Non-motor symptoms and quality of life in subjects with mild parkinsonian signs.

BACKGROUND: Mild parkinsonian signs (MPS) are frequent in the elderly population and associated with the presence of risk markers for Parkinson's disease (PD). Both MPS and non-motor signs may be present in prodromal PD and may significantly impair quality of life (QoL). OBJECTIVE: To disentangle the contribution of motor impairment and extra-motor manifestations to QoL in subjects with MPS (n=63), manifest PD (n=69), disorders with motor symptoms due to non-neurodegenerative diseases (n=213) and healthy controls (n=258). METHODS: Subjects with MPS, healthy controls, disease controls (patients with motor impairment due to, eg, arthrosis and spondylosis), and PD patients (total n=603) were selected from a large epidemiological longitudinal study, the EPIPARK cohort. Motor function was determined using the UPDRSIII protocol, and information on depressive symptoms, anxiety, sleep, and QoL was assessed via rating scales and data were analyzed. RESULTS: Depressive symptoms, anxiety, and sleep problems were equally frequent in the MPS group and controls. Health-related QoL was slightly reduced in the MPS group. Motor impairment and its extent was comparable between the MPS group and disease controls (UPDRSIII 5-6 points). Higher motor dysfunction was associated with lower QoL. Depressive symptoms, but not anxiety and daytime sleepiness, was significant predictors of general QoL, independent of motor function. CONCLUSIONS: Quality of life is slightly decreased in an elderly population with MPS. QoL is associated with severity of motor impairment but also with non-motor aspects, ie, depressive symptoms. Follow-up studies in large cohorts are warranted to determine the natural course of MPS and its impact on QoL.

[The Health-Related Quality of Life as Measured with the SF-12v1 in Elderly People Living in Luebeck 2010/11 in Comparison with the German Norm Data in 1994]. / Die bevölkerungsbezogene Lebensqualität gemessen mit dem SF-12v1 bei 51- bis 80-jährigen Lübeckern in den Jahren 2010/11 im Vergleich zur Deutschen Normstichprobe von 1994.

BACKGROUND: Health-related quality of life (HRQL) is deemed to be a meaningful endpoint when evaluating therapy and prevention interventions. For comparison purposes not only patient data but also representative population samples can serve as reference data. We aim to describe differences between the Luebeck population sample (LBS, year 2010/11) and the German norm population from 1994. Moreover, the influence of diabetes mellitus and hypertension on HRQL is analysed. METHODS: The LBS is a representative sample of 10 000 elderly people living in Luebeck aged 51-80 years, an age group susceptible to chronic diseases. Not only the SF-12v1, but also the item "actual health status in comparison to the last year" of the SF-36 and a list of comorbidities have been applied. Descriptive statistics are given for age, sex and disease groups. A comparison with data from the DNSP going back to 1994 is made using unstandardised data as well as age- and gender-standardised data. RESULTS: 5 835 individuals (response rate 60%) did participate in the survey (48% male, mean age 63.9 years, SD 7.7). PSC and MSC could be computed for 80% of them. Unstandardised values are 44.3±10.8 for the PSC and 50.4±10.3 for the MSC. Applying standardisation by age and gender, PSC values were comparable between the LBS and DNSP (except for the age group 51-60 years). MSC values were significantly lower in the LBS. The "general health Status" does not significantly differ whereas the "actual health status in comparison to the last year" is significantly lower in the LBS than in the DNSP (p<0.001). CONCLUSIONS: The LBS comprises more individuals than older studies in an age group relevant for chronic diseases. RESULTS hint to a comparable physical HRQL but a worse mental HRQL in the current data set. It remains unclear why persons between 51 and 60 years assess their physical HRQL worse than in the DNSP. A further open question is why the "actual health status in comparison to the last year" is assessed more negatively. Changed context conditions in working and social life may have an influence.

[Evaluation of Psychiatric Disorders on the Basis of a SCID Screening]. / Evaluation psychiatrischer Störungen anhand eines erweiterten SKID-Screenings.

