Striatal dysfunction in X-linked dystonia-parkinsonism is associated with disease progression.

BACKGROUND AND PURPOSE: X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative adult-onset movement disorder associated with striatal atrophy. As the dopaminergic system has not yet been systemically studied in this basal ganglia model disease, it is unclear whether nigrostriatal dysfunction contributes to parkinsonism in XDP. METHODS: Pre- and post-synaptic dopaminergic function was assessed in XDP. A total of 10 123 jod-benzamide (IBZM) single-photon emission computed tomography (SPECT) images were obtained for nine patients aged 42.3 ± 9.5 years (SD; range 30-52) and one asymptomatic mutation carrier (38 years), and four ioflupane (FP-CIT) SPECT images were obtained for four patients, aged 41.5 ± 11.6 years (range 30-52 years). Structural magnetic resonance imaging was also performed for all mutation carriers and 10 matched healthy controls. RESULTS: All patients were men who suffered from severe, disabling segmental or generalized dystonia and had varying degrees of parkinsonism. IBZM SPECT images were pathological in 8/9 symptomatic patients with distinct reduced post-synaptic tracer uptake in the caudate nucleus and putamen, and unremarkable in the asymptomatic mutation carrier. Longer disease duration was correlated with lower IBZM binding ratios. All subjects exhibited slightly reduced FP-CIT uptake values compared to controls for each analyzed region (-37% to -41%) which may be linked to basal ganglia volume loss. Visual inspection revealed physiological FP-CIT uptake in 1/4 patients. CONCLUSIONS: This nuclear imaging study provides evidence that the functional decline of post-synaptic dopaminergic neurotransmission is related to disease duration and ongoing neurodegeneration. Given the severe striatal cell loss which could be verified with post-synaptic nuclear imaging, both parkinsonism and dystonia in XDP are probably mainly due to striatal dysfunction.

Biochemical mechanisms of pallidal deep brain stimulation in X-linked dystonia parkinsonism.

OBJECTIVE: Invasive techniques such as in-vivo microdialysis provide the opportunity to directly assess neurotransmitter levels in subcortical brain areas. METHODS: Five male Filipino patients (mean age 42.4, range 34-52 years) with severe X-linked dystonia-parkinsonism underwent bilateral implantation of deep brain leads into the internal part of the globus pallidus (GPi). Intraoperative microdialysis and measurement of gamma aminobutyric acid and glutamate was performed in the GPi in three patients and globus pallidus externus (GPe) in two patients at baseline for 25/30 min and during 25/30 min of high-frequency GPi stimulation. RESULTS: While the gamma-aminobutyric acid concentration increased in the GPi during high frequency stimulation (231 ± 102% in comparison to baseline values), a decrease was observed in the GPe (22 ± 10%). Extracellular glutamate levels largely remained unchanged. CONCLUSIONS: Pallidal microdialysis is a promising intraoperative monitoring tool to better understand pathophysiological implications in movement disorders and therapeutic mechanisms of high frequency stimulation. The increased inhibitory tone of GPi neurons and the subsequent thalamic inhibition could be one of the key mechanisms of GPi deep brain stimulation in dystonia. Such a mechanism may explain how competing (dystonic) movements can be suppressed in GPi/thalamic circuits in favour of desired motor programs.

Human Brucella canis Infection and Subsequent Laboratory Exposures Associated with a Puppy, New York City, 2012.

Human Brucella canis infection incidence is unknown. Most identified cases are associated with pet dogs. Laboratory-acquired infections can occur following contact with Brucella spp. We identified a paediatric B. canis case, the source and other exposed persons. A 3-year-old New York City child with fever and dyspnoea was hospitalized for 48 h for bronchiolitis. After her admission, blood culture grew B. canis, she was prescribed anti-microbials and recovered. B. canis was also isolated from blood of the child's pet dog; these isolates were genetically similar. The dog originated from an Iowa breeding facility which was quarantined after identification of the dog's infection. Additionally, 31 laboratory workers were exposed and subsequently monitored for symptoms; 15 completed post-exposure prophylaxis. To our knowledge, this is the first report strongly suggesting B. canis zoonotic transmission to a child in the United States, and highlights the need for coordinated control policies to minimize human illness.

