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K B Baker

Publications and source records attributed to K B Baker.

At least 19 recordsLinked to original sources
PubMed2006

Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study.

BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Disease Susceptibility↗
PubMed2006

Retention time for corticosteroid-sparing systemic immunosuppressive agents in patients with inflammatory eye disease.

BACKGROUND: Multiple immunosuppressive drugs have been used to manage inflammatory eye disease when control cannot be achieved by corticosteroid alone. However, although clinical studies support the effectiveness of most of these agents, comparative studies have not been undertaken. Retention time, a measure of the duration of treatment with any given drug, is a crude indicator of drug effectiveness and tolerability that facilitates such a comparison. The retention time was compared for corticosteroid-sparing immunosuppressive agents in patients attending our tertiary referral inflammatory eye disease clinic. METHODS: The clinical records of all patients attending an inflammatory eye disease clinic at the Casey Eye Institute over a 1-year period (2003) were reviewed. From these records, we collected the following clinical data: age; sex; ocular diagnosis; and use of steroid-sparing systemic immunosuppression, including drugs, duration of treatment and, if ceased, reasons for cessation. Cox regression analysis, adjusted for clustering, was used to compare other drugs against methotrexate. RESULTS: 107 of 302 (35%) patients seen at the inflammatory eye disease clinic in 2003 had a total of 193 current or past prescriptions for systemic steroid-sparing immunosuppressive agents. The treated group, most of whom had uveitis, included 32 men and 75 women, aged 5-86 years. Most commonly prescribed were methotrexate (66 uses, 34%), ciclosporin (37 uses, 19%), azathioprine (26 uses, 13%), mycophenolate mofetil (22 uses, 11%) and cyclophosphamide (15 uses, 8%). Patients were retained significantly less on ciclosporin (p = 0.004), azathioprine (p = 0.04), mycophenolate mofetil (p = 0.04) and cyclophosphamide (p<0.001) compared with methotrexate. Reasons for cessation included adverse events, lack of effectiveness, success or remission, cost and desire for fertility. CONCLUSIONS: In patients with inflammatory eye disease, methotrexate may offer a superior combination of effectiveness and tolerability over other commonly used corticosteroid-sparing immunosuppressive agents. In this study, there was a twofold risk of not being retained on azathioprine, mycophenolate mofetil and ciclosporin and a fourfold risk of not being retained on cyclophosphamide compared with methotrexate.

Adolescent↗
PubMed2005

BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

Age of Onset↗
PubMed2005

Adenoviral clostridial light chain gene-based synaptic inhibition through neuronal synaptobrevin elimination.

Clostridial neurotoxins have assumed increasing importance in clinical application. The toxin's light chain component (LC) inhibits synaptic transmission by digesting vesicle-docking proteins without directly altering neuronal health. To study the properties of LC gene expression in the nervous system, an adenoviral vector containing the LC of tetanus toxin (AdLC) was constructed. LC expressed in differentiated neuronal PC12 cells was shown to induce time- and concentration-dependent digestion of mouse brain synaptobrevin in vitro as compared to control transgene products. LC gene expression in the rat lumbar spinal cord disrupted hindlimb sensorimotor function in comparison to control vectors as measured by the Basso-Beattie-Bresnahan (BBB) scale (P<0.001) and rotarod assay (P<0.003). Evoked electromyography (EMG) showed increased stimulus threshold and decreased response current amplitude in LC gene-transferred rats. At the peak of functional impairment, neither neuronal TUNEL staining nor reduced motor neuron density could be detected. Spontaneous functional recovery was observed to parallel the cessation of LC gene expression. These results suggest that light chain gene delivery within the nervous system may provide a nondestructive means for focused neural inhibition to treat a variety of disorders related to excessive synaptic activity, and prove useful for the study of neural circuitry.

Adenoviridae↗
PubMed2001

Performance on the PD test battery by relatives of patients with progressive supranuclear palsy.

