Diverse veterans' pre- and post-intervention perceptions of home telemental health for posttraumatic stress disorder delivered via tablet.

Objectives Home telemental health services have the potential to overcome many individual and systemic barriers to care facing military veterans with posttraumatic stress disorder. However, little is known about the home telemental health-related attitudes and experiences of highly underserved rural or ethnically, racially diverse veterans. This study evaluated whether ethnically/racially diverse U.S. veterans residing in the rural Pacific Islands would find the delivery of evidence-based treatment for posttraumatic stress disorder via home telemental health tablet devices useful and helpful. Method Clinicians located in a central urban location delivered Cognitive Processing Therapy for posttraumatic stress disorder directly into patients' homes via a tablet device and secure WiFi connection. Pre- and post-treatment measures were collected from a clinical sample of 47 veterans (average age: 49.3 years). Most (74.4%) self-identified as being of ethnic/racial minority background. Attitudinal, satisfaction, and usability scales were collected from home telemental health engaging ( n = 29) and non-engaging ( n = 18) veterans. Results Ratings on measures of home telemental health comfort, satisfaction with care, and usability were uniformly positive. Veterans were equally open to receiving mental health services at home via home telemental health or in the clinic. In the case of services for a physical problem, however, veterans preferred in-clinic care. Following treatment, veterans' attitudinal scores increased on items such as "There is enough therapist contact in home telemental health interventions." However, a small portion of veterans (7%) reported having technical or privacy concerns. Conclusion The provision of evidence-based posttraumatic stress disorder treatment directly into the patients' homes proved feasible and was well received by the large majority of rural ethnically/racially diverse veterans.

Integration of MAP kinase signal transduction pathways at the serum response element.

The ternary complex factor (TCF) subfamily of ETS-domain transcription factors bind with serum response factor (SRF) to the serum response element (SRE) and mediate increased gene expression. The TCF protein Elk-1 is phosphorylated by the JNK and ERK groups of mitogen-activated protein (MAP) kinases causing increased DNA binding, ternary complex formation, and transcriptional activation. Activated SRE-dependent gene expression is induced by JNK in cells treated with interleukin-1 and by ERK after treatment with phorbol ester. The Elk-1 transcription factor therefore integrates MAP kinase signaling pathways in vivo to coordinate biological responses to different extracellular stimuli.

Subsurface damage in precision ground ULE(R) and Zerodur(R) surfaces.

The total process cycle time for large ULE((R)) and Zerodur((R))optics can be improved using a precise and rapid grinding process, with low levels of surface waviness and subsurface damage. In this paper, the amounts of defects beneath ULE((R)) and Zerodur((R) )surfaces ground using a selected grinding mode were compared. The grinding response was characterised by measuring: surface roughness, surface profile and subsurface damage. The observed subsurface damage can be separated into two distinct depth zones, which are: 'process' and 'machine dynamics' related.

The transcription factors Elk-1 and serum response factor interact by direct protein-protein contacts mediated by a short region of Elk-1.

Transcriptional induction of the c-fos gene in response to epidermal growth factor stimulation is mediated in part by a ternary nucleoprotein complex within the promoter consisting of serum response factor (SRF), p62TCF/Elk-1 and the serum response element (SRE). Both SRF and p62TCF/Elk-1 contact the DNA and bind in a cooperative manner to the SRE. In this study, we demonstrate that SRF and Elk-1 interact directly in the absence of the SRE. A 30-amino-acid peptide from Elk-1 (B-box) is both necessary and sufficient to mediate protein-protein contacts with SRF. Moreover, the Elk-1 B-box is necessary to enable SRF-dependent binding of an alternative ETS domain (from the transcription factor PU.1) to the c-fos SRE. Mutations in either the Elk-1 B-box or the C-terminal half of the SRF DNA-binding domain (coreSRF) which show reduced ability to form ternary complexes also show greatly reduced protein-protein interactions in the absence of the SRE. Our results clearly demonstrate that direct protein-protein interactions between the transcription factors Elk-1 and SRF, in addition to DNA contacts, contribute to the formation of a ternary complex on the c-fos SRE. We discuss the wider applicability of our results in describing specific protein-protein interactions between short well-defined transcription factor domains.