BACKGROUND: Psychiatric symptoms/syndromes such as depression, apathy, anxiety or psychotic episodes are present in a range of neurological disorders including Parkinson's disease. The Structured Clinical Interview for DSM-IV (SCID) represents the gold standard for the assessment of psychiatric disorders but is often too time-consuming for application in clinical practice. METHODS: 66 participants were examined using the screening items and the first two questions of section A of the SCID as well as the complete version of the SCID, part I. The accuracy of the screening and the complete SCID was evaluated, and logistic regression was conducted to analyze factors associated with measure disagreement between the two procedures. RESULTS: Overall, psychiatric disorders were identified by screening in 40/66 (60.6%), as against 31/66 (47.0%) using the complete SCID. Compared to the complete SCID, the sensitivity and specificity of the screening items were 88% and 59%, respectively. CONCLUSION: Based on its good sensitivity, the SCID screening may be used in clinical practice to yield an overview of psychiatric disorders that may require treatment. Due to its moderate specificity, however, the complete version of the SCID should be subsequently used in cases whenever the SCID screening is positive. In any case, the SCID screening must be regarded as inadequate for the detection of psychotic symptoms.

Electronic consultations with Video Supported PowerPoint versus in-clinic face-to-face, pre-travel consultations: A single-centre, comparative analysis.

BACKGROUND: Pretravel consultation involves a face-to-face visit with a Travel Medicine expert and includes time consuming educating/counseling. Efficacy of electronic consultations for pretravel is unknown. We compared pretravel education via face-to-face consult to an electronic consultations combined with education via Video Supported PowerPoint for select travelers. METHODS: We conducted a prospective trial comparing pre-travel education via electronic consultations versus face-to-face consult. Study was conducted from May 2014 through May 2015. RESULTS: Pretravel surveys were completed by 100 in electronic consult arm and 94 in face-to-face consult arm; 67/100 (67%) in the electronic consult and 51/94 (54.2%) in the face-to-face group completed post-travel surveys. Both groups had similar baseline demographics. 36.2% of the face-to-face group felt the trip preparation could have effectively been accomplished through electronic consult, while 33% felt that a face-to-face consult was needed; in contrast, a majority (63.3%) of electronic consult group preferred the electronic consult. Pre-travel education effectiveness was similar in both groups. No statistically significant differences in responses were noted in both groups to 5 of the 6 knowledge assessment questions. A higher proportion (76/100; 76%) in the electronic consult group compared to 55.4% (51/94) (p = 0.0018) in face-to-face group chose the correct response regarding management of febrile bloody diarrhea. 53% reported behavior change to prevent travel related illnesses, with no statistically significant differences between the groups. CONCLUSIONS: electronic consultation with Video Supported PowerPoint pre-travel education is as effective as education via face-to-face consultations and provides a viable alternative to face-to-face consultations in select travelers.

Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles.

To further evaluate (1) transcranial sonography (TCS) for (pre)clinical diagnosis of Parkinson's disease (PD) and (2) to examine asymptomatic carriers of Parkin mutations we investigated substantia nigra (SN) hyperechogenicity in PD patients and unaffected subjects with and without Parkin mutations. The area (aSN) of the hyperechogenic SN were calculated bilaterally and study subjects were assigned to high versus low value groups. Eleven of the (affected and unaffected) mutation carriers had previously undergone 18-fluoro-dopa-(FDOPA)-PET scans. Fifty-eight individuals were investigated, including 24 with clinically definite and 34 without symptoms or signs of PD. Of the patients, three had one mutated and six had two mutated Parkin alleles. Of the unaffected subjects, 13 carried a single Parkin mutated allele. After dichotomization, 21 subjects had high and 37 subjects low values of mean aSN. Regarding the clinical status, 13 (62%) of the individuals with a high mean aSN had PD,while 26 (70%) of the study subjects with low values did not show signs of PD (p = 0.0393). Similarly, probands with high mean aSN values more frequently carried Parkin mutations (58%) than probands with low values (27%, p = 0.0234). A negative correlation between FDOPA uptake in the posterior putamen and maximum aSN was found in the group of mutation carriers (r = -0.809, p = 0.0234). In conclusion, hyperechogenicity of the SN is found in both idiopathic and Parkin-associated PD. Further strengthening the notion of a potential relationship between SN hyperechogenicity and Parkin mutational status, a larger aSN was associated with an increasing number of mutated alleles in our study.