OBJECTIVE: To determine whether there is a greater prevalence of asymptomatic first-degree relatives (FDR) of patients with progressive supranuclear palsy (PSP) performing abnormally on the PD test battery (PD Battery) compared to sex- and age-matched normal control (NC) individuals. The PD Battery incorporates tests of motor function, olfaction, and mood. It has high specificity and sensitivity in distinguishing mildly affected PD patients from NC individuals in previous studies. METHODS: This test battery and regression analysis-derived scoring equations were applied to asymptomatic FDR. RESULTS: Twenty-three FDR and 23 NC individuals were tested. Of the FDR, 39% scored in the abnormal range, whereas none of the NC individuals achieved abnormal scores. This difference was significant. Further analysis demonstrated that the two groups differed significantly on a measure of simple reaction time. CONCLUSIONS: The proportion of FDR who demonstrated abnormal performance on the PD Battery was greater than NC individuals. Thus, the PD Battery may detect the asymptomatic carrier state or risk for PSP or a subclinical effect of a shared environmental exposure.

Adult↗
PubMed2001

Deep brain stimulation in epilepsy.

Since the pioneering studies of Cooper et al. to influence epilepsy by cerebellar stimulation, numerous attempts have been made to reduce seizure frequency by stimulation of deep brain structures. Evidence from experimental animal studies suggests the existence of a nigral control of the epilepsy system. It is hypothesized that the dorsal midbrain anticonvulsant zone in the superior colliculi is under inhibitory control of efferents from the substantia nigra pars reticulata. Inhibition of the subthalamic nucleus (STN) could release the inhibitory effect of the substantia nigra pars reticulata on the dorsal midbrain anticonvulsant zone and thus activate the latter, raising the seizure threshold. Modulation of the seizure threshold by stimulation of deep brain structures-in particular, of the STN-is a promising future treatment option for patients with pharmacologically intractable epilepsy. Experimental studies supporting the existence of the nigral control of epilepsy system and preliminary results of STN stimulation in animals and humans are reviewed, and alternative mechanisms of seizure suppression by STN stimulation are discussed.

Animals↗
PubMed2000

Motor initiation and execution in essential tremor and Parkinson's disease.

Clinical differentiation of essential tremor (ET) from idiopathic Parkinson's disease (iPD) is based on the lack of akinesia and bradykinesia. Nevertheless, early tremor-predominant iPD often is difficult to distinguish from ET. Motor initiation and execution in ET, iPD, and normal control (NC) subjects were investigated. Individuals with iPD, ET and NC performed a reaction-time wrist flexion and extension task. Motor performances were similar between ET and iPD and both were different than normal control subjects. Both the patients with iPD and ET had longer reaction times and slower movement velocities than NC subjects. This may help to explain some of the difficulties in distinguishing patients with these two diseases. The similarities of motor performance suggest that while ET and iPD may be separate disease entities, they may share similar pathogenic motor mechanisms from the perspective of an integrated motor system that drives the motor cortex.

Adult↗
PubMed2000

Mechanisms of deep brain stimulation and future technical developments.

Possible mechanisms underlying the therapeutic effect of deep brain stimulation (DBS) are reviewed, particularly the notion that DBS is inhibitory. Computer simulations are described that model the effect of different frequencies and regularity of neuronal activity (target neuron), either spontaneous or stimulated, on information transfer between two other neurons. Most simulations resulted in a loss of information. These were the least with high frequency and regular activity or stimulation of the target neuron with regularity having the least deleterious effect on information transfer. The simulations suggest that irregular activity in neurons converging with other neurons can result in a loss of information transfer. This may explain why increased irregularity in globus pallidus activity associated with Parkinson's disease, dystonia and hemiballismus may result in symptoms. Further, the therapeutic effect of DBS may be due to driving neurons at higher and perhaps more importantly, regular frequencies. There were simulations in which information transfer was augmented suggesting the presence of stochastic resonance. This most often occurred with low frequency activity in the target neuron. It is hypothesized that low frequency activity, either spontaneous or stimulated, could account for involuntary movements, including tremor. Future directions and challenges to DBS are also discussed.

