Psychedelics in developmental stuttering to modulate brain functioning: a new therapeutic perspective?

Developmental stuttering (DS) is a neurodevelopmental speech-motor disorder characterized by symptoms such as blocks, repetitions, and prolongations. Persistent DS often has a significant negative impact on quality of life, and interventions for it have limited efficacy. Herein, we briefly review existing research on the neurophysiological underpinnings of DS -specifically, brain metabolic and default mode/social-cognitive networks (DMN/SCN) anomalies- arguing that psychedelic compounds might be considered and investigated (e.g., in randomized clinical trials) for treatment of DS. The neural background of DS is likely to be heterogeneous, and some contribution from genetically determinants of metabolic deficiencies in the basal ganglia and speech-motor cortical regions are thought to play a role in appearance of DS symptoms, which possibly results in a cascade of events contributing to impairments in speech-motor execution. In persistent DS, the difficulties of speech are often linked to a series of associated aspects such as social anxiety and social avoidance. In this context, the SCN and DMN (also influencing a series of fronto-parietal, somato-motor, and attentional networks) may have a role in worsening dysfluencies. Interestingly, brain metabolism and SCN/DMN connectivity can be modified by psychedelics, which have been shown to improve clinical evidence of some psychiatric conditions (e.g., depression, post-traumatic stress disorder, etc.) associated with psychological constructs such as rumination and social anxiety, which also tend to be present in persistent DS. To date, while there have been no controlled trials on the effects of psychedelics in DS, anecdotal evidence suggests that these agents may have beneficial effects on stuttering and its associated characteristics. We suggest that psychedelics warrant investigation in DS.

Women with familial risk for breast cancer have an increased frequency of aldehyde dehydrogenase expressing cells in breast ductules.

BACKGROUND: Knowledge is limited regarding the association between stem cells in histologically benign breast tissue and risk factors for breast cancer, and hence we addressed this issue in the present study. Recently, we assessed the histology of benign breast tissue from cancer and non-cancer patients for cells positive for the putative stem cell marker aldehyde dehydrogenase 1 A1 (ALDH), and the findings indicated an association between expression of ALDH and the hormonal factors menopause and hormone therapy. The current investigation examined possible associations between various known clinical and genetic risk factors for breast cancer and cellular expression of ALDH in ductules in benign human breast tissue. METHODS: The study included breast surgery patients that were BRCA1/2 mutation carriers without breast cancer (n = 23), had BRCA1/2 (n = 28) or sporadic (n = 21) breast cancer, or required non-cancer-related mammoplasty (n = 34). The distribution and frequency of ALDH-immunolabelled cells were correlated to patient subgroups with different risk factors, using mammoplasty patients as a control group. Statistical analyses comprised linear and logistic regression, Spearman's rank test, Pearson's test, and Fisher's exact test. In two-tailed tests, p < 0.05 was considered significant. RESULTS: A strong association was found between family history of breast cancer and a high frequency of ALDH+ cells (p = 0.001) at all ductular levels in all groups, regardless of BRCA status, age, parity, or occurrence of cancer. In pre-menopausal non-BRCA cancer patients, the frequency of ALDH+ cells increased with age (p < 0.01) but decreased with increasing parity (p < 0.03). High frequencies of ALDH+ cells were found in the non-basal ductular levels in BRCA1 mutation carriers (p = 0.03), but in the basal ductular level in BRCA2 cancer patients (p = 0.02). Among post-menopausal patients, only on-going hormone replacement therapy was correlated with a high number of ALDH+ cells (p < 0.03). CONCLUSION: In histologically normal breast tissue, we found a positive association between the frequency of ductular ALDH+ cells and several breast cancer risk factors, particularly family history of this disease, which supports previous evidence that ALDH plays a role in breast cancer.

Histidine-rich glycoprotein promotes bacterial entrapment in clots and decreases mortality in a mouse model of sepsis.

