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PubMed1989

Contribution of a conserved arginine near the active site of Escherichia coli D-serine dehydratase to cofactor affinity and catalytic activity.

We have employed site-directed mutagenesis to investigate the contribution of a conserved arginyl residue to the catalytic activity and cofactor affinity of D-serine dehydratase, a model pyridoxal 5'-phosphate (vitamin B6) enzyme. Replacement of R-120 in the active site peptide of D-serine dehydratase by L decreased the affinity of the enzyme for pyridoxal 5'-phosphate by 20-fold and reduced turnover by 5-8-fold. kappa cat displayed modified substrate alpha-deuterium isotope effects and altered dependence on both temperature and pH. Analysis of the pH rate profiles of DSD and the R-120----L variant indicated that R-120 interacts electrostatically with catalytically essential ionizable groups at the active site of wild type D-serine dehydratase. The decrease in cofactor affinity observed for DSD(R120L) was not accompanied by significant perturbations in the UV, CD, or 31P NMR spectrum of the holoenzyme, suggesting that the contribution of R-120 to pyridoxal phosphate affinity may be indirect or else involve an interaction with a cofactor functional group other than the 5'-phosphoryl moiety. The properties of two other site-directed variants of D-serine dehydratase indicated that the pyridoxal 5'-phosphate:K-118 Schiff base was indifferent to a small change in the shape of the side chain at position 117 (I-117----L), whereas replacement of K-118 by H resulted in undetectable levels of enzyme. A poor ability to bind cofactor may have rendered DSD(K118H) susceptible to intracellular proteolysis.

Amino Acid Sequence↗

PubMed1989

Neuropsychologic effects of saturation diving.

Neuropsychologic status of saturation divers was assessed before and after 300-500 msw dives (deep saturation diving--DSD group) and before and after 3.5 yr of ordinary saturation diving (saturation diving--SD group). Average baseline results showed the divers to be slightly superior to nondiving controls. Mild-to-moderate neuropsychologic changes (greater than 10% impairment) were found in measures of tremor, spatial memory, vigilance, and automatic reactivity in 20% of the divers after deep dives (DSD group). One year postdive no recovery was observed except for a vigilance test. In the SD group, 20% of the divers showed greater than 10% impairment after 3.5 yr of ordinary saturation diving. Significant reduction in autonomic reactivity was also found and there was a relationship between low autonomic reactivity before saturation diving and number of greater than 10% impairments. For the whole group (DSD + SD divers), negative correlations were found between saturation experience and results on memory and complex visuomotor tests. Years of diving from first to last examination was positively correlated with number of greater than 10% impairments and with reduction in autonomic reactivity. No similar correlations were found to dive variables after about 3 yr of air diving. The mild-to-moderate changes seen in some divers, therefore, seem to be the effects of saturation diving. Since one deep dive may cause an effect similar to the effect of 3.5 yr of ordinary saturation diving, there is reason to believe that repeated deep diving may lead to more pronounced neuropsychologic impairment.

Adult↗

PubMed1996

[Analysis of the diagnostic delay in tuberculosis].

OBJECTIVE: To identify the situations that influence in the delayed diagnosis of tuberculosis. PATIENTS AND METHOD: We studied 109 patients (87 non HIV-infected and 22 HIV-infected) who were diagnosed of tuberculosis in one year consecutively, using a questionnaire to obtain time intervals in which the whole diagnostic delay (WD) was divided. RESULTS: WD was higher than 1 month in 90 % of non HIV-infected patients. The delay due to the health system (SD) was higher (71% > 1 month) than the delay due to patient (PD; 30% > 1 month) and there was a negative correlation between both (R-0.73). In HIV+ group, WD was lower (59.1% > month) and, although PD was higher (40.9% > 1 month), the time that the system delayed the suspicion of the diagnosis was lower (5.5% > 1 month). In HIV-group there were the following significant differences: higher delay in the suspicion of diagnosis (DSD) (61.4% and 60.8% > 1 month) and shorter time to make the diagnosis (12.3% and 21.6% > 1 month) in sputum smear-positive patients and who had cavitary lesions; PD was higher (67.1% > 1 month) in patients with general symptoms and nearly none in patients with upper airways symptoms; and higher DSD in presence of nonspecific symptoms like cough or/and expectoration (68.6% > 1 month) or upper airways symptoms (100% > 1 month). As these clinical symptoms were consulted in primary care mainly, there was a higher SD (75.75 > 1 month) and DSD (58.1% > 1 month), and were increased when a promptly chest X-ray was not performed (87.1 and 68.7% > 1 month). CONCLUSIONS: Delayed diagnosis of tuberculosis is common. In non HIV-infected patients, it occurs mainly in the health system. Diagnostic delays contribute to raise advanced disease with more contagious potential.