DNA binding by MADS-box transcription factors: a molecular mechanism for differential DNA bending.

The serum response factor (SRF) and myocyte enhancer factor 2A (MEF2A) represent two human members of the MADS-box transcription factor family. Each protein has a distinct biological function which is reflected by the distinct specificities of the proteins for coregulatory protein partners and DNA-binding sites. In this study, we have investigated the mechanism of DNA binding utilized by these two related transcription factors. Although SRF and MEF2A belong to the same family and contain related DNA-binding domains, their DNA-binding mechanisms differ in several key aspects. In contrast to the dramatic DNA bending induced by SRF, MEF2A induces minimal DNA distortion. A combination of loss- and gain-of-function mutagenesis identified a single amino acid residue located at the N terminus of the recognition helices as the critical mediator of this differential DNA bending. This residue is also involved in determining DNA-binding specificity, thus indicating a link between DNA bending and DNA-binding specificity determination. Furthermore, different basic residues within the putative recognition alpha-helices are critical for DNA binding, and the role of the C-terminal extensions to the MADS box in dimerization between SRF and MEF2A also differs. These important differences in the molecular interactions of SRF and MEF2A are likely to contribute to their differing roles in the regulation of specific gene transcription.

Determinants of DNA-binding specificity of ETS-domain transcription factors.

Several mechanisms are employed by members of transcription factor families to achieve sequence-specific DNA recognition. In this study, we have investigated how members of the ETS-domain transcription factor family achieve such specificity. We have used the ternary complex factor (TCF) subfamily as an example. ERK2 mitogen-activated protein kinase stimulates serum response factor-dependent and autonomous DNA binding by the TCFs Elk-1 and SAP-la. Phosphorylated Elk-1 and SAP-la exhibit specificities of DNA binding similar to those of their isolated ETS domains. The ETS domains of Elk-1 and SAP-la and SAP-2 exhibit related but distinct DNA-binding specificities. A single residue, D-69 (Elk-1) or V-68 (SAP-1), has been identified as the critical determinant for the differential binding specificities of Elk-1 and SAP-1a, and an additional residue, D-38 (Elk-1) or Q-37 (SAP-1), further modulates their DNA binding. Creation of mutations D38Q and D69V is sufficient to confer SAP-la DNA-binding specificity upon Elk-1 and thereby allow it to bind to a greater spectrum of sites. Molecular modelling indicates that these two residues (D-38 and D-69) are located away from the DNA-binding interface of Elk-1. Our data suggest a mechanism in which these residues modulate DNA binding by influencing the interaction of other residues with DNA.

Preservation of thoracic spine microarchitecture by alendronate: comparison of histology and microCT.

The effect of bisphosphonates on trabecular microarchitecture may contribute to the reduced risk of vertebral fracture with treatment independent of the bone volume. Trabecular structure was examined at the twelfth thoracic vertebra after 2 years of treatment of two groups of ovariectomized baboons on high and low doses of alendronate, compared with ovariectomized and non-ovariectomized controls. Standard 2D histological measurements showed that alendronate treatment of ovariectomized animals resulted in significantly higher total trabecular length and a lower marrow star volume in comparison with ovariectomized controls indicating preservation of connectivity. Similarly when the vertebrae were examined using a novel thick slice technique that combines 2D and 3D information, ovariectomy produced a significantly higher number of "real" trabecular termini in comparison with normal. When ovariectomized animals were treated with increasing doses of alendronate, fewer "real" termini were seen. MicroCT analysis (2D and 3D) correlated well with the histological measurements, although more variability and less discrimination between groups was seen, with no statistically significant differences with alendronate treatment. Reduced vertebral fracture risk with alendronate may be due to a combination of factors including the increased bone volume, reduced turnover and greater mineralization reported by others. Added to this is now suggested the preservation of several aspects of vertebral cancellous architecture, with microscopy the most sensitive method of analysis.