Streptococcus pyogenes is a significant bacterial pathogen in humans. In this study, histidine-rich glycoprotein (HRG), an abundant plasma protein, was found to kill S pyogenes. Furthermore, S pyogenes grew more efficiently in HRG-deficient plasma, and clots formed in this plasma were significantly less effective at bacterial entrapment and killing. HRG-deficient mice were strikingly more susceptible to S pyogenes infection. These animals failed to control the infection at the local subcutaneous site, and abscess formation and inflammation were diminished compared with control animals. As a result, bacterial dissemination occurred more rapidly in HRG-deficient mice, and they died earlier and with a significantly higher mortality rate than control animals. HRG-deficient mice supplemented with purified HRG gave the same phenotype as control animals, demonstrating that the lack of HRG was responsible for the increased susceptibility. The results demonstrate a previously unappreciated role for HRG as a regulator of inflammation and in the defense at the local site of bacterial infection.

Distribution of aldehyde dehydrogenase 1-positive stem cells in benign mammary tissue from women with and without breast cancer.

AIMS: Aldehyde dehydrogenase 1 (ALDH1) in female breast tissue has been linked to stem cells, but little is known about the benign cellular organization in situ. We investigated the distribution of ALDH1-immunoreactive (ALDH1+) cells in histomorphologically benign breast tissue from 28 women with or without breast cancer. METHODS AND RESULTS: ALDH1+ cells were detected in benign tissue of women aged 20-72 years, located most commonly at the luminal and intermediate ductular levels and in the stroma. ALDH1+ cell populations and Ki67+ cell populations were present in separate ductules, both cell types rarely showing epithelial differentiation. ALDH1+ cells were non-reactive to Ki67 and oestrogen receptor. Stromal round/oval ALDH1+ non-leukocyte cells in both age groups expressed contractile protein. There was a lower concentration of luminal and intermediate ductular ALDH1+ cells in postmenopausal women than in premenopausal women, and in cancer patients than in non-cancer patients, and a higher concentration in women receiving exogenous hormones. CONCLUSIONS: This study provides further evidence for the stem cell character of ALDH1+ cells, here in benign breast tissue of cancer and non-cancer patients throughout non-lactating adult life, and contributes evidence of benign stromal ALDH1+ cells. The distribution of ductular ALDH1+ stem cells appears to be influenced by hormonal status.

Stuttering: A Disorder of Energy Supply to Neurons?

Stuttering is a disorder characterized by intermittent loss of volitional control of speech movements. This hypothesis and theory article focuses on the proposal that stuttering may be related to an impairment of the energy supply to neurons. Findings from electroencephalography (EEG), brain imaging, genetics, and biochemistry are reviewed: (1) Analyses of the EEG spectra at rest have repeatedly reported reduced power in the beta band, which is compatible with indications of reduced metabolism. (2) Studies of the absolute level of regional cerebral blood flow (rCBF) show conflicting findings, with two studies reporting reduced rCBF in the frontal lobe, and two studies, based on a different method, reporting no group differences. This contradiction has not yet been resolved. (3) The pattern of reduction in the studies reporting reduced rCBF corresponds to the regional pattern of the glycolytic index (GI; Vaishnavi et al., 2010). High regional GI indicates high reliance on non-oxidative metabolism, i.e., glycolysis. (4) Variants of the gene ARNT2 have been associated with stuttering. This gene is primarily expressed in the brain, with a pattern roughly corresponding to the pattern of regional GI. A central function of the ARNT2 protein is to act as one part of a sensor system indicating low levels of oxygen in brain tissue and to activate appropriate responses, including activation of glycolysis. (5) It has been established that genes related to the functions of the lysosomes are implicated in some cases of stuttering. It is possible that these gene variants result in a reduced peak rate of energy supply to neurons. (6) Lastly, there are indications of interactions between the metabolic system and the dopamine system: for example, it is known that acute hypoxia results in an elevated tonic level of dopamine in the synapses. Will mild chronic limitations of energy supply also result in elevated levels of dopamine? The indications of such interaction effects suggest that the metabolic theory of stuttering should be explored in parallel with the exploration of the dopaminergic theory.

The Dopamine System and Automatization of Movement Sequences: A Review With Relevance for Speech and Stuttering.