Adult↗

PubMed2004

Botulinum toxin in neuro-urological disorders.

Botulinum toxin has been used in urology since the end of the 1980s. However, this therapeutic option has not been firmly established yet. Valid studies have merely been conducted on detrusor sphincter dyssynergia (DSD) and on detrusor overactivity (hyperreflexia), but even those findings do not allow final conclusions. Success rates in DSD are between 58% and 88%, in detrusor overactivity approximately 80%. Further possible indications for botulinum toxin are motor and sensory urge, urethrospasm, spasticity of the pelvic floor, neobladder, and even chronic prostatic pain. To reach firmer conclusions, controlled studies with well-defined patient populations and using validated and reproducible outcome measures are needed. In addition, we also need information on repeated injections over a long period of time. These data are not available to date. At present, the application of botulinum toxin should be reserved for experienced users only.

Anti-Dyskinesia Agents↗

PubMed2006

Incomplete emptying and urinary retention in multiple-system atrophy: when does it occur and how do we manage it?

Neurogenic urinary retention can be a major cause of morbidity in multiple-system atrophy (MSA). However, the timing of its appearance has not been entirely clear, and neither have the medical and surgical modalities for managing patients. We present the data obtained from our uroneurological assessment and therapeutic interventions at various stages of MSA. We recruited 245 patients with probable MSA. We measured postvoid residuals (PVR) and performed EMG cystometry in all patients. The grand average volume of PVR was 140 mL (range, 0-760) in our patients. The average PVR volume was 71 mL in the first year, increasing to 129 mL in the second year and 170 mL by the fifth year. The percentages of patients with complete urinary retention, acontractile detrusor, and detrusor-sphincter dyssynergia (DSD) also increased. The increase in PVR resulted in a decrease in functional bladder capacity, together with an increase in detrusor overactivity and neurogenic sphincter EMG. Clean intermittent self-catheterization (CISC) was introduced in most patients. Bladder-oriented therapy (cholinergic agents) had a limited value, whereas urethra-oriented therapy benefited patients with DSD (surgery) for up to 2 years, but syncope occurred in a subset of patients (alpha-blockers). MSA patients present with large PVR by the second year of illness, and that large PVR secondarily causes urinary frequency. CISC is the recommended treatment for most patients. Urethra-oriented medication and surgery benefit patients who would have difficulty performing CISC, although careful consideration of the short-term efficacy and potential adverse effects of these alternatives is mandatory.

Adrenergic alpha-Antagonists↗

PubMed2003

Micturitional disturbance in a patient with a spinal cavernous angioma.

A 58-year-old woman had a 3-year history of numbness in the right leg, which developed into thoracic transverse myelopathy and urinary retention. After referral to our department, MRI scans revealed a lesion with a target appearance at the T10-11 spinal cord with multiple silent cerebral lesions, which confirmed the diagnosis of cavernous angioma. Gamma-knife surgery was not indicated, considering the risk of adverse effects. The patient gradually became able to urinate, but had urge urinary incontinence. The first urodynamic studies (conducted 3 months after full clinical manifestations of transverse myelopathy) showed detrusor hyperreflexia (DH), decreased bladder sensation during bladder filling, detrusor-sphincter dyssynergia (DSD), and weak detrusor on voiding. However, urinary retention appeared again without change of neurologic signs. The second urodynamic studies (conducted 2 months later) showed less marked DH during bladder filling, and equivocal DSD but marked weak detrusor on voiding. The patient started taking oral prazosin hydrochloride (6 mg/day), which gradually ameliorated her voiding difficulty. Lesions in the lateral and dorsal columns of the spinal cord seem to be responsible for the micturitional disturbance in our patient with spinal cavernous angioma.