Molecular dissection and anatomical basis of dystonia: X-linked recessive dystonia-parkinsonism (DYT3).

Pathological findings in dystonia have been unclear. X-linked recessive dystonia-parkinsonism (XDP, DYT3), endemic in the Panay island, the Philippines, is characterized by the clinical onset with dystonia followed by parkinsonism. It provides a unique opportunity to explore the anatomical basis of dystonia, because it has discernible pathological changes even at its early phase of dystonia. After extensive searches for the anatomical basis in XDP, we found selective loss of striosomal neurons in the striatum in dystonic patients' brain. Because striosomal neurons inhibit nigrostriatal dopaminergic neurons via GABAergic innervation, the striosomal lesion could account for dopamine excess in the striatum, which in turn causes a hyperkinetic state or dystonia. We also identified the causative gene as one of the general transcription factor genes, TAF1. XDP has certain similarities to Huntington disease not only in pathological and clinical findings, but also the molecular mechanism, which disturbs expression of genes essential for striatal neurons, such as DRD2. Therapeutic intervention may become possible through pharmacological measures that affect gene expression.

[Molecular and anatomical bases of dystonia: X-linked recessive dystonia-parkinsonism (DYT3)].

Pathological findings in dystonia have been unclear. X-linked recessive dystonia-parkinsonism (XDP, DYT3), endemic in the Panay island, the Philippines, is characterized by the clinical onset with dystonia followed by parkinsonism. It provides a unique opportunity to explore the anatomical basis of dystonia, because it has discernible pathological changes even at its early phase of dystonia. After extensive searches for the anatomical basis in XDP, we found selective loss of striosomal neurons in the striatum in dystonic patients' brain. Because striosomal neurons inhibit nigrostriatal dopaminergic neurons via GABAergic innervation, the striosomal lesion could account for dopamine excess in the striatum, which in turn causes a hyperkinetic state or dystonia. We also identified the causative gene as one of the general transcription factor genes, TAF1. This abnormality markedly reduced the expression of dopamine D2 receptor gene (DRD2) in neurons. XDP has certain similarities to Huntington disease not only in pathological and clinical findings, but also the molecular mechanism, which disturbs expression of genes essential for striatal neurons, such as DRD2. Therapeutic intervention may become possible through pharmacological measures that affect gene expression.

Substrate specificity and kinetic mechanism of Escherichia coli ribulokinase.

L-ribulokinase is unusual among kinases since it phosphorylates all four 2-ketopentoses with almost the same k(cat) values. The K(m)'s differ, however, being 0.14 mM for L- and 0.39 mM for d-ribulose and 3.4 mM for l- and 16 mM for d-xylulose. In addition, L-arabitol is phosphorylated at C-5 (K(m) 4 mM) and ribitol (adonitol) is phosphorylated to D-ribitol-5-phosphate (K(m) 5.5 mM), but D-arabitol, xylitol, and aldopentoses are not substrates. The K(m)'s for MgATP depend on the substrates, being 0.02 mM with L-ribulose, 0.027 mM with D-ribulose and L-xylulose, and 0.3-0.5 mM with the other substrates. In the absence of a sugar substrate there is an ATPase with K(m) of 7 mM and k(cat) 1% of that with sugar substrates. The initial velocity pattern is intersecting, and MgAMPPNP is competitive vs MgATP and uncompetitive vs L-ribulose. L-Erythrulose is competitive vs L-ribulose and when MgATP concentration is varied induces substrate inhibition which is partial. These data show that the mechanism is random, but there is a high level of synergism in the binding of sugar and MgATP, and the path in which the sugar adds first is strongly preferred.

Sex linked recessive dystonia parkinsonism of Panay, Philippines (XDP).

Sex linked dystonia parkinsonism (XDP), also referred to as "lubag" in American literature, was described in 1975 occurring endemically in Panay, Philippines. It is an adult onset, sex linked, predominantly male, severe, progressive movement disorder with high penetrance and a high frequency of generalisation. The movement disorder is characterised by dystonic movements, usually starting in the 3rd or 4th decade, spreading to generalisation within two to five years. The dystonia coexists or is replaced by parkinsonism usually beyond the 10th year of illness. No treatment has been found to be effective. Neuroimaging shows caudate and putamenal atrophy in patients reaching the parkinsonian stage. Neuropathology reveals pronounced atrophy of the caudate and putamen, mostly in the cases with long standing illness. The sex linked pattern of inheritance has been established. Genetic studies have located the affected gene (DYT3) to Xq13.1, with one group mapping the XDP gene to a < 350 kb locus in the DXS 7117-DXS 559 region.