The DNA recognition subunit of a DNA methyltransferase is predominantly a molten globule in the absence of DNA.

Enzyme-catalysed DNA methylation provides an opportunity for the modulation of protein-DNA recognition in biological systems. Recently we have demonstrated that the smaller of the two subunits of the heterodimeric, cytosine-specific DNA methyltransferase, M. AquI, is largely responsible for sequence-specific DNA recognition. Here we present evidence from a series of NMR, fluorescence and circular dichroism spectroscopy experiments that the DNA binding subunit of M. AquI has the characteristics of a molten globule in the absence of the catalytic machinery. In this metastable state this subunit retains its ability to bind DNA in a sequence-specific manner. We believe this finding offers an insight into the structural flexibility which underpins the mechanism of action of these enzymes, and may provide a possible biological role for molten globules in protein function.

Autosomal dominant striatonigral degeneration. A clinical, pathologic, and biochemical study of a new genetic disorder.

An autosomal dominant striatonigral degeneration is present in a family of Portuguese ancestry numbering in excess of 329 persons in eight generations. The illness begins in the second, third, or fourth decade, and progresses for about 15 years with parkinsonian rigidity, spasticity, spastic dysarthria, and abnormalities of eye movement. Neuropathologic findings are severe neuronal loss and astrocytic gliosis in the corpus striatum and substantia nigra, with a moderate neuronal loss in the dentate nucleus of the cerebellum and nucleus ruber of the midbrain. This is a new genetic entity, distinct from other autosomal dominant neurologic disorders such as nigrospinodentatal degeneration, olivopontocerebellar degeneration, dystonia musculorum deformans, Machado's disease, and Huntington's disease.

Trabecular architecture in women and men of similar bone mass with and without vertebral fracture: II. Three-dimensional histology.

We recently developed a simple and inexpensive method that complements established bone histomorphometry procedures by enabling the two-dimensional imaging of cancellous bone to be viewed within its three-dimensional context with the marrow tissue in place and without detriment to the material for other histological purposes. The method, based on the preparation and superficial staining of slices 300 microm thick, enables "real" (i.e., unstained) trabecular termini to be separated from "artifactual" (i.e., stained) termini, providing a direct measure of cancellous connectivity in osteopenic bone. The technique was applied to osteopenic age-matched, white, postmenopausal women (31 with and 22 without vertebral compression fractures) with a similar bone status, as measured at the spine by absorptiometry and at the iliac crest by histology (see part I of this study). Despite the similarity in the mass of trabecular bone at either site, the results showed a significant difference (p < 0. 05) in the number of "real" trabecular termini between the groups, such that the fracture group had almost four times as many termini (mean +/- SE: 1.98 +/- 0.51/30 mm(2)) at the iliac crest as the nonfracture group (mean +/- SE: 0.53 +/- 0.31/30 mm(2)). Previous histomorphometry of the same material failed to detect a structural distinction between the two groups using established variables. It was concluded that a mass-independent trabecular discontinuity contributes to skeletal failure and that determination of the number of "real" disconnections (i.e., unstained termini) by the direct method proposed may provide a more sensitive discriminant of fracture than the present indirect procedures. A group of fracture and nonfracture men (see part I) suggested a similar distinction (fracture: 0.69 +/- 0.30/30 mm(2); nonfracture: 0.18 +/- 0.18/30 mm(2)), although the difference was not significant.

On the mechanism of action of clozapine on the adrenergic neurone.