Adrenergic alpha-Antagonists↗

PubMed1993

Voiding dysfunction in patients with spastic paraplegia: urodynamic evaluation and response to continuous intrathecal baclofen.

Patients with hereditary spastic paraplegia (HSP), a degenerative central nervous system disorder characterized by progressive lower extremity spasticity, frequently experience symptoms of voiding dysfunction. Urodynamic evaluation of patients with HSP has not been reported, and the etiology of voiding dysfunction remains unexplained. We present our evaluation of three men (ages 42-62 years) with this rare syndrome. Urgency of urination was a uniform and dominant complaint, and two patients regularly experienced urge incontinence. Other symptoms included frequency (n = 3), nocturia (n = 3), and diminished force of stream (n = 1). Postvoid residual volumes were less than 25 ml in all patients. On urodynamic evaluation the two patients with urge incontinence displayed cystometric evidence of involuntary detrusor contractions. Pelvic floor EMG recordings suggested detrusor-sphincter dyssynergia (DSD). In addition, one patient exhibited markedly diminished bladder compliance (1.0 ml/cm H2O) and capacity (50 ml). All patients reported marked symptomatic improvement when treated with continuous intrathecal baclofen. Evaluation during baclofen treatment revealed increases in bladder compliance and capacity, with apparent resolution of DSD in one patient. Voiding symptoms in these patients most likely arise from a neurogenic etiology; however, a contributory role for chronic outlet obstruction from striated muscle spasticity may also exist.

Adult↗

PubMed1995

Long-term follow-up of sphincterotomy in the treatment of autonomic dysreflexia.

Autonomic dysreflexia (AD) is a syndrome affecting a majority of patients with high spinal cord lesions. An association between AD and detrusor-sphincter dyssynergia (DSD) is often seen. Between 1980 and 1988 we performed 51 transurethral sphincterotomies in 38 patients. Twelve of these patients underwent procedures primarily for the prevention of AD related to bladder distension. This study presents their long-term follow-up. One patient was lost to follow-up secondary to unrelated death; the remaining 11 patients were followed on average 117.5 months (94-154) after the initial operative procedure. Repeat sphincterotomy was required in 9 of 11 patients (82%). Six (66%) of these were performed within 24 months. One patient (11%) required delayed sphincterotomy greater than 100 months from the initial procedure. Overall, sphincterotomy was successful in controlling symptoms of AD in 10 of 11 (91%) patients. No major complications were recorded. Sphincterotomy is a safe and effective treatment for AD associated with DSD, however long-term urologic follow-up and management are necessary.

Adult↗

PubMed1996

The time course of loss of dopaminergic neurons and the gliotic reaction surrounding grafts of embryonic mesencephalon to the striatum.