The last decades of research have gradually elucidated the complex functions of the dopamine system in the vertebrate brain. The multiple roles of dopamine in motor function, learning, attention, motivation, and the emotions have been difficult to reconcile. A broad and detailed understanding of the physiology of cerebral dopamine is of importance in understanding a range of human disorders. One of the core functions of dopamine involves the basal ganglia and the learning and execution of automatized sequences of movements. Speech is one of the most complex and highly automatized sequential motor behaviors, though the exact roles that the basal ganglia and dopamine play in speech have been difficult to determine. Stuttering is a speech disorder that has been hypothesized to be related to the functions of the basal ganglia and dopamine. The aim of this review was to provide an overview of the current understanding of the cerebral dopamine system, in particular the mechanisms related to motor learning and the execution of movement sequences. The primary aim was not to review research on speech and stuttering, but to provide a platform of neurophysiological mechanisms, which may be utilized for further research and theoretical development on speech, speech disorders, and other behavioral disorders. Stuttering and speech are discussed here only briefly. The review indicates that a primary mechanism for the automatization of movement sequences is the merging of isolated movements into chunks that can be executed as units. In turn, chunks can be utilized hierarchically, as building blocks of longer chunks. It is likely that these mechanisms apply also to speech, so that frequent syllables and words are produced as motor chunks. It is further indicated that the main learning principle for sequence learning is reinforcement learning, with the phasic release of dopamine as the primary teaching signal indicating successful sequences. It is proposed that the dynamics of the dopamine system constitute the main neural basis underlying the situational variability of stuttering.

Streptococcal Infection as a Major Historical Cause of Stuttering: Data, Mechanisms, and Current Importance.

Stuttering is one of the most well-known speech disorders, but the underlying neurological mechanisms are debated. In addition to genetic factors, there are also major non-genetic contributions. It is here proposed that infection with group A beta-hemolytic streptococcus (GAS) was a major underlying cause of stuttering until the mid-1900s when penicillin was introduced in 1943. The main mechanism proposed is an autoimmune reaction from tonsillitis, targeting specific molecules, for example within the basal ganglia. It is here also proposed that GAS infections may have continued to cause stuttering to some extent, to the present date, though more rarely. If so, early diagnosis of such cases would be of importance. Childhood cases with sudden onset of stuttering after throat infection may be particularly important to assess for possible GAS infection. The support for this hypothesis primarily comes from three lines of argument. First, medical record data from the 1930s strongly indicates that there was one type of medical event in particular that preceded the onset of childhood stuttering with unexpected frequency: diseases related to GAS throat infections. In particular, this included tonsillitis and scarlet fever, but also rheumatic fever. Rheumatic fever is a childhood autoimmune sequela of GAS infection, which was a relatively widespread medical problem until the early 1960s. Second, available reports of changes of the childhood prevalence of stuttering indicate striking parallels between stuttering and the incidence of rheumatic fever, with: (1) decline from the early 1900s; (2) marked decline from the introduction of penicillin in the mid 1940s; and (3) reaching a more stable level in the 1960s. The correlations between the data for stuttering and rheumatic fever after the introduction of penicillin are very high, at about 0.95. Third, there are established biological mechanisms linking GAS tonsillitis to immunological effects on the brain. Also, a small number of more recent case reports have provided further support for the hypothesis linking stuttering to GAS infection. Overall, it is proposed that the available data provides strong evidence for the hypothesis that GAS infection was a major cause of stuttering until the mid-1900s, interacting with genetic predisposition.

Impaired glucose-stimulated insulin secretion in the GK rat is associated with abnormalities in islet nitric oxide production.

