenous oLH treatment (no oLH, one dose at 12 h after antagonist or three doses at 6-h intervals with initial dose 6 h after antagonist) during each collection period. Exogenous oLH decreased the number of LH pulses during the recovery period (Hours 48 to 72 of experiment; 24 to 48 h after antagonist; P

Serum levels of various lipid parameters, i.e., triglycerides, total cholesterol, alpha lipoprotein or high density lipoprotein (HDL)-cholesterol and beta lipoprotein or low density lipoprotein (LDL)-cholesterol were measured in a total of 138 histologically proven cases of breast cancer along with 146 control women. The mean levels of serum triglycerides, total cholesterol and LDL-cholesterol were found to be significantly higher in breast cancer cases as compared to controls. However, lower mean levels of serum HDL-cholesterol and sex-hormone binding glubulin (SHBG) were observed in breast cancer patients than the control subjects. The results indicate a probable relation between serum lipids and the activity of sex-hormones. Moreover, the study reflects an overall disturbance of lipid metabolism in the pathological process of breast cancer.

Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning. In the current study, we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with L-DOPA during motor tasks in patients with Parkinson's disease (PD). Forty-five PD patients were genotyped for the DRD2 polymorphism (rs 1076560, G > T). Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF L-DOPA states. For motor sequence learning, DRD2 genotype mediated L-DOPA effects such that L-DOPA associated improvements were only observed in the minor T allele carriers (associated with lower D2 receptor availability, t10 = −2.71, p = 0.022), whereas G homozygotes showed no performance change with L-DOPA. For the grooved pegboard test, performance improved with L-DOPA independent of patients’ DRD2 genotype. Collectively these results demonstrate that common DRD2 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals.

Fluent speakers and people who stutter manifest alterations in autonomic and emotional responses as they view stuttered relative to fluent speech samples. These reactions are indicative of an aroused autonomic state and are hypothesized to be triggered by the abrupt breakdown in fluency exemplified in stuttered speech. Furthermore, these reactions are assumed to be the basis for the stereotypes held by different communicative partners towards people who stutter.To examine the autonomic and emotional reactions of graduate student clinicians in speech-language pathology as they viewed fluent and severe stuttered speech samples.Twenty-one female graduate student clinicians in speech-language pathology participated in this study. Each participant viewed four 30-s video samples (two fluent and two stuttered speech samples) while their autonomic responses (skin conductance response (SCR) and heart rate (HR)) were concurrently captured. Furthermore, emotional responses to stuttered and fluent speech samples were captured using the self-assessment manikin (SAM) and a rating scale with nine bipolar adjectives reflecting one's feelings.An increase in SCR and deceleration in HR was observed as graduate clinicians viewed stuttered speech samples versus fluent speech samples and the differences were statistically significant. In addition, results from the self-rating scales showed that participants had negative feelings (e.g., emotionally aroused, unpleasant, embarrassed, uncomfortable, etc.) while viewing stuttered speech.Findings suggest that graduate student clinicians in speech-language pathology demonstrated altered autonomic and emotional responses similar to those manifested by fluent and stuttered speakers as they viewed stuttered speech samples. Collectively, these findings support the contention that the inherent nature of stuttered speech triggers a visceral reaction in a listener, irrespective of their background and knowledge about the disorder.

Analysis of the amplitude of low frequency BOLD signal fluctuations (ALFF) in the resting state has recently been used to study the dynamics of intrinsic neural activity. Several studies have also suggested its potential as a biomarker for neuropsychiatric disease. In the current study, we quantified ALFF to determine changes in intrinsic neural oscillations in patients with Parkinson's disease (PD) on and off L-DOPA. Twenty-four PD patients and 24 healthy age-matched controls participated in the study. PD patients underwent two resting state fMRI sessions, either ON a controlled dose of L-DOPA or following a placebo pill (OFF). Control participants underwent one test session. We found that there was increased amplitude of low frequency BOLD signal oscillations for PD patients OFF L-DOPA in the primary and secondary motor areas, and in the middle and medial prefrontal cortices. L-DOPA significantly reduced the amplitude of low frequency oscillations within these regions. The degree of ALFF in the premotor cortex predicted patients' motor performance as measured by the Grooved Pegboard task, such that greater ALFF was associated with poorer performance. These results are in line with the pathophysiology of PD, which shows changes in neural oscillations. Thus, frequency domain analyses of resting state BOLD fMRI signals may provide a useful means to study the pathophysiology of PD and the physiology of the brain's dopaminergic pathways.