Neurotuberculosis among Filipino children: an 11 years experience at the Philippine Children's Medical Center.

Tuberculous meningitis (TBM) remains the most common form of neurotuberculosis in children. Four hundred and five cases of tuberculous meningitis (ages 3-156 months) seen at the Philippine Children's Medical Center (PCMC) from 1987 to 1998 were reviewed. Inclusion criteria include clinical and laboratory profile of TBM with pertinent evidence on imaging such as computed tomography and/or cranial sonography or histologic evidence of TBM. Nearly half of the cases were below age 2. The most common neurologic findings were altered sensorium, neck rigidity, motor and cranial deficits. The mortality rate was 16%. The neuropathologic findings in 31 autopsied cases were basal exudates in 100%, hydrocephalus in 71%, caseation necrosis in 68%, and 35% with infarcts. The most important determinant of outcome is the stage of illness at which the diagnosis is made and appropriate treatment is given. Although computed tomography was more definitive, cranial sonography was a very useful diagnostic tool considering the frequent occurrence below age 2. A short course (6 months) anti-tuberculous therapy for neurotuberculosis was shown to be adequate; shunting of cases with hydrocephalus did not show definite benefit.

Defining left ventricular segmental and global function by echocardiographic intraventricular contrast flow patterns.

Contrast echocardiography improves left ventricular (LV) endocardial border delineation by enhancement of the blood-tissue interface. In particular, the contrast appearing within the LV chamber exhibits characteristic flow patterns over the cardiac cycle, which may be related to the surrounding myocardial wall motion. To determine the relation between the LV intracavitary contrast flow pattern and surrounding wall motion, we reviewed the contrast-enhanced images of 348 consecutive patients studied at rest. We defined 2 different patterns of intracavitary contrast flow as visualized from apical views: a swift, vertical, and homogeneous flow towards the apex (pattern A), and a distinctly protracted, swirling, and heterogeneous flow (pattern B). Images recorded on videotapes were reviewed and the type of pattern (A or B) was determined within the initial 30 to 45 seconds of contrast appearance in the left ventricle. Contrast flow patterns interpreted by independent reviewer were then compared with the interpretation of the LV segmental and global function in each patient. Results demonstrate that 224 of 245 (91%) patients exhibiting pattern A had normal LV segmental function. Furthermore, all but 1 patient (102 of 103) with pattern B had > or =1 wall motion abnormality (p <0.0001). Contrast flow pattern B was observed irrespective of the location of LV wall motion abnormality. Global LV function was normal in 93% of patients exhibiting pattern A, whereas varying degrees of LV dysfunction were noted in 83% of patients with pattern B (p <0.0001). The presence of mitral regurgitation (p = 0.46), aortic insufficiency (p = 0.066), or mitral inflow Doppler abnormality (p = 0.102) was not significantly associated with either pattern. Thus, during contrast echocardiography, the LV intracavitary contrast flow pattern complements the assessment of global and segmental LV function.

13C and deuterium isotope effects suggest an aldol cleavage mechanism for L-ribulose-5-phosphate 4-epimerase.