A large protein complex containing the yeast Sin3p and Rpd3p transcriptional regulators.

The SIN3 gene is required for the transcriptional repression of diverse genes in Saccharomyces cerevisiae. Sin3p does not bind directly to DNA but is thought to be targeted to promoters by interacting with sequence-specific DNA-binding proteins. We show here that Sin3p is present in a large multiprotein complex with an apparent molecular mass, estimated by gel filtration chromatography, of greater than 2 million Da. Genetic studies have shown that the yeast RPD3 gene has a function similar to that of SIN3 in transcriptional regulation, as SIN3 and RPD3 negatively regulate the same set of genes. The SIN3 and RPD3 genes are conserved from yeasts to mammals, and recent work suggests that RPD3 may encode a histone deacetylase. We show that Rpd3p is present in the Sin3p complex and that an rpd3 mutation eliminates SIN3-dependent repression. Thus, Sin3p may function as a bridge to recruit the Rpd3p histone deacetylase to specific promoters.

SIN3-dependent transcriptional repression by interaction with the Mad1 DNA-binding protein.

The SIN3 gene in Saccharomyces cerevisiae encodes a negative regulator of transcription of a large number of genes. Mouse homologs of SIN3 have been identified through screens for proteins interacting with the mammalian Mad1 protein, a transcriptional repressor. We find that yeast Sin3 (ySin3) interacts with Madl and that, as for mouse Sin3, the N terminus of Mad1 interacts with the PAH2 domain of ySin3. Although Mad1 (a basic helix-loop-helix leucine zipper [bHLH-Zip) protein) forms a heterodimer with the Max bHLH-Zip protein, LexA-Mad1 and VP16-Max do not activate transcription of a reporter gene in a two-hybrid assay. This failure in activation is due to direct repression by ySin3, as LexA-Mad1 and VP16-Max are able to activate the two-hybrid reporter in a sin3 mutant. This inhibition of activation by LexA-Mad1 and VP16-Max requires the PAH2 domain of ySin3 and the N-terminal interaction region of Mad1. These data demonstrate that ySin3 functions as a transcriptional repressor by being brought to promoters by interacting with proteins bound to DNA.

Nongenetic causes of Parkinson's disease.

Study of the nongenetic causes of Parkinson's disease (PD) was encouraged by discovery of a cluster of parkinsonism produced by neurotoxic pyridine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the 1980s. Since that time, epidemiologic investigations have suggested risk factors, though their results do not establish causality. Pesticide exposure has been associated with increased risk in many studies. Other proposed risks include rural residence and certain occupations. Cigarette smoking, use of coffee/caffeine, and non-steroidal antiinflammatory drugs (NSAIDs) all appear to lower risk of PD, while dietary lipid and milk consumption, high caloric intake, and head trauma may increase risk. The cause of PD is likely multifactorial. Underlying genetic susceptibility and combinations of risk and protective factors likely all contribute. The combined research effort by epidemiologists, geneticists, and basic scientists will be needed to clarify the cause(s) of PD.

Motor reorganization in asymptomatic carriers of a single mutant Parkin allele: a human model for presymptomatic parkinsonism.