Craig discussed fluency outcomes following stuttering therapy that involved retraining the speech system, on the assumption that the speech end product is truly fluent. As previously outlined by Dayalu and Kalinowski, we strongly disagree with the notion that behavioral paradigms can ever result in automatic, long lasting natural sounding fluent speech. Fluent speech is within the grasp of one who stutters as seen in the effects of choral speech and derivatives such as delayed auditory feedback.

We previously reported a differential effect of dopaminergic medication across the time course of motor sequence learning in early stage Parkinson's (PD) patients [1]. There was a medication-associated impairment specific to the early phase of learning. In the current study, we investigated the BOLD responses associated with this deleterious medication effect on motor sequence learning. We hypothesized that levodopa (l-DOPA) would negatively affect the recruitment of the ventral striatal circuitry during the early phase of learning. Seventeen early stage PD patients ON and OFF l-DOPA and 21 healthy control participants performed an explicit motor sequence learning task inside the MRI scanner. We observed sequence learning-specific activation during the early phase in the ventral putamen for controls and PD OFF but not for PD ON l-DOPA. A comparison of activation between PD OFF and PD ON showed that activation within the ventral putamen was decreased in PD ON compared to PD OFF. The extent of the l-DOPA associated activation decrease in the ventral putamen showed a small, positive correlation with the degree of sequence learning performance decrease in the early phase of learning (r=0.45-0.54 across measures, p

Perceptions of benefits of speech therapy, success of therapy across clinical settings, reasons for returning to therapy, client-clinician relationships, and clinicians' competency were assessed in 57 participants (47 men, 10 women; M age = 34 yr.) trying a new therapy. A majority of respondents had cumulatively five or more years in therapy and at least two stuttering therapies. Respondents rated university or hospital settings as more successful than services in public schools. 70% of the respondents noted difficulty communicating basic needs; they blamed themselves for inability to maintain posttherapeutic gains while perceiving their clinicians to be competent and attentive — although 47% of the respondents had minimal to no contact with their therapist after therapy.

The inhibitory effects of continuously presented audio signals (/a/, /s/, 1,000 Hz pure-tone) on stuttering were examined. Eleven adults who stutter participated. Participants read four 300-syllable passages (i.e. in the presence and absence of the audio signals). All of the audio signals induced a significant reduction in stuttering frequency relative to the control condition (P = 0.005). A significantly greater reduction in stuttering occurred in the /a/ condition (P0.05), while there was no significant difference between the /s/ and 1,000 Hz pure-tone conditions (P0.05). These findings are consistent with the notion that the percept of a second signal as speech or non-speech can respectively augment or attenuate the potency for reducing stuttering frequency.