On the basis of (13)C and deuterium isotope effects, L-ribulose-5-phosphate 4-epimerase catalyzes the epimerization of L-ribulose 5-phosphate to D-xylulose 5-phosphate by an aldol cleavage to the enediolate of dihydroxyacetone and glycolaldehyde phosphate, followed by rotation of the aldehyde group and condensation to the epimer at C-4. With the wild-type enzyme, (13)C isotope effects were 1.85% at C-3 and 1.5% at C-4 at pH 7, with the values increasing to 2.53 and 2.05% at pH 5.5, respectively. H97N and Y229F mutants at pH 7 gave values of 3.25 and 2.53% at C-3 and 2. 69 and 1.99% at C-4, respectively. Secondary deuterium isotope effects at C-3 were 2.5% at pH 7 and 3.1% at pH 5.5 with the wild-type enzyme, and 4.1% at pH 7 with H97N. At C-4, the corresponding values were 9.6, 14, and 19%. These data suggest that H97N shows no commitments, while the wild-type enzyme has an external commitment of approximately 1.4 at pH 7 and an internal commitment independent of pH of approximately 0.6. The Y229 mutant shows only the internal commitment of 0.6. The sequence of the epimerase is similar to those of L-fuculose-1-phosphate and L-rhamnulose-1-phosphate aldolases for residues in the active site of L-fuculose-1-phosphate aldolase, suggesting that Asp76, His95, His97, and His171 of the epimerase may be metal ion ligands, and Ser44, Gly45, Ser74, and Ser75 may form a phosphate binding pocket. The pH profile of V/K for L-ribulose 5-phosphate is bell-shaped with pK values of 5.94 and 8.24. The CD spectra of L-ribulose 5-phosphate and D-xylulose 5-phosphate differ sufficiently that the epimerization reaction can be followed at 300 nm.

Role of metal ions in the reaction catalyzed by L-ribulose-5-phosphate 4-epimerase.

H97N, H95N, and Y229F mutants of L-ribulose-5-phosphate 4-epimerase had 10, 1, and 0.1%, respectively, of the activity of the wild-type (WT) enzyme when activated by Zn(2+), the physiological activator. Co(2+) and Mn(2+) replaced Zn(2+) in Y229F and WT enzymes, although less effectively with the His mutants, while Mg(2+) was a poorly bound, weak activator. None of the other eight tyrosines mutated to phenylalanine caused a major loss of activity. The near-UV CD spectra of all enzymes were nearly identical in the absence of metal ions and substrate, and addition of substrate without metal ion showed no effect. When both substrate and Zn(2+) were present, however, the positive band at 266 nm increased while the negative one at 290 nm decreased in ellipticity. The changes for the WT and Y229F enzymes were greater than for the two His mutants. With Co(2+) as the metal ion, the CD and absorption spectra in the visible region were different, showing little ellipticity in the absence of substrate and a weak absorption band at 508 nm. With substrate present, however, an intense absorption band at 555 nm (epsilon = 150-175) with a negative molar ellipticity approaching 2000 deg cm(2) dmol(-1) appears with WT and Y229F enzymes. With the His mutants, the changes induced by substrate were smaller, with negative ellipticity only half as great. The WT, Y229F, H95N, and H97N enzymes all catalyze a slow aldol condensation of dihydroxyacetone and glycolaldehyde phosphate with an initial k(cat) of 1.6 x 10(-3) s(-1). The initial rate slowed most rapidly with WT and H97N enzymes, which have the highest affinity for the ketopentose phosphates formed in the condensation. The EPR spectrum of enzyme with Mn(2+) exhibited a drastic decrease upon substrate addition, and by using H(2)(17)O, it was determined that there were three waters in the coordination sphere of Mn(2+) in the absence of substrate. These data suggest that (1) the substrate coordinates to the enzyme-bound metal ion, (2) His95 and His97 are likely metal ion ligands, and (3) Tyr229 is not a metal ion ligand, but may play another role in catalysis, possibly as an acid-base catalyst.

The relationship of soluble fibrin and cross-linked fibrin degradation products to the clinical course of myocardial infarction.

Recently, increases in the plasma concentration of soluble fibrin (SF) have been suggested to be sensitive and specific for myocardial infarction (MI). However, the relationship between elevations in the SF concentration and the onset of symptoms and clinical course of MI is unknown. In addition, there are no data regarding the relationship between SF concentrations and concentrations of other markers of procoagulant (fibrinopeptide A [FPA]) and fibrinolytic (cross-linked fibrin degradation products [XL-FDPs]) activity in patients with MI. In this study, concentrations of SF were measured with a novel antigen-based assay for 93 MI patients and 29 control subjects, and the relationship between SF concentrations and those of XL-FDPs and FPA was determined. Increases in SF, FPA, and XL-FDP concentrations were documented in 55.9%, 45.2%, and 73.9%, respectively, of patients with MI, but there was no relationship between the concentrations of these markers. Increases in the concentration of SF or XL-FDPs did not show a relationship to increases in the concentration of FPA. Concentrations of XL-FDPs but not of SF were elevated to a greater extent in patients with MI complications (defined as death, ventricular arrhythmia, severe congestive heart failure, or mural thrombus). Increases in SF and XL-FDPs were not sensitive enough for the diagnosis of MI, but increased concentrations of XL-FDPs appear to predict those patients who are at higher risk for MI-related complications.