Animals↗
PubMed1999

Chronic thalamic stimulation for the tremor of multiple sclerosis.

The authors studied chronic high-frequency stimulation of the ventral intermediate nucleus of the thalamus (Vim) for controlling upper extremity tremor in patients with MS using MRI, CT, and microelectrode recordings and stimulation to locate optimal target sites. Fifteen patients underwent surgery. All patients had reduced tremor but developed tolerance requiring repeated programming of the stimulator. Benefit at optimal stimulator settings was maintained. Two patients experienced complications: intracerebral hematoma and MS exacerbation. Chronic high-frequency stimulation of Vim provides tremor reduction if patients have access to frequent stimulator adjustments. This surgery is relatively safe.

Adult↗
PubMed1999

Abnormal performance on the PD test battery by asymptomatic first-degree relatives.

OBJECTIVE: To determine whether a sensitive and specific battery of tests (PD Battery) could identify a subset of asymptomatic first-degree relatives (FDRs) of PD patients who were significantly more impaired than age-matched normal control (NC) subjects. The PD Battery incorporates tests of motor function, olfaction, and mood. In previous studies, it has shown high specificity and sensitivity in distinguishing mildly affected PD patients from NC subjects. METHODS: The PD Battery and regression analysis-derived scoring equations were applied to asymptomatic FDRs. RESULTS: Eighty FDRs and 100 NC subjects were tested. Of the FDRs, 22.5% scored in the abnormal range, and 9% of NC subjects had abnormal scores. This difference was statistically significant. Further analysis demonstrated that FDRs with abnormal scores on the PD Battery differed on all three components of the test battery from FDRs who had normal scores. Among the sons and daughters whose scores were abnormal, there was a much higher prevalence of the affected parent being the father. CONCLUSIONS: The proportion of FDRs who demonstrated abnormal performance on the PD Battery was greater than that of NC subjects. Thus, the PD Battery may detect the asymptomatic carrier state or risk for PD. Sons and daughters whose scores were in the abnormal range were more likely to have fathers with PD.

Adult↗
PubMed1999

Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes.

Stable association of certain proteins, such as E2F1 and p21, with cyclin-cdk2 complexes is dependent upon a conserved cyclin-cdk2 binding motif that contains the core sequence ZRXL, where Z and X are usually basic. In vitro phosphorylation of the retinoblastoma tumor suppressor protein, pRB, by cyclin A-cdk2 and cyclin E-cdk2 was inhibited by a short peptide spanning the cyclin-cdk2 binding motif present in E2F1. Examination of the pRB C terminus revealed that it contained sequence elements related to ZRXL. Site-directed mutagenesis of one of these sequences, beginning at residue 870, impaired the phosphorylation of pRB in vitro. A synthetic peptide spanning this sequence also inhibited the phosphorylation of pRB in vitro. pRB C-terminal truncation mutants lacking this sequence were hypophosphorylated in vitro and in vivo despite the presence of intact cyclin-cdk phosphoacceptor sites. Phosphorylation of such mutants was restored by fusion to the ZRXL-like motif derived from pRB or to the ZRXL motifs from E2F1 or p21. Phospho-site-specific antibodies revealed that certain phosphoacceptor sites strictly required a C-terminal ZRXL motif whereas at least one site did not. Furthermore, this residual phosphorylation was sufficient to inactivate pRB in vivo, implying that there are additional mechanisms for directing cyclin-cdk complexes to pRB. Thus, the C terminus of pRB contains a cyclin-cdk interaction motif of the type found in E2F1 and p21 that enables it to be recognized and phosphorylated by cyclin-cdk complexes.

Amino Acid Sequence↗