We investigated implications of nitric oxide (NO) derived from islet neuronal constitutive NO synthase (ncNOS) and inducible NOS (iNOS) on insulin secretory mechanisms in the mildly diabetic GK rat. Islets from GK rats and Wistar controls were analysed for ncNOS and iNOS by HPLC, immunoblotting and immunocytochemistry in relation to insulin secretion stimulated by glucose or l-arginine in vitro and in vivo. No obvious difference in ncNOS fluorescence in GK vs control islets was seen but freshly isolated GK islets displayed a marked iNOS expression and activity. After incubation at low glucose GK islets showed an abnormal increase in both iNOS and ncNOS activities. At high glucose the impaired glucose-stimulated insulin release was associated with an increased iNOS expression and activity and NOS inhibition dose-dependently amplified insulin secretion in both GK and control islets. This effect by NOS inhibition was also evident in depolarized islets at low glucose, where forskolin had a further amplifying effect in GK but not in control islets. NOS inhibition increased basal insulin release in perfused GK pancreata and amplified insulin release after glucose stimulation in both GK and control pancreata, almost abrogating the nadir separating first and second phase in controls. A defective insulin response to l-arginine was seen in GK rats in vitro and in vivo, being partially restored by NOS inhibition. The results suggest that increased islet NOS activities might contribute to the defective insulin response to glucose and l-arginine in the GK rat. Excessive iNOS expression and activity might be deleterious for the beta-cells over time.

Projective risk variables in early adolescence and subsequent disinhibitory psychopathology.

The objective was to examine early adolescent projective risk indicators for the development of antisocial behaviour as related to adult personality traits, psychopathy, and violent behaviour over the life span. Assessment data included Rorschach (Rr) ratings (at age 11-14 years), personality inventories (EPQ-I and KSP scales), and a shortened Psychopathy Check List (PCL) (administered at age 32-40 years), obtained from a group of 199 male subjects; and smoking habits (at age 36-44 years) obtained from 125 of those subjects. Results, controlled for intelligence, indicated that the high and very high risk groups, as determined by level of total Rr risk scores, were (1) significantly higher on self-rated IVE Impulsiveness, the anxiety-related KSP Muscular Tension, and nonconformity traits, as compared to the low Rr risk group--the very high risk group also scoring significantly higher on the EPQ Psychoticism scale, related to aggressiveness and cruelty; (2) higher on clinically rated PCL total sum and factor scores; and (3) they were overrepresented among Ss with subsequent violent offence, and Ss with heavy smoking habits. The results are discussed in terms of the possible usefulness of psychodynamic oriented cognitive-emotional indicators in the search for underlying mechanisms in the development of disinhibitory psychopathology.

Stuttering in adults: the acoustic startle response, temperamental traits, and biological factors.

UNLABELLED: The purpose of this study was to investigate the relation between stuttering and a range of variables of possible relevance, with the main focus on neuromuscular reactivity, and anxiety. The explorative analysis also included temperament, biochemical variables, heredity, preonset lesions, and altered auditory feedback (AAF). An increased level of neuromuscular reactivity in stuttering adults has previously been reported by [Guitar, B. (2003). Acoustic startle responses and temperament in individuals who stutter. Journal of Speech Language and Hearing Research, 46, 233-240], also indicating a link to anxiety and temperament. The present study included a large number of variables in order to enable analysis of subgroups and relations between variables. Totally 32 stuttering adults were compared with nonstuttering controls. The acoustic startle eyeblink response was used as a measure of neuromuscular reactivity. No significant group difference was found regarding startle, and startle was not significantly correlated with trait anxiety, stuttering severity, or AAF. Startle was mainly related to calcium and prolactin. The stuttering group had significantly higher scores for anxiety and childhood ADHD. Two subgroups of stuttering were found, with high versus low traits of childhood ADHD, characterized by indications of preonset lesions versus heredity for stuttering. The study does not support the view that excessive reactivity is a typical characteristic of stuttering. The increased anxiety is suggested to mainly be an effect of experiences of stuttering. LEARNING OUTCOMES: As a result of reading this article, the reader will be able to: (a) critically discuss the literature regarding stuttering in relation to acoustic startle, anxiety, and temperament; (b) describe the effect of calcium on neuromuscular reactivity; (c) discuss findings supporting the importance of early neurological incidents in some cases of stuttering, and the relation between such incidents and traits of ADHD or ADD; and (d) discuss the role of genetics in stuttering.

Role of monoamine oxidase A genotype and psychosocial factors in male adolescent criminal activity.