Mutations in the Parkin gene are the most common known single cause of early-onset parkinsonism. It has been shown that asymptomatic carriers with a single mutant allele have latent presynaptic dopaminergic dysfunction in the striatum. Here we used functional MRI to map movement-related neuronal activity during internally selected or externally determined finger movements in 12 asymptomatic carriers of a Parkin mutation and 12 healthy non-carriers. Mean response times were 63 ms shorter during internally selected movements than during externally guided movements (P = 0.003). There were no differences in mean response times between groups (P > 0.2). Compared with externally determined movements, the internal selection of movements led to a stronger activation of rostral motor areas, including the rostral cingulate motor area (rCMA), rostral supplementary motor area, medial and dorsolateral prefrontal cortices. The genotype had a significant impact on movement-related activation patterns. Asymptomatic carriers showed a stronger increase in movement-related activity in the right rCMA and left dorsal premotor cortex, but only if movements relied on internal cues. In addition, synaptic activity in the rCMA had a stronger influence on activity in the basal ganglia in the context of internally selected movements in asymptomatic carriers relative to non-carriers. We infer that this reorganization of striatocortical motor loops reflects a compensatory effort to overcome latent nigrostriatal dysfunction.

Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity.

Cdk10 is a Cdc2-related kinase that may play a role in regulating the G2/M phase of the cell cycle. However little is known about the proteins that interact with this putative kinase and contribute to its function in the cell. We report in this study that Cdk10 interacts with the N-terminus of the Ets2 transcription factor, which contains the highly conserved Pointed domain and transactivation domain. The Pointed domain has been implicated in protein-protein interactions and we find that Ets2 requires an intact Pointed domain to bind Cdk10. The Pointed domain of Ets1 is highly similar to Ets2, however Cdk10 does not recognize Ets1 in a two-hybrid assay thereby demonstrating significant binding specificity on the part of Cdk10. We find that Cdk10 binds full length Ets2 in vitro and in vivo and inhibits Ets2 transactivation in mammalian cells.

Purification and characterization of a serine proteinase inhibitor from human articular cartilage.

An inhibitor of serine proteinases from human articular cartilage was purified to homogeneity by sequential ultrafiltration and ion exchange chromatography on CM-Sephadex C-50. The apparent molecular weight of the cationic glycoprotein (pI greater than 10) was determined to be 16.5 X 10(3) by SDS gel electrophoresis. The inhibitor blocked the activity of leukocyte elastase, cathepsin G and trypsin but not leukocyte collagenase. In kinetic studies for the interactions with leukocyte elastase a firm enzyme-inhibitor binding was obtained. Amino acid analyses did not reveal homologies with other serine proteinase inhibitors already purified from human tissues.

pRb and the cdks in apoptosis and the cell cycle.

Apoptosis is a fundamental biological process present in metazoan cells. Linking apoptosis to the cell cycle machinery provides a mechanism to maintain proper control of cell proliferation in a multicellular organism. pRb and the cyclin-dependent kinases may have dual roles as integral components of the cell cycle and regulators of apoptosis. In many instances manipulation of the cell cycle through these molecules can induce or inhibit apoptosis. Recent studies also identify pRb as a substrate for an apoptotic protease; however, other cell cycle components are not known substrates. While it is clear that many common molecules can affect cell proliferation and cell death, the universality of any one cell cycle molecule in apoptosis has yet to be determined.

Cell cycle and apoptosis.

In multicellular organisms, cell proliferation and death must be regulated to maintain tissue homeostasis. Many observations suggest that this regulation may be achieved, in part, by coupling the process of cell cycle progression and programmed cell death by using and controlling a shared set of factors. An argument in favor of a link between the cell cycle and apoptosis arises from the accumulated evidence that manipulation of the cell cycle may either prevent or induce an apoptotic response. This linkage has been recognized for tumor suppressor genes such as p53 and RB, the dominant oncogene, c-Myc, and several cyclin-dependent kinases (Cdks) and their regulators. These proteins that function in proliferative pathways may also act to sensitize cells to apoptosis. Indeed, unregulated cell proliferation can result in pathologic conditions including neoplasias if it is not countered by the appropriate cell death. Translating the knowledge gained by studying the connection between cell death and cell proliferation may aid in identifying novel therapies to circumvent disease progression or improve clinical outcome.

A prepro-orexin gene polymorphism is associated with narcolepsy.

