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Central neurons develop and maintain molecularly distinct synaptic specializations for excitatory and inhibitory transmitters, often only microns apart on their dendritic arbor. Progress towards understanding the molecular basis of synaptogenesis has come from several recent studies using a coculture system of non-neuronal cells expressing molecules that generate presynaptic or postsynaptic "hemi-synapses" on contacting neurons. Together with molecular properties of these protein families, such studies have yielded interesting clues to how glutamatergic and GABAergic synapses are assembled. Other clues come from heterochronic cultures, manipulations of activity in subsets of neurons in a network, and of course many in vivo studies. Taking into account these data, we consider here how basic parameters of synapses--competence, placement, composition, size and longevity--might be determined.

Genetic ablation of the fibroblast growth factor (Fgf) 14 gene in mice or a missense mutation in Fgf14 in humans causes ataxia and cognitive deficits. These phenotypes suggest that the neuronally expressed Fgf14 gene is essential for regulating normal neuronal activity. Here, we demonstrate that FGF14 interacts directly with multiple voltage-gated Na(+) (Nav) channel alpha subunits heterologously expressed in non-neuronal cells or natively expressed in a murine neuroblastoma cell line. Functional studies reveal that these interactions result in the potent inhibition of Nav channel currents (I(Na)) and in changes in the voltage dependence of channel activation and inactivation. Deletion of the unique amino terminus of the splice variant of Fgf14, Fgf14-1b, or expression of the splice variant Fgf14-1a modifies the modulatory effects on I(Na), suggesting an important role for the amino terminus domain of FGF14 in the regulation of Na(v) channels. To investigate the function of FGF14 in neurones, we directly expressed Fgf14 in freshly isolated primary rat hippocampal neurones. In these cells, the addition of FGF14-1a-GFP or FGF14-1b-GFP increased I(Na) density and shifted the voltage dependence of channel activation and inactivation. In fully differentiated neurones, FGF14-1a-GFP or FGF14-1b-GFP preferentially colocalized with endogenous Nav channels at the axonal initial segment, a critical region for action potential generation. Together, these findings implicate FGF14 as a unique modulator of Nav channel activity in the CNS and provide a possible mechanism to explain the neurological phenotypes observed in mice and humans with mutations in Fgf14.

Activity plays multiple roles in the expression of synaptic plasticity, and has been shown to regulate the localization of both neurotransmitter receptors and downstream signaling machinery. However, the role of activity in central synapse formation and organization is incompletely understood. Some studies indicate that synapse formation can occur in the absence of synaptic activity, while others indicate that activity is required for synapse maintenance and receptor recruitment. In addition, the effects of long-term blockade of transmission generally, rather than blockade of specific receptors, on postsynaptic protein complement has been poorly characterized. In order to address the role of activity in synapse formation and postsynaptic specialization, we used tetanus toxin to chronically cleave VAMP2 and inhibit SNARE-mediated neurotransmitter release in cultured hippocampal neurons. Although these neurons are deficient in synaptic release, they are of normal size and morphology. In addition, both excitatory and inhibitory synapses form along their processes with normal density. These synapses have a remarkably similar cellular and molecular organization compared to controls, and are capable of recruiting postsynaptic scaffolding proteins, GABA, and glutamate receptors. Subcellular enrichment of synaptic proteins into specialized domains also appears intact. These data indicate that global activity inhibition is insufficient to disrupt central synapse formation or organization., (Copyright (c) 2005 Wiley-Liss, Inc.)

The formation of synapses in the vertebrate central nervous system is a complex process that occurs over a protracted period of development. Recent work has begun to unravel the mysteries of synaptogenesis, demonstrating the existence of multiple molecules that influence not only when and where synapses form but also synaptic specificity and stability. Some of these molecules act at a distance, steering axons to their correct receptive fields and promoting neuronal differentiation and maturation, whereas others act at the time of contact, providing positional information about the appropriateness of targets and/or inductive signals that trigger the cascade of events leading to synapse formation. In addition, correlated synaptic activity provides critical information about the appropriateness of synaptic connections, thereby influencing synapse stability and elimination. Although synapse formation and elimination are hallmarks of early development, these processes are also fundamental to learning, memory, and cognition in the mature brain.

Disease registries have traditionally been vehicles for the collection of clinical data, in most instances following a large number of patients for a long time period in an observational manner, and enhancing our understanding of disease aetiology and epidemiology. However, over recent decades, the potential for additional data collection and analyses to be conducted within the framework of a registry has been recognised and utilised. This is evident by the sheer number of registries that are now referenced in the medical literature, covering a vast array of therapeutic areas and topics much more varied than incidence, prevalence and survival. The opportunity to collect QOL and pharmacoeconomic data has been utilised within the registry framework as more and more countries have increased their demands for such information for regulatory procedures, including pricing and reimbursement decisions. This increased need for information has led to a marked increase in the number of registries undertaken that are primarily sponsored by the pharmaceutical industry. Disease registries offer tremendous opportunities to realise improvements in care. The length of data collection and the large number of patients involved offer some unusual advantages for QOL and health economic analyses; however, these advantages are not yet fully exploited.

Chlamydia trachomatis is probably the most common sexually transmitted disease in the Western industrialised countries with devastating consequences. However, it is an infection that can be so easily treated. There are over 50 million new cases occurring each year. In the United States chlamydia is seen as the most common and costly of the bacterial sexually transmitted diseases (STD), with approximately 4 million new cases occurring each year at an estimated total cost of $2.4 billion. The characteristic of this infection is its difficulty of detection that promotes its spread and making its prediction rather complex. Chlamydial infections are commonly asymptomatic or cause mild or non-specific symptoms and signs, which are not easily detected. Approximately 70% of women with endocervical infections and up to 50% of men with urethral infections are asymptomatic and thus not likely to seek medical care. Chlamydia has become known as the "silent epidemic". It is the more frequently identifiable single cause of pelvic inflammatory disease (PID), occurring in an estimated 15-40% of women. The primary objective of the study was to identify factors and quantify their contribution to the risk of being infected with Chlamydia and to construct an easy to use friendly method for early detection. The importance of developing some means of early detection is vital and previous studies suggest that selective screening might be one solution. A logit model was fitted to three broad variables: behavioural, patients' characteristics, and signs/symptoms noted by patient. The age of the women, the number of sexual partners over the past year, previous history of sexually transmitted disease, the use of barrier contraception and patients' and their partners' signs and symptoms were found to be among the most important variables. Such a model should allow patients who are in a high-risk category, allowing appropriate treatment.