BACKGROUND: A number of important sociological, psychological, and biological predictors of adolescent criminal behavior have been identified during the most recent decades. The aim of this study was to replicate recent findings that interactions between a polymorphism in the monoamine oxidase A (MAO-A) gene promoter region and psychosocial factors might predict male adolescent criminal activity. METHODS: A cross-sectional study with a randomized sample from the total population of 16- and 19-year-olds from the county of Västmanland, Sweden. Eighty-one male adolescents, who volunteered to participate, were randomly selected from groups representing different degrees of deviant risk behavior. RESULTS: The present study strongly supports the notion that carrying the 3-repeat allele of the MAO-A-gene promoter increases the risk of male adolescent criminal behavior, when interacting with psychosocial factors. No effects at all of the MAO-A genotype on adolescent criminal activity were found when MAO-A genotype was considered alone (i.e., without its psychosocial context). The explained variance of the bio-psychosocial model (controlling for MAO-A) in this study exceeded the psychosocial model by 12%. CONCLUSIONS: The findings support the notion that genotype and psychosocial factors interact to precipitate male adolescent criminal behavior.

Stuttering and sensory gating: a study of acoustic startle prepulse inhibition.

It was hypothesized that stuttering may be related to impaired sensory gating, leading to overflow of superfluous disturbing auditory feedback and breakdown of the speech sequence. This hypothesis was tested using the acoustic startle prepulse inhibition (PPI) paradigm. A group of 22 adults with developmental stuttering were compared with controls regarding the degree of PPI. No significant differences were found between the stuttering adults and the control group; the groups showed similar means and distribution. Likewise, no relation between the degree of PPI and the effect of altered auditory feedback on stuttering was found. In summary, the results of the study indicate that there is no relation between stuttering and PPI.

The absence of aldehyde dehydrogenase 1 A1-positive cells in benign mammary stroma is associated with risk factors for breast cancer.

In this study, aldehyde dehydrogenase 1 (ALDH1)-expressing cells in stroma of histologically normal breast tissue from premenopausal women were investigated in situ regarding cellular morphology, cell distribution, and relation to the additional stem cell markers, CD44 (+) and CD24 (-). These results were correlated with hormonal and genetic risk factors for breast cancer. Triple immunofluorescence labeling was performed on tissues from premenopausal women with a family history of breast cancer, and breast reduction specimens from premenopausal women with no family history of breast cancer were used as a control group. The majority of ALDH1-immunoreactive cells in stroma were spindle-shaped or polygonal, and such cells that were CD44(-) and CD24(-) were absent in the breast stroma of a significantly larger number of nulliparous than parous women. A less common morphological type of ALDH1-positive cells in stroma was round or oval in shape, and such cells that were CD44(+) and CD24(-) were absent in a significant number of women with a family history of breast cancer. The CD44(+)/CD24(-) immunophenotype is consistent with stem cells, and the round/oval morphology suggests mesenchymal cells. This study demonstrates that there are two morphologically distinct types of ALDH1-positive cells in histologically benign mammary stroma, and the absence of these cells is correlated with clinical risk factors for breast cancer in premenopausal women.

Defective glucose-stimulated insulin release in the diabetic Goto-Kakizaki (GK) rat coincides with reduced activity of the islet carbon monoxide signaling pathway.

The Goto-Kakizaki (GK) rat displays a markedly reduced insulin response to glucose, a defect that is thought to be coupled to an impaired glucose signaling in the beta-cell. We have examined whether carbon monoxide (CO), derived from beta-cell heme oxygenase (HO), might be involved in the secretory dysfunction. Immunocytochemical labeling of constitutive HO (HO-2) showed no overt difference in fluorescence pattern in islets from GK vs. Wistar controls. However, isolated islets from GK rats displayed a markedly impaired HO activity measured as CO production (-50%), and immunoblotting revealed an approximately 50% reduction of HO-2 protein expression compared with Wistar controls. Furthermore, there was a prominent expression of inducible HO (HO-1) in GK islets. Incubation of isolated islets showed that the glucose-stimulated CO production and the glucose-stimulated insulin response were considerably reduced in GK islets compared with Wistar islets. Addition of the HO activator hemin or gaseous CO to the incubation media brought about a similar amplification of glucose-stimulated insulin release in GK and Wistar islets, suggesting that distal steps in the HO-CO signaling pathway were not appreciably affected. We conclude that the defective insulin response to glucose in the GK rat can be explained, at least in part, by a marked impairment of the glucose-HO-CO signaling pathway as manifested by a prominent decrease in glucose stimulation of islet CO production and a reduced expression of HO-2. A possible role of HO-1 expression as a compensatory mechanism in the GK islets is presently unclear.