The orexin (hypocretin) neurotransmitter system was recently shown to be directly involved in the pathogenesis of narcolepsy in two animal models. Furthermore, decreased levels of orexin A in the CSF were shown in narcoleptic patients. To define any genetic contribution of orexin to the etiology of narcolepsy, the authors screened the entire prepro-orexin gene for mutations or polymorphisms in 133 patients suffering from narcolepsy. They report an association of a rare polymorphism in the prepro-orexin gene with narcolepsy in a cohort of 178 patients.

Alpha3beta4 subunit-containing nicotinic receptors dominate function in rat medial habenula neurons.

Regional-specific differences in nicotinic acetylcholine receptors (nAChRs) were examined using the whole-cell patch clamp technique in rat medial habenula (MHb) slices. The majority of cells in the ventral two thirds of the MHb responded robustly to local pressure application of nAChR agonists. Mean agonist potency profiles in the middle and ventral thirds of the MHb were similar: cytisine was the most potent agonist and DMPP the weakest, consistent with a significant contribution of the beta4 subunit to functional nAChRs in all areas of the MHb. In acutely isolated MHb neurons, the alpha3beta4-selective toxin alpha-CTx-AuIB (1 microM) reversibly blocked approximately 75% of the nicotine-induced currents, as expected for cells solely expressing alpha3beta4 nAChRs. However, the alpha3beta2-selective toxin, alpha-CTx-MII (100 nM), blocked a variable fraction (0-90%) of the MHb nicotinic response implying that beta2 subunits may contribute to some functional receptors. We suggest that the effects of alpha-CTx-MII may arise from interaction with alpha3beta2beta4 subunit-containing nAChRs. This idea is supported by the findings (1) that alpha-CTx-MII antagonizes receptors comprised of alpha3, beta2 and beta4 subunits in Xenopus oocytes, and (2) that a mutant alpha-CTx-MII toxin[H12A], which blocks alpha3beta2beta4 receptors but not alpha3beta2 or alpha3beta4 nAChRs, also reduces nicotinic currents in some MHb neurons. Overall these data imply that most functional nAChRs on MHb cells contain at least alpha3 and beta4 subunits, and that a variable subpopulation additionally contains the beta2 subunit.

ApoE polymorphisms in narcolepsy.

BACKGROUND: Narcolepsy is a common neuropsychiatric disorder characterized by increased daytime sleepiness, cataplexy and hypnagogic hallucinations. Deficiency of the hypocretin neurotransmitter system was shown to be involved in the pathogenesis of narcolepsy in animals and men. There are several hints that neurodegeneration of hypocretin producing neurons in the hypothalamus is the pathological correlate of narcolepsy. The ApoE4 allele is a major contributing factor to early-onset neuronal degeneration in Alzheimer disease and other neurodegenerative diseases as well. METHODS: To clarify whether the ApoE4 phenotype predisposes to narcolepsy or associates with an earlier disease onset, we have genotyped the ApoE gene in 103 patients with narcolepsy and 101 healthy controls. RESULTS: The frequency of the E4 allele of the ApoE gene was 11% in the patient and 15% in the control groups. Furthermore, the mean age of onset did not differ between the ApoE4+ and ApoE4- patient groups. CONCLUSION: Our results exclude the ApoE4 allele as a major risk factor for narcolepsy.

Clindamycin, metronidazole, and chloramphenicol.

Clindamycin, metronidazole, and chloramphenicol are three antimicrobial agents useful in the treatment of anaerobic infections. Clindamycin is effective in the treatment of most infections involving anaerobes and gram-positive cocci, but emerging resistance has become a problem in some clinical settings. Metronidazole is effective in the treatment of infections involving gram-negative anaerobes, but it is unreliable in the treatment of gram-positive anaerobic infections and is ineffective in treating aerobic infections. Additionally, metronidazole is often the drug of choice in treating infections in which Bacteroides fragilis is a serious concern. Chloramphenicol is effective in the treatment of a wide variety of bacterial infections, including serious anaerobic infections, but is rarely used in Western countries because of concerns about toxicity, including aplastic anemia and gray baby syndrome.