Wilson disease patients present with any of several neurologic phenotypes, and their treated outcomes vary widely. Our goal was to determine whether presenting clinical features of neurologic Wilson disease (WD) predict longer term neurologic outcomes in patients receiving anticopper treatment.Patients enrolled in four WD treatment trials received a standardized neurologic examination at trial enrollment and then at pre-specified intervals following anticopper therapy, initially with tetrathiomolybdate or trientine and then with zinc. The examination scored patients' motor signs, including tremor, rigidity, dystonia, dyarthria, and gait. The Total Score was obtained by summing these subscores. Eighty-six patients were included in our analysis, with a mean follow-up of 34.7 months. Retrospectively, the analysis compared scaled and unscaled sign subscores at enrollment and follow-up with change in the Total Score, using a generalized estimating equations approach.In the primary analysis, improvement in the Total Score was best predicted by sign subscores for tremor (beta -0.7, p = 0.006), gait abnormalities (beta -3.7, p 0.001), and speech (beta = -1.3, p = 0.05). Dystonia (beta = 1.8, p 0.001) and facial expression (beta = 1.9, p = 0.03) were associated with worsening Total Score. Of the motor signs followed individually, dystonia proved most resistant to treatment.This is the first large-scale prospectively acquired study assessing prognostic significance of specific neurologic signs in WD. Our data support the historical observations that tremor is a favorable prognostic sign while dystonia is relatively refractory to treatment in WD.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI (fcMRI) in mild to moderate stage Parkinson’s patients on and off L-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off L-DOPA compared to controls. This enhanced connectivity was down-regulated by L-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off L-DOPA exhibited increased power in the frequency band 0.02 – 0.05 Hz compared to controls and to PD on L-DOPA. The L-DOPA associated decrease in the power of this frequency range modulated the L-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the L-DOPA associated decrease in power in this frequency band also correlated with the L-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and L-DOPA modulate striatal resting state BOLD signal oscillations and corticostriatal network coherence.

A novel phenomenon of fluency enhancement via visual gestures of speech in the absence of traditional auditory feedback is reported herein. The effect on visual choral speech on stuttering frequency was investigated. Ten participants who stuttered recited memorized text aloud under two conditions. In a visual choral speech (VCS) condition participants were instructed to focus their gaze on the face, lips and jaw of a research assistant who 'silently mouthed' the text in unison. In a control condition, participants recited memorized text to the research assistant who sat motionless. A statistically significant (P=0.0025) reduction of approximately 80% in stuttering frequency was observed in the VCS condition. As visual linguistic cues are sufficient to activate the auditory cortex, one may speculate that VCS induces fluency in a similar yet undetermined manner as altered auditory feedback does.

Antipsychotic drugs have revolutionized the management of psychosis. Unfortunately, these drugs may cause a variety of distressing acute and delayed movement disorders, collectively known as 'extrapyramidal symptoms' (EPS).This review summarizes the current knowledge of the phenomenology, epidemiology, and pathophysiology of EPS, while highlighting their prevention and management.The review is limited to movement disorders resulting from typical and atypical antipsychotics. Recent and higher-quality evidence is emphasized.The pathophysiology of these disorders is still unclear. The use of atypical antipsychotics may have reduced EPS but has far from eliminated them. Available treatment options are often disappointing, especially for akathisia and the tardive syndromes. Future work will identify better treatments for these symptoms, as well as new antipsychotic agents that do not cause EPS.

B-lymphocytes possess a specialized lysosomal compartment, the regulated transformation of which has been implicated in B-cell antigen presentation. Members of the mucolipin (TRPML) family of cation channels have been implicated in regulated vesicular transport in several tissues, but a role for TRPML function in lymphocyte vesicular transport physiology has not been previously described. To address the role of TRPML proteins in lymphocyte vesicular transport, we analyzed the lysosomal compartment in cultured B-lymphocytes engineered to lack TRPML1 or after expression of N- or C-terminal GFP fusion proteins of TRPML1 or TRPML2. Consistent with previous analyses of lymphocytes derived from human patients with mutations in TRPML1, we were not able to detect abnormalities in the lysosomes of TRPML1-deficient DT40 B-lymphocytes. However, while N-terminal GFP fusions of TRPML2 localized to normal appearing lysosomes, C-terminal GFP fusions of either TRPML1 or TRPML2 acted to antagonize endogenous TRPML function, localizing to large vesicular structures, the histological properties of which were indistinguishable from the enlarged lysosomes observed in affected tissues of TRPML1-deficient humans. Endocytosed B-cell receptors were delivered to these enlarged lysosomes, demonstrating that a TRPML-dependent process is required for normal regulation of the specialized lysosome compartment of vertebrate B-lymphocytes.