Grafts of embryonic ventral mesencephalic tissue placed in the striatum of 6-hydroxydopamine-lesioned rats survive, and make and receive connections to and from the host brain. The dopaminergic neurons of the graft can grow processes into the host brain, and thereby alleviate many of the behavioral deficits of this form of experimental Parkinson's disease. However, when examined some weeks after implantation, grafted substantia nigra only contains about 5% of the expected complement of dopaminergic neurons. We have examined the time course of loss of grafted neurons. We find that the majority die during the first 7 days after transplantation. However, we have shown previously that three-dimensional cultures with the same dimensions as a graft, made of identical cell suspensions, have much better dopaminergic neuronal survival. There must, therefore, be features in the environment surrounding a graft that are toxic to dopaminergic neurons. A limiting factor in the efficacy of dopaminergic grafts is the small distance over which the neurons are able to grow neurites and form connections in the host brain. We find that the growth of neurites from dopaminergic neurons into the host striatum occurs in two phases. Neurites reach their maximum length within 7 days of transplantation, and this is followed by a much slower process of branch and terminal formation. Since axon growth in the adult brain may be inhibited by a number of factors associated with reactive gliosis, we have immunostained various ages of graft for vimentin, tenascin, chondroitin sulfate proteoglycan (CS-PG) using the CS56 antibody, the DSD-1 proteoglycan, and microglia using the OX-42 antibody. We have compared this staining with that surrounding a simple stab wound. Vimentin staining was initially seen in the graft and in astrocytes immediately surrounding it. By 7 weeks staining was restricted to a ring of astrocytes surrounding the graft. Tenascin, DSD-1, and CS-PG were initially seen in and around the grafts. By 7 weeks they had disappeared from grafts, but CS-PG and tenascin persisted in small amounts around stab wounds. In general, immunostaining of these molecules persisted longer around a stab lesion than around a graft. There was also an intense local microglial reaction surrounding both grafts and stab wounds which had largely resolved by 7 weeks.

Animals↗

PubMed2001

D(n)-symmetrical tertiary templates for the design of tubular proteins.

Antiparallel helical bundles are found in a wide range of proteins. Often, four-helical bundles form tube-like structures, with binding sites for substrates or cofactors near their centers. For example, a transmembrane four-helical bundle in cytochrome bc(1) binds a pair of porphyrins in an elongated central cavity running down the center of the structure. Antiparallel helical barrels with larger diameters are found in the crystal structures of TolC and DSD, which form antiparallel 12-helical and six-helical bundles, respectively. The backbone geometries of the helical bundles of cytochrome bc(1), TolC, and DSD are well described using a simple D(n)-symmetrical model with only eight adjustable parameters. This parameterization provides an excellent starting point for construction of minimal models of these proteins as well as the de novo design of proteins with novel functions.

Bacterial Outer Membrane Proteins↗

PubMed1999

Effects of glutamate receptor antagonists on lower urinary tract function in conscious unanesthetized rats.

OBJECTIVES: To study the effects of the intrathecal administered glutamate receptor antagonists on the bladder and urethral activities during isovolumetric bladder contraction in conscious normal and chronic spinal rats. METHODS: Twenty-eight female Wistar rats with and without previous spinal cord transection were used. Before and after intrathecal administration of glutamate receptor antagonist, urodynamic parameters under isovolmetric condition of the bladder were analyzed. RESULTS: In normal rats, MK-801 (noncompetitive N-methyl-D-aspartate [NMDA] receptor antagonist) and LY 293558 (competitive AMPA receptor antagonist) produced a decrease in bladder contraction pressure and urethral activity with dose dependent manner. In chronic spinal rats, detrusor-sphincter dyssynergia (DSD) was developed before drug administration. MK-801 and LY 293558 partially inhibited bladder contraction pressure, and markedly depressed urethral contraction concomitant with bladder contraction. LY 293558 produced urethral relaxation concomitant with bladder contraction. CONCLUSIONS: In both normal rats and chronic spinal rats, two subtypes of glutamate receptors (NMDA and AMPA receptors) in the spinal cord were involved in the control of bladder and urethral activities. The AMPA receptor in the spinal cord seems to take an important role in the development of DSD.

Animals↗

PubMed2004

A systematic review of research findings on the efficacy of interpersonal therapy for depressive disorders.