A rare form of narcolepsy (HLA-DR2-) shows possible association with (functionally relevant) alpha-interferon gene polymorphisms.

Narcolepsy is a neuropsychiatric disease caused by complex disturbance of sleep regulation. The main symptoms comprise daytime sleepiness and cataplexy. Although the aetiology remains unclear so far, narcolepsy is genetically characterized by strong linkage to the human leukocyte antigen complex as more than 90% of the patients are typed HLA-DR2+. Recently, it has become apparent that the orexin (hypocretin) neurotransmitter system plays a key role in the pathogenesis of the disease. Canine narcolepsy is caused by mutations in the orexin receptor 2 gene, and narcoleptic patients show specifically decreased cerebrospinal fluid orexin levels. Decreased promotor activity of the prepro-orexin gene is caused by binding of alpha-interferon in vitro. To investigate the possible role of IFNA gene polymorphisms in the pathogenesis of narcolepsy, we have genotyped two single nucleotide polymorphisms in IFNA genes as well as a neighbouring microsatellite. No association was evident in the prevalent DR2+ group. Yet, the IFNA10 single nucleotide polymorphisms and the IFNA microsatellite are associated with the DR2- patient group. Thus, the pathogenetic role of interferons needs to be defined in DR2- narcolepsy.

Current understanding of AIDS pathogenesis.

From the mid 1990s, considerable progress has been achieved in understanding the biology of the human immunodeficiency virus type 1 (HIV-1), and the pathogenesis of the acquired immunodeficiency syndrome (AIDS). However, these achievements are still not sufficient to indicate the reasons for failure of the host immune response in suppressing HIV-1 infection and why the immune system collapses at the end of the clinical latency period, followed by progression to the terminal course of the disease. A more complete view of the dynamics of AIDS pathogenesis may greatly facilitate the development of novel and ambitious therapeutic interventions, that are needed to counteract the onset of HIV-1 variants resistant to current antiretroviral treatments, to ensure affordable therapy programs for developing countries, and, in the long term, to eradicate the virus from patients and to confer protective immunity to HIV-1 infection.

An analysis of sagittal curves and balance after Cotrel-Dubousset instrumentation for kyphosis secondary to Scheuermann's disease. A review of 32 patients.

STUDY DESIGN: This study compared preoperative and postoperative saggittal curves and spinal balance in patients undergoing spinal fusion with Cotrel-Dubousset instrumentation for severe kyphosis secondary to Scheuermann's disease. Also determined was patient satisfaction regarding relief of pain and correction of the deformity. Thirty two patients with kyphosis > 75 degrees underwent spinal fusion with Cotrel-Dubousset instrumentation. OBJECTIVES: To evaluate the initial and long-term correction of the primary kyphosis and changes in lumbar lordosis and sagittal balance, and to determine the incidence and etiology of junctional sagittal deformities. SUMMARY OF BACKGROUND DATA: The average preoperative kyphosis was 85 degrees (range, 75 degrees to 105 degrees) with an average correction at final follow-up of 43 degrees (range, 26 degrees to 65 degrees). Preoperative lumbar lordosis averaged 75 degrees (range, 58 degrees to 100 degrees) and at final follow-up averaged 55 degrees (range, 23 degrees to 74 degrees). Most of the patients demonstrated negative sagittal balance and became slightly more negatively balanced postoperatively. RESULTS: Maintenance of correction postoperatively was excellent, with only a 4 degree average loss of correction. There was spontaneous reduction in lumbar lordosis of varying degrees. Proximal junctional kyphosis was associated with over-correction (> 50%) of the kyphotic deformity or a fusion starting short of the proximal vertebra in the measured kyphosis. Distal junctional kyphosis developed in patients whose fusion ended short of the first lordotic segment. CONCLUSIONS: This procedure appeared to yield good results when proper levels of fusion were selected and correction > 50% was not attempted.