Genetic contributions to Parkinson's disease

Sporadic Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by the loss of midbrain dopamine neurons and Lewy body inclusions. It is thought to result from a complex interaction between multiple predisposing genes and environmental influences, although these interactions are still poorly understood. Several causative genes have been identified in different families. Mutations in two genes [α-synuclein and nuclear receptor-related 1 (Nurr1)] cause the same pathology, and a third locus on chromosome 2 also causes this pathology. Other familial PD mutations have identified genes involved in the ubiquitin–proteasome system [parkin and ubiquitin C-terminal hydroxylase L1 (UCHL1)], although such cases do not produce Lewy bodies. These studies highlight critical cellular proteins and mechanisms for dopamine neuron survival as disrupted in Parkinson's disease. Understanding the genetic variations impacting on dopamine neurons may illuminate other molecular mechanisms involved. Additional candidate genes involved in dopamine cell survival, dopamine synthesis, metabolism and function, energy supply, oxidative stress, and cellular detoxification have been indicated by transgenic animal models and/or screened in human populations with differing results. Genetic variation in genes known to produce different patterns and types of neurodegeneration that may impact on the function of dopamine neurons are also reviewed. These studies suggest that environment and genetic background are likely to have a significant influence on susceptibility to Parkinson's disease. The identification of multiple genes predisposing to Parkinson's disease will assist in determining the cellular pathway/s leading to the neurodegeneration observed in this disease.     

ERP evidence of impaired central nervous system function in virally suppressed HIV patients on antiretroviral therapy.

OBJECTIVE: To examine the effects of human immunodeficiency virus (HIV) on central nervous system (CNS) function in patients receiving antiretroviral therapy (ART) who have suppressed viral loads. METHODS: Event-related brain potentials (ERPs) were recorded from 15 virally suppressed HIV patients and 15 age-, sex-, and education-matched controls while they performed a 3-stimulus auditory oddball task. The amplitude and latency of the P3a, P3b, and early auditory components were examined in HIV patients and controls. RESULTS: Virally suppressed HIV patients on ART were more depressed than controls, as determined by the Beck Depression Inventory (BDI). After controlling for the effects of depression, HIV patients had smaller P2, P3a, and P3b amplitudes and longer P3a and P3b latency than control subjects. BDI scores correlated positively with N1 latency in HIV patients and negatively with P3b amplitude in all subjects. CONCLUSIONS: These electrophysiological results suggest that, even in the absence of detectable levels of HIV in the peripheral blood, viral replication persists in the CNS and continues to cause disease in HIV patients on ART.     

Immature circulating lymphocytes in severely malnourished Guatemalan children

The percentage of peripheral blood lymphocytes forming rosettes with sheep erythrocytes (E-rosettes) was determined in 33 severely malnourished Guatemalan children, and in two groups of clinically well but mildly growth retarded children from the same environment. Mean E-rosettes in the acutely ill patients was lower than the value observed in the mildly malnourished children, although there was considerable overlap between groups. These data differ from previously published studies of severely malnourished children from other parts of the world in that not all patients had decreased values for E-rosettes, in contrast to the uniform depression reported by others. As all patients were clinically similar, the results suggest that there may be specific nutrient defects associated with protein-energy malnutrition that particularly affect immune function. In addition, in vitro incubation of lymphocytes from the acutely malnourished children with the thymic factor, thymosin fraction 5, increased the percentage of E-rosettes in a dose-dependent fashion. These data suggest that immature, thymosin-responsive T cells are present in circulation. It is possible that in vivo thymosin administration may be beneficial for malnourished individuals.     

Pseudo-outbreak of Acinetobacter lwoffii infection in a tertiary care center in Thailand.

We describe a pseudo-outbreak of Acinetobacter lwoffii infection that was recognized early. The pseudo-outbreak involved 16 patients and occurred 3.5 months after the GNS-506 Vitek automated system was introduced in the microbiology laboratory. Prompt confirmation of incomplete use of the automated system's algorithm as the point source of the misidentified A. lwoffii clinical isolates averted a full outbreak investigation and excess use of infection control resources.     

Mitigation of hearing loss from semi-circular canal transection in pseudomonas otitis media with ciprofloxacin-dexamethasone irrigation.