1 The antipsychotic drug, clozapine, lowered noradrenaline and metaraminol (MA) concentrations in the rat heart. This action was blocked by the presence of a ganglionic blocking drug. 2 Other alpha-adrenoceptor blocking drugs (phenoxybenzamine, phentolamine) did not significantly lower heart amine concentrations. An inhibitor of neuronal amine uptake (desipramine) caused only a slight lowering. The combination of phentolamine and desipramine showed considerable activity, and this action was blocked by ganglionic blockade. 3 Clozapine had little or no action in blocking amine uptake, yet greatly potentiated amine release caused by the phentolamine-desipramine combination. 4 Other antipsychotic drugs (haloperidol, chlorpromazine, thioridazine) or other agents (propranolol, atropine) did not share this action of clozapine. 5 Ganglionic blockade markedly delayed amine release induced by reserpine administration. 6 It is suggested that clozapine may have an incomplete reserpine-like effect specifically on the adrenergic neurone, facilitating impulse-induced amine release.

Differences in amine storage in rat heart and brain.

1 The characteristics of storage of amphetamine-releasable amine in rat heart and brain were studied in vitro with labelled and unlabelled metaraminol ([(3)H]-MA and MA).2 In one series of experiments, heart and brain slices were incubated with [(3)H]-MA prior or subsequent to incubation with the same concentration of MA.3 When brain slices, thus treated, were subjected successively to field stimulation and to amphetamine, it was found that the ratio of [(3)H]-MA release by field stimulation to release by amphetamine was dependent upon the order in which brain tissue was exposed to [(3)H]-MA and MA.4 With heart slices, on the other hand, the field stimulation/amphetamine ratio of [(3)H]-MA release remained the same whether the tissue was exposed to [(3)H]-MA before or after MA.5 The (+)-isomer of amphetamine released three to four times more [(3)H]-MA from brain slices than did the (-)-isomer, while the isomers were equipotent with regard to [(3)H]-MA release from heart slices.6 Amphetamine-induced [(3)H]-MA release from heart slices was unaffected by the presence of alpha-methyl-p-tyrosine, while release from brain slices was inhibited.7 On the basis of the foregoing results it appears that amine storage differs in brain and heart, with brain exhibiting more than one functional amine pool.

Midbrain dopamine neurons: differential responses to amphetamine isomers.

Intravenously administered D- and L-amphetamine have different potency ratios in reducing the firing rates of dopamine cells in the substantia nigra and in the ventral tegmental area. While D-amphetamine is considerably more potent than L-amphetamine in reducing ventral substantia nigra dopamine neuronal impulse flow, D- and L-amphetamine are of similar potency in reducing dorsal substantia nigra and ventral tegmental dopamine neuronal impulse flow. These results suggest that all dopamine cell groups are not pharmacologically identical and that different dopamine nuclei may respond differently to psychoactive drugs. The comparable potencies of the D- and L-isomers on dorsal substantia nigra and ventral tegmental area dopamine neurons may explain, by a dopamine mechanism, the finding that comparable doses of the isomers produce schizophrenic-like symptoms.

Electrophysiological and biochemical responses of noradrenergic neurons to a non-amphetamine CNS stimulant.

Amfonelic acid (AFA), a potent non-amphetamine CNS stimulant, has been shown previously to have marked effects on dopamine (DA) metabolism and DA neuronal activity, but no effect on norepinephrine (NE) metabolism. AFA is known to inhibit the NE neuronal uptake mechanism. Other NE uptake inhibitors, such as desipramine (DMI), have been shown to decrease the firing rate of NE-containing locus coeruleus (LC) neurons. The purpose of the present study was to compare the actions of AFA and DMI electrophysiologically on LC neurons, and biochemically on NE metabolism in whg rate, with DMI being more potent. Brain NE metabolism was not influenced by either AFA or DMI at doses considerably higher than those which were effective in reducing NE neuronal impulse flow. Thus, NE uptake inhibition coupled with a decrease in impulse flow results in no net change in NE metabolite formation. The effects of AFA on LC unit activity do not seem to be due to its marked effects on brain DA, since DA receptor blockade with haloperidol had little effect on LC unit responsiveness to AFA (or amphetamine). Whereas AFA has dramatic effects on DA metabolism via enhanced release per impulse, the drug has minimal effects on NE metabolism, and this specificity of action may be related to differences in NE and DA transmitter storage mechanisms. It is concluded that the effects of AFA on NE neuronal firing rate are likely due to the drug's DMI-like action and not to enhanced NE release per impulse.