Expression of nitric oxide synthase isoforms in the mouse kidney: cellular localization and influence by lipopolysaccharide and Toll-like receptor 4.

We determined the cellular mRNA expression of all intrarenal nitric oxide (NO)-producing NO synthase (NOS) isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS) and inducible NOS (iNOS) in kidneys from wild-type mice (WT) and immune deficient Toll-like receptor 4 (TLR4) mutant mice, during normal physiological conditions and during a short-term (6-16 h) endotoxic condition caused by systemically administered lipopolysaccaride (LPS). Investigations were performed by means of in situ hybridization and polymerase chain reaction amplification techniques. In WT, LPS altered the expression rate of all intrarenal NOS isoforms in a differentiated but NOS-isoform coupled expression pattern, with iNOS induction, and up- and down-regulation of the otherwise constitutively expressed NOS isoforms, e.g. eNOS and nNOS and an iNOS isotype. In TLR4 mutants, LPS caused none or a lowered iNOS induction, but altered the expression rate of the constitutive NOS isoforms. It is concluded that the intrarenal spatial relation of individual NOS-isoforms and their alteration in expression provide the basis for versatile NO-mediated renal actions that may include local interactions between NOS isoforms and their individual NO-target sites, and that the NOS-isoform dependent events are regulated by TLR4 during endotoxic processes. These regulatory mechanisms are likely to participate in different pathophysiological conditions affecting NO-mediated renal functions.

Neuroprotective effects of nitric oxide synthase inhibitors in spinal cord injury-induced pathophysiology and motor functions: an experimental study in the rat.

The role of nitric oxide (NO) in spinal cord injury (SCI)-induced motor dysfunction, breakdown of the blood-spinal cord barrier (BSCB), edema formation, and cell injury was examined using a pharmacological approach. We used three types of nitric oxide synthase (NOS) inhibitors: a nonselective blocker, L-NAME; an irreversible inhibitor of all isoforms of NOS, L-NMMA; and a long-term competitive inhibitor of neuronal NOS with equal potency to inhibit endothelial NOS, L-NNA. The compounds were administered once daily in separate groups of rats for 7 days. On the 8th day, SCI was performed by making a longitudinal incision into the right dorsal horn of the T10-11 segments, and the rats were allowed to survive 5 h after injury. Long-term treatment with L-NNA attenuated SCI-induced NOS upregulation, BSCB breakdown, edema formation, and cell injury, whereas comparatively less neuroprotection is offered by L-NMMA. The magnitude of neuroprotection is much less evident in injured animals that received L-NAME. Interestingly, SCI-induced motor dysfunction measured according to the Tarlov scale showed close correlation with the magnitude of neuroprotection. Thus, an improvement in motor function was seen in animals pretreated with L-NNA, whereas rats treated with L-NAME or L-NMMA did not show any influence on motor dysfunction after SCI. This observation suggests that inhibition of neuronal NOS is important for neuroprotection, and the disturbances in motor function following SCI are associated with the state of spinal cord pathology.

Methodological development: structured outcome assessment and community risk monitoring (SORM).

This paper describes an effort to develop a clinical tool for the continuous monitoring of risk for violence in forensic mental health clients who have left their institutions and who are dwelling in the community on a conditional release basis. The model is called Structured Outcome Assessment and Community Risk Monitoring (SORM). The SORM consists of 30 dynamic factors and each factor in SORM is assessed in two ways: The current absence, presence or partial och intermittent presence of the factors, which is an actuarial (systematized and 'objective') assessment. Secondly, the risk effect, i.e. whether the presence/absence of factors currently increases, decreases or is perceived as unrelated to violence risk, is a clinical (or impressionistic) assessment. Thus, the factors considered via the SORM can be coded as risk factors or protective factors (or as factors unimportant to risk of violence) depending on circumstances that apply in the individual case. Further, the SORM has a built-in module for gathering idiographical information about risk-affecting contextual factors. The use of the SORM and its potential as a risk monitoring instrument is illustrated via preliminary data and case vignettes from an ongoing multicenter project. In this research project, patients leaving any of the 9 participating forensic hospitals in Sweden is assessed at release on a variety of static background factors, and the SORM is then administered every 30 days for 2 years.

