Environmental exposure to manganese in air: Tremor, motor and cognitive symptom profiles.

BACKGROUND: Excessive exposure to manganese (Mn) may cause parkinsonian-like motor and tremor symptoms and adverse cognitive effects, including problems with executive functioning (EF), resembling those found in later-stage Parkinson's disease (PD). Studies seeking to differentiate PD patients into subgroups with associated cognitive and functional outcomes using motor and tremor symptoms identified tremor-dominant (TD) and non-tremor dominant (NTD) subtypes. It is unclear whether differing patterns of pathophysiology and symptoms exist in Mn neurotoxicity, as they do in PD. METHODS: Residents of East Liverpool (n=83) and Marietta, OH (n=99) exposed to chronic (>10years) environmental Mn through industrial pollution were administered neuropsychological measures and a physician-rated scale of movement-disorder symptoms. Two-step cluster analysis was used to group residents based on tremor symptoms, bradykinesia/rigidity symptoms, gait disturbance, and executive function. Cluster membership was validated using modeled air-Mn exposure and a computerized tremor measure. RESULTS: Elevated tremor and motor symptoms and executive dysfunction were observed, and TD and NTD symptom clusters were identified. Two additional clusters were also identified: Executive Dysfunction and Normal Functioning. The NTD residents, with elevated levels of gait disturbance and other movement disorder symptoms, did not evidence EF impairment, as predicted. Instead, residents with EF impairment formed their own cluster, and were relatively free of movement disorder symptoms. CONCLUSIONS: Results resemble reports in the PD literature with TD and NTD clusters identified, but executive dysfunction did not cluster with NTD symptoms. PD and Mn exposure likely have differing pathophysiology and developmental courses, and therefore different symptom patterns, even when similar symptoms are present.

Missed appointments in general practice: retrospective data analysis from four practices.

Little is known about which patients miss appointments or why they do so. Using routinely collected data from four practices, we aimed to determine whether patients who missed appointments differed in terms of their age, sex, and deprivation scores from those who did not, and to examine differences between the practices with respect to missed appointments. The likelihood of someone missing at least one appointment was independently associated with being female, living in a deprived area, and being a young adult. Living in a deprived area was associated with a threefold increase in the likelihood of missing an appointment, and the extent of this association was the same across all four practices. Interventions aimed at reducing missed appointments need to be based upon these findings.

The effect of the full moon on general practice consultation rates.

BACKGROUND: The effect of the full moon on human behaviour, the so-called 'Transylvania hypothesis', has fascinated the public and occupied the mind of researchers for centuries. OBJECTIVE: The aim of the present study was to determine whether or not there was any change in general practice consultation patterns around the time of the full moon. METHOD: We analysed data from the fourth national morbidity study of general practice. The data set was split into two groups and analysed separately: consultations on ordinary weekdays and consultations on weekends and bank holidays. The data were split randomly into two equal sets, one for model building and one for model validation. The lunar cycle effect was assumed to be sinusoidal, on the grounds that any effect would be maximal at the time of the full moon and decline to the new moon, following a cosine curve (with a period of 29.54 days, the mean length of a lunar cycle). RESULTS: There was a statistically significant, but small, effect associated with the lunar cycle of 1.8% of the mean value [95% confidence interval (CI) 0.9-2.7%]. This equates to an average difference between the two extremes during the cycle of 3.6%. For this data set, this accounts for 190 (95% CI 95-285) more consultations on days at the peak of the cycle compared with those at the bottom of the cycle, or, put another way, about three consultations per practice. CONCLUSION: We can speculate neither as to what the nature of these moon-related problems may be, nor as to the mechanisms underpinning such behaviour. However, we have confirmed that it does not seem to be related to anxiety and depression.

Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex.