Effects of amphetamine and amfonelic acid on the disposition of striatal newly synthesized dopamine.

A comparison of the in vivo biochemical actions of the psychotomimetic central stimulants, d-amphetamine (d-AMPH) and amfonelic acid (AFA), on the metabolism of rat striatal newly synthesized [3H]dopamine (DA) was made by pulse labeling with [3H]tyrosine. No evidence for the formation of the alcoholic DA metabolites [3H]3-methoxy-4-hydroxyphenylethanol (MOPET) or [3H]3,4-dihydroxyphenylethanol (DOPET) was found in control or drug-treated animals. Both [3H]3,4-dihydroxyphenylacetic acid (DOPAC) and [3H]homovanillic acid (HVA) concentrations were increased by AFA in the presence of haloperidol, while [3H]DA content was decreased. In contrast, d-AMPH, in the presence of haloperidol, decreased [3H]DOPAC and increased [3H]DA, even in monoamine oxidase-blocked rats. Thus monoamine oxidase inhibition did not appear to be a major factor in the action of amphetamine to increase [3H]DA, but cannot be excluded as a contributing factor to the lowering of [3H]DOPAC. Similar actions of d-AMPH were seen on preformed DA. Amphetamine may release newly synthesized DA in such a way that some of the released DA enters the neuronal storage system.

Comparative effects of clozapine and alpha-adrenoceptor blocking drugs on regional noradrenaline metabolism in rat brain.

Clozapine increased brain noradrenaline (NA) metabolism, as indicated by changes in 3-methoxy-4-hydroxyphenylglycol sulfate content, in brain regions corresponding to the predominance of alpha- over beta-receptors, i.e., hypothalamus, medulla, midbrain and cortex, but not corpus striatum or cerebellum. Phenoxybenzamine had a stronger effect in the hypothalamus than did clozapine, but did not change cortical NA metabolism within a 60 min treatment time; however, cortical NA metabolism was increased 150 min after phenoxybenzamine. The delayed effect of phenoxybenzamine may be due to either a poor affinity for some central receptors or a slow rate of entry into certain brain regions. Thioridazine and the benzodioxane, dibozane, had regional effects similar to clozapine. The similarity between clozapine and dibozane in ther effects on regional brain NA metabolism may reflect a preference for presynaptic alpha-receptors. It is unlikely that the antipsychotic activity of clozapine is related to a specific adrenolytic effect, but may reflect the combined activity of this drug on several transmitter systems.

On a prime role for newly synthesized dopamine in striatal function.

Rats were given either the tyrosine hydroxylase inhibitor, alpha-methyltyrosine (alphaMT), in doses of 10 or 250 mg/kg or the neuroleptic, haloperidol (0.25 mg/kg). Other rats received both drugs (haloperidol 30 min after alphaMT). This dose of haloperidol alone caused only a slight, gradually developing catalepsy, while alphaMT alone caused none. The combination quickly caused a strong catalepsy. Striatal dopamine (DA) stores were only minimally depleted at the time of catalepsy potentiation. Th e marked elevation of striatal homovanilluc acid concentration seen after haloperidol administration was greatly inhibited by alphaMT pretreatment. It is concluded that the marked potentiation of haloperidol-induced catalepsy by alpha MT is related to the absence of newly synthesized DA rather than to an exhausted main DA pool and that newly synthesized DA has a greater role in striatal function than does DA of the main striatal storage pool.

Effects of chronic desipramine treatment on rat brain noradrenergic responses to alpha-adrenergic drugs.