Initial experience with hirudin and streptokinase in acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 6 trial.

Hirudin is a potent, direct, and highly specific inhibitor of both free and clot-bound thrombin. Previous reports have shown hirudin to be superior to heparin when given with tissue plasminogen activator and aspirin for improving the incidence and rate of reperfusion as well as reducing reocclusion of infarct-related arteries. Patients with acute myocardial infarction were randomized to hirudin versus heparin in conjunction with streptokinase (1.5 x 10(6) U) and aspirin (325 mg/day). Study drug treatment was a 5-day infusion of either heparin, as a 5,000 U bolus, followed by a 1,000 U/hour infusion adjusted to a target activated partial thromboplastin time of 65 to 90 seconds (n = 71), or a constant infusion of hirudin at 1 of 3 doses (dose 1, n = 55: 0.15 mg/kg bolus + 0.05 mg/kg/hour infusion; dose 2, n = 31: 0.3 mg/kg bolus + 0.1 mg/kg/hour infusion; or dose 3, n = 36: 0.6 mg/kg bolus + 0.2 mg/kg/hour infusion). The incidence of major hemorrhage was similar between the heparin group (5.6%) and any of the hirudin dose groups (dose 1 = 5.5%, dose 2 = 6.5%, dose 3 = 5.6%). At hospital discharge the occurrence of death, nonfatal reinfarction, congestive heart failure, or cardiogenic shock was greater in patients receiving the lowest dose of hirudin (21.6%) than in those receiving the higher doses of hirudin (dose 2 = 9.7%, dose 3 = 11.4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Investigations of the bacteriologic factors in cervical disk surgery.

A study was undertaken to evaluate the potential risk of wound infection in cervical disk disease, the appropriateness of the current prophylactic regimen of intravenous cefazolin at Good Samaritan Hospital, and the increasing resistance of coagulase-negative staphylococci in nosocomial infections. In addition, the methodology used in three prior studies was used to verify that double-gloving is a more effective barrier to bacterial contamination than single-gloving and that topical streptomycin lavage is superior to constant irrigation with plain saline. No wound infections were documented in the 40 patients who underwent cervical disk surgery in a 12-month period. Coagulase-negative Staphylococcus species were the most common bacterial isolate, but only 20% were resistant to cefazolin. Of the 11 S. aureus isolates, 9 were sensitive to cefazolin and 2 were methicillin resistant. A remarkable 95% (114/120) of the intraoperative wound cultures were free of bacteria. In only 2 cases was there a serial increase in colonies of the same organism over the course of the operation. There was one positive glove culture--coagulase-negative Staphylococcus sensitive to cefazolin. The patient's skin was identified as the source of contamination in 3 intraoperative cultures of the wound and 2 cultures of the ambient operating room air. Neither individual biotyping of bacteria nor antimicrobial susceptibility testing uncovered any consistent source or pattern to account for the organisms in the surgical wound or ambient operating room air. Bacteria resistant to cefazolin were found in 36% of the intraoperative environmental cultures but in only 16% of the isolates from patients' skin.(ABSTRACT TRUNCATED AT 250 WORDS)

The phenotype of the X-linked dystonia-parkinsonism syndrome. An assessment of 42 cases in the Philippines.