Compartmentalization of glutamate receptors with the signaling enzymes that regulate their activity supports synaptic transmission. Two classes of binding proteins organize these complexes: the MAGUK proteins that cluster glutamate receptors and AKAPs that anchor kinases and phosphatases. In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150. The SH3 and GK regions of the MAGUKs mediate binding to the AKAP. Cell-based studies indicate that phosphorylation of AMPA receptors is enhanced by a SAP97-AKAP79 complex that directs PKA to GluR1 via a PDZ domain interaction. As AMPA receptor phosphorylation is implicated in regulating synaptic plasticity, these data suggest that a MAGUK-AKAP complex may be centrally involved.

Neuregulin-increased expression of acetylcholine receptor epsilon-subunit gene requires ErbB interaction with Shc.

Selective transcription of acetylcholine receptor (AChR) subunit genes by neuregulin is one of the mechanisms involved in the synaptic localization of AChRs to the neuromuscular junction. Neuregulin stimulates ErbB receptor tyrosine kinases and subsequently activates the Ras/ERK pathway, which is required for neuregulin-mediated induction of AChR subunit genes in muscle cells and synapse-specific expression in vivo. Here we investigated the neuregulin transduction mechanism that leads to ERK activation after ErbB receptor tyrosine phosphorylation. Neuregulin increases the association of the adaptor proteins Grb2 and Shc with both ErbB2 and ErbB3 in C2C12 muscle cells. Dephosphorylation of the tyrosine-phosphorylated ErbB proteins abolished their association with both Grb2 and Shc, suggesting a tyrosine phosphorylation-dependent interaction. The interaction of Shc with the ErbB receptors is mediated by Shc's phosphotyrosine-binding domain. In addition, neuregulin increased tyrosine phosphorylation of Shc. Mutagenesis approaches demonstrated that tyrosine phosphorylation of Shc is required for neuregulin induction of AChR subunit gene expression. Taken together, these data indicate that the interaction of ErbB receptors with Grb2 alone is insufficient for neuregulin-activated transcription, but that ErbB receptor signaling via Shc is necessary and important.

AKAPs: from structure to function.

Compartmentalization of signalling molecules through association with anchoring proteins ensures specificity in signal transduction by placing enzymes close to their appropriate effectors and substrates. For example, 'A-kinase anchoring proteins' (AKAPs) bind to the regulatory subunit of cAMP-dependent protein kinase (PKA) to direct the kinase to discrete intracellular locations. Recently, functional studies aimed at disrupting AKAP-PKA complexes have demonstrated a role for anchored PKA in various cellular processes, including gene transcription, hormone-mediated insulin secretion and ion-channel modulation. By binding to additional signalling molecules, AKAPs might function to coordinate multiple components of signal-transduction pathways.

Signals mediating ion channel clustering at the neuromuscular junction.

High densities of acetylcholine receptors and sodium channels in the crests and troughs of the postsynaptic folds, respectively, ensure reliable neuromuscular signalling. Clustering of both ion channels is mediated by agrin. In the case of acetylcholine receptors, agrin activates the tyrosine kinase receptor muscle-specific kinase (MuSK), initiating a process requiring rapsyn and possibly also receptor phosphorylation. In many respects, the interactions between agrin and MuSK and their downstream effectors are atypical of conventional receptor tyrosine kinase signalling systems. A new understanding of the structural features of rapsyn involved in receptor clustering, as well as syntrophin's role in sodium channel targeting, has recently been revealed. Perhaps the most surprising result of the past year with regard to synaptogenesis is a negative one--mice lacking both dystrophin and utrophin have nearly normal neuromuscular junctions.

Good health care: patient and professional perspectives.

Many health needs assessment exercises are professionally led, employing complex epidemiological methods. An alternative method that gives valuable information about patient preferences is a forced-choice questionnaire, which this study used in five practices in the West of Scotland. In each practice, patient-centred care was the most highly valued attribute of service provision.

Tyrosine phosphorylation of nicotinic acetylcholine receptor mediates Grb2 binding.