It has been previously reported that long-term tricyclic antidepressant treatment in the rat causes a subsensitivity of central beta-receptor-stimulated adenylate cyclase along with alterations of brain norepinephrine (NE) content and metabolism. We have confirmed earlier findings that after one week of desipramine treatment (5.0 mg/kg b.i.d.) brain NE levels decline while NE metabolism is similar to control animals, but is above control after 12 days of treatment. Single cell recordings from noradrenergic neurons of the locus coeruleus (LC) show that after one week of desipramine treatment, neuronal firing rate is lower than in control rats but greater than that seen in response to acutely administered drug. Furthermore, desipramine injection in a dose which profoundly altered LC impulse flow in control rats produced little or no effect on impulse flow in chronically treated rats. Of 25 or 250 microgram/kg doses of clonidine, which are equieffective for decreasing brain NE metabolism in control animals, only the larger dose decreased NE metabolism in 12 day desipramine-treated rats. The postsynaptic alpha-antagonist prazosin (5.0 mg/kg) increased NE metabolism in both groups. These results suggest that presynaptic (alpha 2) adrenoreceptors become subsensitive during long-term desipramine treatment, thus allowing recovery of noradrenergic impulse flow in the presence of NE uptake inhibition.

Role of dopamine storage function in the control of rat striatal tyrosine hydroxylase activity.

Pretreatment of rats with reserpine prevents and post-treatment with RO4-1284 depletes the gamma-butyrolactone (GBL)-induced increase of striatal dopamine (DA) levels. This suggests that the accumulation of DA in striatal nerve endings that normally follows GBL-induced cessation of nigrostriatal impulse flow is in reserpine-sensitive sites. Three days after a single injection of reserpine, the ability of either haloperidol, a DA receptor blocker, or GBL to enhance DA synthesis is greatly reduced and these responses recover slowly over a two week period. Similarly, the ability of haloperidol to elevate striatal DA metabolite concentrations shows a similar pattern of inhibition. The rate of recovery after reserpine of haloperidol effects on DA metabolite concentrations and the activation of striatal tyrosine hydroxylase (measured in vivo by the 30 min L-DOPA accumulation after decarboxylase inhibition with NSD-1015) after either haloperidol or GBL parallels the rate of recovery of basal DA levels. The accumulation of DA after GBL proceeds for 60 min before beginning to plateau in normal rats, but 3 days after reserpine the DA elevation stops after 15 min and lasts for only 30 min in 10 day reserpinized animals. The initial 15 min accumulation of DA after GBL is the same in normal, 3 day and 10 day reserpinized rats, indicating that the initial enzymic rate of activity is the same, but the duration of activation is less. Thus, inhibition of DA storage function by reserpine alters the coupling of DA autoreceptor activity with tyrosine hydroxylase activity. It is suggested that DA storage function modulates tyrosine hydroxylase activity by controlling the amount of DA available for attachment to and inhibition of tyrosine hydroxylase enzyme. This hypothesis is consistent with recent immunocytochemical observations which suggest an association of tyrosine hydroxylase with synaptic vesicles in DA neuronal terminal areas.

On the formation of adrenergic amine storage granules as measured by reserpine labeling.

Reserpine appears to be bound specifically and irreversibly to amine storage granules in the adrenergic neuron. The presence of reserpine persistently attached to amine granule should reflect the life span of the vesicles, and any additional binding of reserpine should then measure the rate of appearance of newly formed amine granules. Measurement of the persistent binding of tritiated reserpine (3H-Reserpine) in hearts of rats given labeled compound at various times after a saturating dose of unlabeled reserpine showed that the recovery of 3H-reserpine binding capacity occurred rapidly. Four days after reserpine the 3H-reserpine binding was 30% of control rats. The rate of return of binding capacity was then slowed being 65% of normal in 24 days. Calculation of the mean daily increment of binding capacity showed that the rate was an inverse linear function of the binding capacitu existing in the neurone at an early phase (1--8 days) but became constant at a later interval (8--24 days). It is suggested that the return of reserpine binding capacity reflects the appearance of new storage granules and that the rate of storage granule synthesis in the cell body is under feedback control. The signal for enhanced granule formation does not appear to be related to the intensity of nerve traffic not to the concentration of transmitter in the neuron since manaeuvers which alter these parameters did not change the rate of reserpine binding recovery.