This study examined fluency enhancement in people who stutter via the concomitant presentation of silently mouthed visual speech. Ten adults who stutter recited memorized text while watching another speaker silently mouth linguistically equivalent and linguistically different material. Relative to a control condition, in which no concomitant stimulus was provided, stuttering was reduced by 71% in the linguistically equivalent condition versus only 35% in the linguistically different condition. Despite being an 'incomplete' second speech signal, visual speech possesses the capacity to immediately and substantially enhance fluency when it is linguistically equivalent to the intended utterance. It is suggested that fluency enhancement via concomitantly presented external speech is achieved through the extraction of relevant speech gestures from the external speech signal that compliment the intended production, thereby compensating for possible internal inconsistencies in the matching of speech codes in people who stutter. As visual speech perception relies on fewer redundant cues to demarcate the intended gestures, when used as an external stuttering inhibitor, higher degrees of linguistic equivalence seem to be necessary for optimal stuttering inhibition.

Self-contained ear-level devices delivering altered auditory feedback (AAF) for the application with those who stutter have only been recently developed.The paper examines the first therapeutic application of self-contained ear-level devices in three experiments. The effect of the device on the proportion of stuttered syllables and speech naturalness was investigated following initial fitting and at 4 months post-fitting.Three experiments were undertaken: In Experiment 1, the effect of a self-contained in-the-ear device delivering AAF was investigated with those who stutter during reading and monologue. Two adolescents and five adults who stuttered read and produced monologue with and without a device fit monaurally. The device provided a frequency shift of +500 Hz in combination with a delayed auditory feedback of 60 ms. Custom-made ITC and CIC devices were fabricated for four adults and four youths in Experiment 2. The effect of group (i.e. youth versus adult), time (i.e. initial fitting versus 4-month follow-up), speech task (i.e. reading versus monologue), and device (i.e. present versus absent) on stuttering rate was examined. In Experiment 3, 15 naïve listeners rated the speech naturalness of speech produced by the participants in Experiment 2. Speech samples from six conditions were rated: reading and monologue without the device at the initial visit, reading and monologue with the device at the initial visit, and reading and monologue with the device at 4 months.In Experiment 1, the proportion of stuttered syllables was significantly (p=0.011) reduced by approximately 90% during reading and 67% during monologue with the device relative to no device. Only a significant main effect of device (p=0.0028) was found in Experiment 2. That is, stuttering rate was significantly reduced with the device in place regardless of speech task or group and remained so 4 months later. In Experiment 3, speech samples generated while wearing the device were judged to be more natural sounding than those without the device (p0.0001) for reading and monologue with both adults and youths. There was no significant difference between the mean naturalness ratings of speech samples generated during the initial fitting with the device relative to that at 4 months with the device (p0.05) in all cases except with the youths while engaged in monologue. For that condition, raters judged the speech produced at the initial fitting as more natural.These findings support the notion that a self-contained in-the-ear device delivering AAF assists those who stutter. With the device in place, stuttering is reduced and speech produced is judged to be more natural than with out the device.

Endogenous oestrogens are thought to be involved in breast cancer, but few studies could show the direct relationship between hormones and pathological process of the disease. In the present study, oestradiol was estimated in the serum of pre-and postmenopausal breast cancer patients along with normal healthy controls and patients with carcinoma of the uterine cervix which is not dependent on oestrogens. Premenopausal patients with breast cancer showed higher levels of oestradiol as compared to premenopausal control women as well as cervical cancer patients. Whereas, no statistically significant differences were observed in serum oestradiol levels amongst postmenopausal groups of breast cancer, cervical cancer and normal women. The result of the study reflects the association of oestradiol as well as its difference in the pathological events of pre and postmenopausal breast cancer.