HYPOTHESIS: Irrigation of the mastoid with a quinolone antibiotic-steroid solution may mitigate hearing loss caused by iatrogenic semicircular canal injury in the presence of Pseudomonas aeruginosa (PA) otitis media (OM). BACKGROUND: Studies have shown the cochlea to be more vulnerable to semicircular canal transection (SCT)-related hearing loss in the presence of PA OM. Prophylactic systemic antibiotics and steroids may decrease this hearing loss, but SCT is usually not planned. The aim of this study was to determine if irrigation with ciprofloxacin-dexamethasone (cipro-dex) could improve hearing outcomes following SCT in PA OM. METHODS: PA OM was induced in 28 animals. After three to five days, unilateral SCT was performed in each animal, with sham SCT on the contralateral ear. At surgery, half of the animals (n = 14) underwent irrigation of the both mastoid bullae with cipro-dex; the second group of animals (n = 14) underwent irrigation of the bullae with sterile saline. Auditory thresholds were obtained immediately prior to SCT and 7-10 days after SCT. RESULTS: SCT ears treated with cipro-dex showed a mean click threshold improvement of 4.6 dB from pre-transection to 7-10 days post-transection, whereas thresholds in the SCT ears treated with saline worsened by 7.5 dB (p = 0.15). CONCLUSION: Irrigation of the guinea pig bulla with cipro-dex following SCT in the setting of PA OM appears safe and may yield beneficial effects on hearing.     

Nonreceptor binding of human chorionic gonadotropin (hCG): detection of hCG or a related molecule bound to endometrial tissue during pregnancy using labeled monoclonal antibodies that bind to exposed epitopes on the hormone

When hCG adsorbs to surfaces, including membranes from tissues that lack specific hCG receptors, it adsorbs with a particular orientation. Some sites on the alpha- and beta-subunits project away from the surface and can be detected with radiolabeled monoclonal antibodies. Other epitopes, which are located on a region on the hormone that presumably contacts the surface, lose their ability to bind antibody. Using antibodies specific for epitopes on hCG which remain exposed and can be detected when the hormone is adsorbed to rat brain homogenates, we found hCG or closely related substances bound to progestational decidual tissues. Immunologically reactive material adsorbed to the decidual tissue increased and decreased in parallel with the serum levels of hCG throughout pregnancy. Binding of labeled monoclonal antibody to substances similar or identical to hCG in other tissues, including placenta and fetal lung, but not red cells, also was identified. Unlike material adsorbed to decidual tissues, receptor-bound hCG was not recognized by any of our alpha-subunit-specific antibodies. This finding suggests either that the adsorbed hormone has a different orientation than receptor-bound hormone or that the adsorbed hormone has dissociated into subunits. These studies represent the first detection of nonreceptor binding of hCG or related molecules to tissues lacking receptors or presumed not to synthesize the hormone. The role of nonreceptor-bound hCG, if any, is unknown. Other than its effects on stimulation of luteal steroidogenesis during early pregnancy, the role of hCG during most of pregnancy has not been determined. Conceivably, the nonreceptor binding we identified is related to a role for hCG in pregnancy that is not associated with an action on the ovarian LH receptor.     

Double-orifice mitral valve with intact atrioventricular septum: an echocardiographic study with anatomic and functional considerations.

We identified 18 patients with double-orifice mitral valve (DOMV) and intact atrioventricular (AV) septum out of 40,179 echocardiographic studies performed between 1997 and 2002 at Children's Hospital, Denver, CO. In this study we describe (1) the anatomic characteristics of the DOMV in the absence of AV septal defect, (2) the function of the mitral valve by spectral and color Doppler flow mapping, and (3) associated lesions. The topographic location of the orifices in the leaflets suggests possible embryologic mechanisms of DOMV. In this series, DOMV was most commonly associated with left-sided obstructive lesions (in 39% of patients). Spectral and color Doppler interrogation demonstrated a normal flow profile in most cases; only 2 patients had significant mitral regurgitation or stenosis. Therefore, due to the uncertain natural history of this lesion and the potential need for endocarditis prophylaxis, careful imaging of the mitral valve is recommended, particularly in the presence of left-sided obstructive lesions.