The clinical phenotype of X-linked recessive torsion dystonia was documented in 42 affected individuals from 21 families. In 7 families, there were 9 sibships (core families) with 2 or more affected individuals available for evaluation. The ages of the patients ranged from 29 to 79 years with a mean of 46.2 +/- 10.1 years; the mean age of onset of dystonia was 35.0 +/- 8.0 years with a range of 12 to 48 years; and the mean duration of illness was 11.1 +/- 7.9 years. First manifestations were noted in the lower extremities in 36%, the axial musculature in 29%, the upper extremities in 23%, and in the head in 12% of the cases. The majority of patients displayed gait abnormalities (90%), leg dystonia (79%), oromandibular dystonia (64%), neck dystonia (57%), blepharospasm (57%), and truncal dystonia (52%). The disease generalized in 90% of the cases within 1 to 11 years of onset (median duration, 5 years). Overall, the condition was disabling, but the Fahn-Marsden disability score did not correlate with age of onset, duration of illness, site of onset, rate of generalization, or presence of parkinsonism. Thirty-six percent of the cases displayed at least 1 of the following "parkinsonian symptoms": bradykinesia, tremor, rigidity, loss of postural reflexes and a shuffling gait. Parkinsonism was diagnosed as definite in 14%, probable in 2%, and possible in 19% of the cases. Given this high association of dystonia and parkinsonism, we propose to call the disorder X-linked dystonia-parkinsonism syndrome (XDP).(ABSTRACT TRUNCATED AT 250 WORDS)

The risk of wound infection in lumbar disk surgery.

A number of questions were left unanswered by the empirical success of a 15-year regimen of prophylactic antibiotics in preventing postoperative sepsis at three community hospitals. Although intraoperative cephalosporins have eliminated the morbidity of primary wound infection, the susceptibility to these agents of nosocomial flora has fallen considerably. The principles of antimicrobial prophylaxis have been established, but the debate over the importance of meticulous aseptic technique versus prophylactic antibiotics goes on. We investigated the microbiologic factors in lumbar disk surgery at Nyack Hospital over one year to study (a) potential sources of random contamination, (b) the flora of the operating room, and (c) the efficacy of various aspects of antiseptic routine.

Assignment of the X-linked torsion dystonia gene to Xq21 by linkage analysis.

We performed linkage analysis of X-linked torsion dystonia (XLTD) in 7 Filipino families, studying DNA from a total of 36 family members (9 obligate carrier females, and 18 affected and 9 unaffected males). Application of 21 informative X chromosomal DNA sequences allowed assignment of the XLTD locus to the proximal long arm of the X chromosome (Xq21). A maximum LOD score of 3.06 at [symbol: see text] = 0.0 was obtained with DXYS2, previously assigned to Xq21.3.

X-linked recessive torsion dystonia in the Philippines.

The occurrence of an X-linked form of torsion dystonia in the Philippines was demonstrated by the genetic and biochemical analysis of affected males and their relatives. Thirty-six affected males were ascertained in 21 families by clinical neurologic evaluation. The mean age-of-onset of dystonia was 37.9 years with a range from 12 to 52 years. Neurologic symptoms began focally and progressed to either segmental or generalized involvement in all cases. Generalized dystonia developed in 78% of the patients after a mean duration of 6.8 years from the onset of symptoms. A family history of dystonia was elicited in 17 of the 21 kindreds, accounting for a total of 64 males and one possibly affected female, distributed among 224 individuals in 33 sibships. In 18 of the 33 sibships, 2 or more brothers reportedly had dystonia. There were 12 kindreds with a history of multigenerational dystonia. In those, only males of maternal ancestry were affected, and in 7 of these families, maternal grandfathers reportedly had dystonia. There were no instances of male-to-male transmission. Cytogenetic analysis did not show any X chromosome abnormalities in 4 affected propositi. Several secondary causes of torsion dystonia were excluded, including Wilson disease, aminoacidopathies, organic acidurias, oligosaccharidoses, and chronic hexosaminidase A and B deficiency. These findings substantiate the existence of an X-linked recessive form of primary torsion dystonia.

Torsion dystonia in Panay, Philippines.

There is an unusually high frequency of torsion dystonia in Panay. Of the 28 Filipino cases, 23 (82%) are from the island of Panay and 19 of the 23 (82%) are from the province of Capiz. The 28 cases belong to 25 families Six sets of brothers are noted. All are males. Pedigree analysis reveals six families with several members affected. Two families show features suggesting possible sex-linked recessive transmission, a mode of inheritance previously undescribed in the literature. The clinical features of the cases seen in this series differ from previously described cases in the literature in several aspects: (a) sex preponderance--all males; (b) age at onset--older age of onset, mean of 31; (c) hereditary--possible sex-linked recessive transmission; (d) spasmodic eye blinking as first symptom in four patients.