Ambulatory blood pressure in type 2 diabetic patients with albuminuria: relation to the renal function and structural lesions.

BACKGROUND/AIMS: To investigate possible relationships between ambulatory blood pressure (BP) and renal structure and function in type 2 diabetic patients. METHODS: Renal biopsies were performed on 39 patients with urine albumin concentrations above 100 mg/l. BP was investigated with a 24-h, automated, portable BP device. RESULTS: None of the patients in the study had signs of other renal disease than nephrosclerosis or diabetic nephropathy. Ten patients had slight, 13 intermediate, and 6 severe diabetic nephropathy on the renal biopsy. Among the remaining patients, 4 had normal microscopy findings and 6 had nephrosclerosis. The degree of albuminuria correlated to the systolic BP during the day (r = .43; P < .01) and night (r = .49; P < .01). The glomerular filtration rate (GFR) was associated with the systolic BP daytime (r = -.32; P < .05) and nighttime (r = -.47; P < .01). Neither degree of albuminuria nor GFR was associated with the diastolic BP levels. The degree of the glomerular pathology correlated to the systolic BP during daytime (P < .05), whereas the degree of interstitial fibrosis did not correlate to the BP levels. CONCLUSIONS: We have demonstrated that degree of albuminuria and GFR was significantly associated with daytime and nocturnal BP and glomerular structure with daytime BP. Furthermore, no renal disease other than diabetic nephropathy was found.

Stuttering and the basal ganglia circuits: a critical review of possible relations.

UNLABELLED: The possible relation between stuttering and the basal ganglia is discussed. Important clues to the pathophysiology of stuttering are given by conditions known to alleviate dysfluency, like the rhythm effect, chorus speech, and singing. Information regarding pharmacologic trials, lesion studies, brain imaging, genetics, and developmental changes of the nervous system is reviewed. The symptoms of stuttering are compared with basal ganglia motor disorders like Parkinson's disease and dystonia. It is proposed that the basal ganglia-thalamocortical motor circuits through the putamen are likely to play a key role in stuttering. The core dysfunction in stuttering is suggested to be impaired ability of the basal ganglia to produce timing cues for the initiation of the next motor segment in speech. Similarities between stuttering and dystonia are indicated, and possible relations to the dopamine system are discussed, as well as the interaction between the cerebral cortex and the basal ganglia. Behavioral and pharmacologic information suggests the existence of subtypes of stuttering. LEARNING OUTCOMES: As a result of this activity, the reader will (1) become familiar with the research regarding the basal ganglia system relating to speech motor control; (2) become familiar with the research on stuttering with indications of basal ganglia involvement; and (3) be able to discuss basal ganglia mechanisms with relevance for theory of stuttering.

Stuttering, emotions, and heart rate during anticipatory anxiety: a critical review.

UNLABELLED: Persons who stutter often report their stuttering is influenced by emotional reactions, yet the nature of such relation is still unclear. Psychophysiological studies of stuttering have failed to find any major association between stuttering and the activity of the sympathetic nervous system. A review of published studies of heart rate in relation to stressful speech situations indicate that adults who stutter tend to show a paradoxical reduction of heart rate compared with nonstuttering persons. Reduction of heart rate has also been observed in humans and mammals during anticipation of an unpleasant stimulus, and is proposed to be an indication of anticipatory anxiety resulting in a "freezing response" with parasympathetic inhibition of the heart rate. It is suggested that speech-related anticipatory anxiety in persons who stutter is likely to be a secondary, conditioned reaction based on previous experiences of stuttering. EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe how the autonomic nervous system is modulated by emotional responses; (2) explain how anticipatory fear often results in inhibition of heart rate due to parasympathetic activation; (3) discuss why emotional reactions in persons who stutter may be secondary to negative experiences of speech problems.