Extending the clinicopathological spectrum of neurofilament inclusion disease

We describe features of a patient that broadens the clinical and pathological spectrum of neurofilament inclusion disease (NFID). The patient was a 52-year-old man with a 5–6 year history of progressive, asymmetrical spastic weakness of the upper and lower extremities; l-DOPA-unresponsive parkinsonism; and SPECT evidence of asymmetrical frontoparietal and basal ganglia hypoperfusion. The brain had marked frontoparietal parasagittal cortical atrophy, including the motor cortex, with histopathological evidence of neurofilament- and -internexin-immunoreactive neuronal inclusions. The corticospinal tract had degeneration, but there was minimal lower motor neuron pathology. There was also severe neuronal loss and gliosis in the posterolateral putamen and the substantia nigra, mimicking multiple system atrophy; however, glial cytoplasmic inclusions were not detected with -synuclein immunohistochemistry. This case extends the clinical and pathological spectrum of NFID to include cases with predominant parkinsonian and pyramidal features.Gerry Shaw holds equity in EnCor Biotechnology Inc., a company commercializing the alpha-internexin antibody used in this study, and may benefit by receiving royalties or equity growth.     

The fatigue properties of human cortical bone

Rotating cantileverfatigue tests were performed on specimens extracted longitudinally from the cortices of human femora. The usual inverse relationship between stress amplitude and fatigue life was found; the median life was 1·3×10⁴ cycles at a stress amplitude of 12,200 1bf/in² (84·1 MN/m²) and 4·6×10⁶ cycles at 6750 1bf/in² (46·6 MN/m²). Arguments are advanced which suggest that these results are compatible with what is known of the stresses applied in life and the clinical occurrence of fatigue fractures.     

Randomized double-blind study comparing 3- and 6-day regimens of azithromycin with a 10-day amoxicillin-clavulanate regimen for treatment of acute bacterial sinusitis

A randomized, double-blind, multicenter study of adults with acute bacterial sinusitis (ABS) compared the efficacy and safety of two azithromycin (AZM) regimens, 500 mg/day once daily for 3 days (AZM-3) or 6 days (AZM-6) to the efficacy and safety of an amoxicillin-clavulanate (AMC) regimen of 500-125 mg three times daily for 10 days. A total of 936 subjects with clinically and radiologically documented ABS were treated (AZM-3, 312; AZM-6, 311; AMC, 313). Clinical success rates were equivalent among per-protocol subjects at the end of therapy (AZM-3, 88.8%; AZM-6, 89.3%; AMC, 84.9%) and at the end of the study (AZM-3, 71.7%; AZM-6, 73.4%; AMC, 71.3%). Subjects treated with AMC reported a higher incidence of treatment-related adverse events (AE) (51.1%) than AZM-3 (31.1%, P < 0.001) or AZM-6 (37.6%, P < 0.001). More AMC subjects discontinued the study (n = 28) than AZM-3 (n = 7) and AZM-6 (n = 11) subjects. Diarrhea was the most frequent treatment-related AE. AZM-3 and AZM-6 were each equivalent in efficacy and better tolerated than AMC for ABS.     

Methylphenidate effects on functional outcomes in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS)

OBJECTIVE: The purpose of this study was to examine the effects of methylphenidate (MPH) on functional outcomes, including children's social skills, classroom behavior, emotional status, and parenting stress, during the 4-week, double-blind placebo controlled phase of the Preschoolers with Attention Deficit/Hyperactivity Disorder (ADHD) Treatment Study (PATS). METHODS: A total of 114 preschoolers who had improved with acute MPH treatment, were randomized to their best MPH dose (M = 14.22 mg/day; n = 63) or placebo (PL; n = 51). Assessments included the Clinical Global Impression-Severity (CGI-S), parent and teacher versions of the Strengths and Weaknesses of ADHD-Symptoms and Normal Behaviors (SWAN), Social Competence Scale (SCS), Social Skills Rating System (SSRS), and Early Childhood Inventory (ECI), and Parenting Stress Index (PSI). RESULTS: Medication effects varied by informant and outcome measure. Parent measures and teacher SWAN scores did not differentially improve with MPH. Parent-rated depression (p < 0.02) and dysthymia (p < 0.001) on the ECI worsened with MPH, but scores were not in the clinical range. Significant medication effects were found on clinician CGI-S (p < 0.0001) and teacher social competence ratings (SCS, p < 0.03). CONCLUSIONS: Preschoolers with ADHD treated with MPH for 4 weeks improve in some aspects of functioning. Additional improvements might require longer treatment, higher doses, and/or intensive behavioral treatment in combination with medication.     