OBJECTIVE: Interpersonal psychotherapy (IPT) is a time-limited psychotherapy for major depression. The aim of this study is to summarize findings from controlled trials of the efficacy of IPT in the treatment of depressive spectrum disorders (DSD) using a meta-analytic approach. METHODS: Studies of randomized clinical trials of IPT efficacy were located by searching all available data bases from 1974 to 2002. The searches employed the following MeSH categories: Depression/ Depressive Disorder; Interpersonal therapy; Outcome/Adverse Effects/Efficacy; in the identified studies. The efficacy outcomes were: remission; clinical improvement; the difference in depressive symptoms between the two arms of the trial at endpoint, and no recurrence. Drop out rates were used as an index of treatment acceptability. RESULTS: Thirteen studies fulfilled inclusion criteria and four meta-analyses were performed. IPT was superior in efficacy to placebo in nine studies (Weight Mean Difference (WMD) - 3.57 [-5.9, -1.16]). The combination of IPT and medication did not show an adjunctive effect compared to medication alone for acute treatment (RR 0.78 [0.30, 2.04]), for maintenance treatment (RR 1.01 [0.81, 1.25]), or for prophylactic treatment (RR 0.70 [0.30, 1.65]). IPT was significantly better than CBT (WMD -2.16 [-4.16,-0.15]). CONCLUSION: The efficacy of IPT proved to be superior to placebo, similar to medication and did not increase when combined with medication. Overall, IPT was more efficacious than CBT. Current evidence indicates that IPT is an efficacious psychotherapy for DSD and may be superior to some other manualized psychotherapies.

Antidepressive Agents↗

PubMed2006

Treatment of detrusor sphincter dyssynergia with baclofen and doxazosin.

Detrusor sphincter dyssynergia (DSD) is an involuntary contraction of the external urethral sphincter during detrusor contraction. A high proportion of patients needing repeat surgery and long term failure have both been described in the literature. In the present study, we evaluated clinical characteristics, underlying disorders and outcomes of conservative medical treatment in 21 female patients. Two patients were newly diagnosed multiple sclerosis. Urodynamic studies were performed in all symptomatic patients, and consisted of measurement of post-micturition residuals, urethral pressure profilometry and EMG cystometry according to the criteria of the International Continence Society. All patients were treated with baclofen 15 mg/day and doxazosin 4 mg/day. Seven patients received tolterodine 4 mg/day in addition to baclofen and doxazocin because they had detrusor hyperreflexia (DH). In conclusion, treatment with either combined baclofen and doxazosin or anticholinergic agent tolterodine appeared to be effective. In addition, it should be kept in mind that DSD could be the first sign to any neurologic diseases.

Adolescent↗

PubMed1989

Linkage analysis of depression spectrum disease.

As part of a study of the possible subgroups of unipolar affective disease, 27 families were ascertained as depression spectrum disease (DSD) families. The purpose of this study was an investigation of the linkage relationships between DSD and 30 genetic markers using the robust sib-pair and lod-score methods. Using the sib-pair methods, evidence for linkage was found with orosomucoid (ORM) on chromosome 9q (p = 0.006), regardless of whether only individuals with unipolar depression, alcoholism, or antisocial personality were considered to be affected, or whether individuals with any psychiatric disorder were considered to be affected. Weak evidence of linkage with ORM was corroborated using lod-score methods when a narrow definition of depression spectrum disease was used, although stronger evidence of linkage was found with ORM when any psychiatric disorder was considered to be affected. The maximum lod-score for ORM was 1.68 at a male recombination fraction of 0.23 and a female recombination fraction of 0.01.

Adult↗

PubMed1993

Polymerizable phospholipids with lipoic acid as head group: synthesis and phase properties.

Lipoic acid-substituted phospholipids were synthesized from phosphatidyl cholines by exchanging the choline residue with a glycol group using phospholipase D, forming phosphatidylglycols, and coupling of lipoic acid (1,2-dithiolane-3-pentanoic acid) to the residual glycol hydroxyl group by esterification. The thermotropic properties of aqueous dispersions of the phosphatidylglycols and the phosphatidylglycolipoates with different chain lengths were studied by differential scanning calorimetry (DSC) and differential scanning densitometry (DSD). The exchange of choline with glycol increases the phase transition temperature Tm for the gel to liquid-crystalline phase transition by approximately 5 degrees, independent of the chain length. Consecutive esterification of the glycol residue with lipoic acid causes a decrease of the transition temperature Tm by approximately 22 degrees compared with the phosphatidylglycols. Polymerization of vesicles prepared from phosphatidylglycolipoates was induced by the addition of dithiothreitol and followed by DSC and DSD. Polymerization has only slight influence on the transition behavior, indicating that the polymer chain in the head group is effectively decoupled from the hydrocarbon region. Polymerized vesicles show increased stability towards aggregation and fusion.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1996

Micturitional disturbance after acute hemispheric stroke: analysis of the lesion site by CT and MRI.