Tyrosine phosphorylation of the nicotinic acetylcholine receptor (AChR) is associated with an altered rate of receptor desensitization and also may play a role in agrin-induced receptor clustering. We have demonstrated a previously unsuspected interaction between Torpedo AChR and the adaptor protein Grb2. The binding is mediated by the Src homology 2 (SH2) domain of Grb2 and the tyrosine-phosphorylated delta subunit of the AChR. Dephosphorylation of the delta subunit abolishes Grb2 binding. A cytoplasmic domain of the delta subunit contains a binding motif (pYXNX) for the SH2 domain of Grb2. Indeed, a phosphopeptide corresponding to this region of the delta subunit binds to Grb2 SH2 fusion proteins with relatively high affinity, whereas a peptide lacking phosphorylation on tyrosine exhibits no binding. Grb2 is colocalized with the AChR on the innervated face of Torpedo electrocytes. Furthermore, Grb2 specifically copurifies with AChR solubilized from postsynaptic membranes. These data suggest a novel role for tyrosine phosphorylation of the AChR in the initiation of a Grb2-mediated signaling cascade at the postsynaptic membrane.

Clustering of the acetylcholine receptor by the 43-kD protein: involvement of the zinc finger domain.

A postsynaptic membrane-associated protein of M(r) 43,000 (43-kD protein) is involved in clustering of the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. Previous studies have shown that recombinant mouse 43-kD protein forms membrane-associated clusters when expressed in Xenopus oocytes. Coexpression with the AChR results in colocalization of the receptor with the 43-kD protein clusters (Froehner, S. C., C. W. Luetje, P. B. Scotland, and J. Patrick, 1990. Neuron. 5:403-410). To understand the mechanism of this clustering, we have studied the role of the carboxy-terminal region of the 43-kD protein. The amino acid sequence of this region predicts two tandem zinc finger structures followed by a serine phosphorylation site. Both Torpedo 43-kD protein and the carboxy-terminal region of the mouse 43-kD protein bind radioisotopic zinc. Mutation of two histidine residues in this predicted domain greatly attenuates zinc binding, lending support to the proposal that this region forms zinc fingers. When expressed in oocytes, the ability of this mutant 43-kD protein to form clusters is greatly reduced. Its ability to interact with AChR, however, is retained. In contrast, a mutation that eliminates the potential serine phosphorylation site has no effect on clustering of the 43-kD protein or on interaction with the AChR. These findings suggest that protein interactions via the zinc finger domain of the 43-kD protein may be important for AChR clustering at the synapse.

Economic cycles and health. Towards a sociological understanding of the impact of the recession on health and illness.

Does the impact of large scale and long term unemployment have a negative influence on the health of a community? This paper critically examines research evidence at a macro and micro level of analysis debating the major theoretical issues, and the difficulty in establishing causality between changing mortality patterns over time and fluctuations in the business cycle. It is argued that macro analysis cannot stand on its own as an explanation but needs to be combined with an understanding of the career progression of the unemployed and the stages of psychological transition that occur to bridge the gap between macro and micro environments, and give some understanding of the changes in health status that may be observed in a population following a period of unemployment or economic uncertainty. Both quantitative and qualitative research suggest that not only is the health of those actually at risk but also their immediate family and the community at large during a recession. From this proposition two significant factors emerge in the literature which could explain the association between unemployment rates and changing patterns of mortality. Firstly stress is highlighted in most of the research reviewed, and could be the linking factor for material reasons and also those of social well being. Secondly health status, like that of unemployment is not equally shared in the United Kingdom community, but rather shouldered on a class basis, the most consistent finding being an inverse relationship between economic status and mortality placing the burden squarely on the lower social economic groups who are most vulnerable to unemployment. Taken together all the evidence suggests the inferences made from the macro statistics despite the difficulties in demonstrating causality, suggesting a strong link between mortality rates and cycles of economic activity.