Midbrain,diencephalic and cortical relationships of the basal nucleus of meynert and associated structures in primates

The structure and connectivity of the basal nucleus of Meynert, the substantia innominata in which it lies, and certain related areas have been examined in New World and Old World Monkeys, using retrograde and anterograde axonal transport methods. Experiments using the retrograde, horseradish peroxidase method confirm the observations of Kievet and Kuypers ('75) that the basal nucleus and substantia innominata project directly, heavily and with a somewhat crude topography upon the neocortex. Experiments involving the anterograde, autoradiographic method show that the basal nucleus and substantia innominata form part of a complex pathway that links them together with the lateral hypothalamus, certain parts of the amygdala and the peripeduncular nucleus of the midbrain. The peripeduncular nucleus is often regarded as a part of the central auditory pathway; it gives rise to a fiber bundle of considerable size that ascends on the dorsal surface of the ipsilateral optic tract and terminates ultimately in the lateral hypothalamic area of both sides. As well as distributing fibers to the basal nucleus, substantia innominata and lateral hypothalamus, this pathway provides a heavy projection to a cytoarchitectonically distinct posterior part of the lateral nucleus of the amygdala, the medial and intercalated nuclei of the amygdala and a less dense projection to the bed nucleus of the stria terminalis. Certain parts of the hypothalamus and possibly the preoptic areas give rise to a complementary descending pathway that distributes fibers to the ipsilateral basal nucleus, substantia innominata and amygdala, and ends in the peripeduncular nuclei of both sides. Decussating fibers in both the ascending and descending pathways cross in the ventral supraoptic commissure. It is concluded that the basal nucleus should include most of the aggregated and unaggregated large cells that lie in the substantia innominata and which in places intrude upon the preoptic regions and the nucleus of the diagonal band of Broca. Together, these may form a complex that receives inputs from a variety of brainstem sources, and projects widely and diffusely upon all cortical structures of the telencephalon.     

ADHD and cannabis use in young adults examined using fMRI of a Go/NoGo task

Children diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for substance abuse. Response inhibition is a hallmark of ADHD, yet the combined effects of ADHD and regular substance use on neural networks associated with response inhibition are unknown. Task-based functional Magnetic Resonance Imaging (fMRI) data from young adults with childhood ADHD with (n?=?25) and without (n?=?25) cannabis use ≥ monthly in the past year were compared with a local normative comparison group (LNCG) with (n?=?11) and without (n?=?12) cannabis use. Go/NoGo behavioral and fMRI data were evaluated for main and interaction effects of ADHD diagnosis and cannabis use. ADHD participants made significantly more commission errors on NoGo trials than controls. ADHD participants also had less frontoparietal and frontostriatal activity, independent of cannabis use. No main effects of cannabis use on response inhibition or functional brain activation were observed. An interaction of ADHD diagnosis and cannabis use was found in the right hippocampus and cerebellar vermis, with increased recruitment of these regions in cannabis-using controls during correct response inhibition. ADHD participants had impaired response inhibition combined with less fronto-parietal/striatal activity, regardless of cannabis use history. Cannabis use did not impact behavioral response inhibition. Cannabis use was associated with hippocampal and cerebellar activation, areas rich in cannabinoid receptors, in LNCG but not ADHD participants. This may reflect recruitment of compensatory circuitry in cannabis using controls but not ADHD participants. Future studies targeting hippocampal and cerebellar-dependent function in these groups may provide further insight into how this circuitry is altered by ADHD and cannabis use.     

An autoradiographic study of the efferent connections of the lateral hypothalamic area in the rat.

The efferent connections of the lateral hypothalamic area (LHA) have been analyzed in a series of 30 rat brains with injections of 3H-amino acids into different parts of the area and the surrounding regions. Our findings indicate that all parts of the LHA contribute ascending and descending fibers to the medial forebrain bundle, and also project medially to certain of the adjoining hypothalamic nuclei. All levels of the LHA appear to send some fibers to a continuous group of structures that extends from the medial septal-diagonal band complex rostrally, through the lateral preoptic and lateral hypothalamic areas to the mammillary complex and the ventral tegmental area caudally. In addition, it is evident that cells at different levels within the LHA may have differential projections. Thus, the anterior and lateral parts of the LHA also appear to project substantially to the anterior hypothalamic area, the ventromedial and dorsomedial hypothalamic nuclei, the parataenial and paraventricular nuclei of the thalamus, and the medial part of the lateral habenular nucleus. Similarly, cells in the tuberal and posterior parts of the LHA project to the central gray, the longest projections from the posterior region reaching as far caudally as the central tegmental field, the parabrachial nucleus, the locus coeruleus, and the superior central and dorsal nuclei of the raphe. Viewed as a whole, the LHA is therefore well-suited to integrate inputs from the limbic system and brainstem and to relay them on the one hand to the medial zone of the hypothalamus and on the other to virtually every structure closely associated with the medial forebrain bundle and to the nuclei of origin of the major ascending monoaminergic systems.