This study investigated the effects of producing and listening to the vowel /a/ on the frequency of overt stuttering moments in eight people who stuttered. Stuttering frequency counts were made for the speech produced in the control condition, and after each of these four experimental conditions: (a) producing a vowel /a/ for 4 s; (b) producing a vowel /a/ for 4 s and waiting for 4 s; (c) listening to a recording of the vowel /a/ for 4 s; and (d) listening to a recording of the vowel /a/ for 4 s and waiting for 4 s. A significant reduction in the stuttering frequency was only observed following production of the vowel /a/ without a 4 s delay (P=0.02), suggesting that the vowel production prior to speech, serves as a temporary fluency enhancer. Its similarity to the occurrence of overt stuttering moments (e.g. discrete part-word repetitions and prolongation's) and its relationship to the fundamental nature of the pathology are discussed.

This study examined the power of an exogenously generated stuttered speech signal on stuttering frequency when compared to an exogenously generated normal speech signal. In addition, we examined the specific components of the second speech signal, which might be responsible for the inducement of fluency in people who stutter. Eight males and two females who stuttered participated in this study. Experiment I involved meaningful speech: normal continuous speech, normal interrupted speech, stuttered continuous speech, and stuttered interrupted speech, whereas Experiment II involved vowels and consonants: /a/, /a-i-u/, /s/, /s-sh-f/. The results indicated that stuttered and normal speech signals were equally effective in reducing stuttering frequency. Further, the vowels were more powerful than consonants in inducing fluency for people who stutter. It is suggested that acoustic manifestations of stuttering, rather than a problem, may be a natural compensatory mechanism to bypass or inhibit the 'involuntary block' at the neural level.

This analysis investigates the ancestry of a single modern human specimen from Australia, WLH-50 (Thorne et al ., in preparation; Webb, 1989). Evaluating its ancestry is important to our understanding of modern human origins in Australasia because the prevailing models of human origins make different predictions for the ancestry of this specimen, and others like it. Some authors believe in the validity of a complete replacement theory and propose that modern humans in Australasia descended solely from earlier modern human populations found in Late Pleistocene Africa and the Levant. These ancestral modern populations are believed to have completely replaced other archaic human populations, including the Ngandong hominids of Indonesia. According to this recent African origin theory, the archaic humans from Indonesia are classified as Homo erectus , a different evolutionary species that could not have contributed to the ancestry of modern Australasians. Therefore this theory of complete replacement makes clear predictions concerning the ancestry of the specimen WLH-50. We tested these predictions using two methods: a discriminant analysis of metric data for three samples that are potential ancestors of WLH-50 (Ngandong, Late Pleistocene Africans, Levant hominids from Skhul and Qafzeh) and a pairwise difference analysis of nonmetric data for individuals within these samples. The results of these procedures provide an unambiguous refutation of a model of complete replacement within this region, and indicate that the Ngandong hominids or a population like them may have contributed significantly to the ancestry of WLH-50. We therefore contend that Ngandong hominids should be classified within the evolutionary species, Homo sapiens . The Multiregional model of human evolution has the expectation that Australasian ancestry is in all three of the potentially ancestral groups and best explains modern Australasian origins.

High-speed digital data links from 4-K superconductor electronics to room temperature are challenging due to the fact that energy/bit for single flux quantum logic is many (six) orders of magnitude lower than that of standard room-temperature logic. Our approach of building an energy-efficient high-speed data link involves a joint electrical-thermal design of a temperature-distributed architecture using different electronic technologies. This differential digital data link design involves superconductor, multiple cryogenic semiconductor and additional room-temperature semiconductor circuitry. The current design involves three cryogenic semiconductor ICs for integration with a multistage cryocooled digital system. The first cryogenic semiconductor IC is designed to operate at 4 K with a power consumption of 0.3 mW and interface directly with the superconductor differential single flux quantum/dc drivers. For testing it, a superconductor carrier chip containing an analog-to-digital converter has been designed for the HYPRES dual- (4.5 and 20 ) fabrication process.