Micturitional histories and urodynamic studies were performed in 72 acute hemispheric stroke patients. Within 3 months from the onset, 53% of the patients had urinary symptoms including irritative as well as obstructive, and the most common symptom was nocturnal urinary frequency in 36%, which was followed by urge urinary incontinence in 29% and difficulty of voiding in 25% of the patients. We found a correlation between micturitional disturbance with hemiparesis (p <0.05) and not with hemianopsia (p <0.05). Micturitional disturbance was more common in lesions of the frontal lobe (p <0.05) than in those of the occipital lobe. Brain CT or MRI in symptomatic patients showed lesions of anterior and medial surface of the frontal lobe, anterior edge of the paraventricular white matter, genu of the internal capsule and large lesions of putamen or thalamus. Urodynamic studies of 22 symptomatic patients revealed various findings in 91% of them, including detrusor hyperreflexia in 68%, detrusor-sphincter dyssynergia (DSD) in 14% and uninhibited sphincter relaxation in 36%. Patients with urinary retention had atonic cystometrogram and DSD. Detrusor hyperreflexia was noted in lesions of the frontal lobe as well as the basal ganglia, uninhibited sphincter relaxation in the frontal lobe, and detrusor-sphincter dyssynergia common in the basal ganglia. Above findings seem to indicate that anteromedial frontal lobe and its descending pathway, and the basal ganglia seem to be mainly responsible for supranuclear types of pelvic and pudendal nerve dysfunction in our patients with stroke.

Adult↗

PubMed1992

Family history of psychiatric disorder and low self-confidence: predictors of depressive symptoms at 12-month follow-up.

We examined effects of two risk factors for depression, family psychiatric history and Low Self-Confidence, on (1) baseline characteristics of major depression and (2) depressive symptoms one year later. Subjects (N = 104) in the midst of a depressive episode were assigned to one of three family history subtypes identified in earlier research: Pure Depressive Disease (PDD) Depressive Spectrum Disease (DSD), Sporadic Depressive Disease (SDD). Results indicate that effects of Self-Confidence on depressive symptoms at follow-up varied by family subtype. In multivariate analyses with controls for demographic and illness characteristics, the mean follow-up depressive score was below the depressive threshold for PDD subjects and above it for SDD subjects regardless of the level of Self-Confidence. In contrast, DSD subjects with High Self-Confidence reported significantly more symptoms than those with Low Self-Confidence.

Adult↗

PubMed1995

Depression spectrum disease with and without depression in first-degree relatives.

Family history was assessed in 211 outpatients with unipolar major depression and diagnoses were rendered according to Winokur et al. (Winokur et al. (1978) J. Nerv. Ment. Dis. 166, 764-768) family history typology. The subclassification of Depression Spectrum Disease with Alcoholism and Depression (DSDA + D) was applied to those patients reporting at least one first-degree relative suffering from alcoholism and another first-degree relative suffering from depression (n = 103), while Depression Spectrum Disease with Alcoholism (DSDA) was applied to those patients with at least one first-degree relative suffering from alcoholism, but none suffering from depression (n = 108). These two groups were compared on demographic, clinical and biological characteristics. They were also compared with 162 patients who reported the presence of depression and absence of alcoholism in first-degree relatives, designated as Familial Pure Depressive Disease (FPDD) by the Winokur et al. (1978) classification. Results revealed that the DSDA + D group was younger, had an earlier age at onset of depression and experienced more episodes of depression than did the DSDA group. No differences were found between the two groups on biological measures. The FPDD group was more similar to the DSDA + D group than the DSDA group in terms of age at onset and number of depressives episodes. However, the FPDD group had a longer length of illness than either of the DSD groups. These data suggest that the DSD group should be more narrowly defined (excluding those with a positive family history of depression) in future clinical research studies.

Adult↗