Acromegaly: pathogenesis & treatment

Acromegaly is a multi-system disorder whose etiology is most often traced back to a growth hormone-secreting pituitary adenoma (PA). Growth hormone (GH) secretion promotes insulin-like growth factor 1 (IGF-1) release from peripheral tissues, leading to the clinical manifestations of acromegaly. Current treatment methods for acromegaly include surgery, medical therapy, and radiation therapy. The goals of acromegaly treatment are to reduce GH levels and IGF-1 levels to age/sex-normalized levels, relieve comorbidities, normalize mortality rate, and to remove the pituitary mass causing high hormone levels. This study aims to provide a comprehensive review of current treatment methods and an analysis of novel therapies for treatment of acromegaly. The primary treatment method of acromegaly is surgery due to limited complications, relatively low cost, and remission in the majority of cases. However, surgery is not an effective treatment method for invasive macroadenomas with extension into the intracranial space. Medical therapies such as dopamine agonists (DAs) and somatostatin receptor ligands (SRLs) are effective at reducing GH and IGF-1 levels and may have anti-tumor effects. However, DAs are only effective at treating minor elevations in GH and IGF-1 levels and SRLs may cause hyperglycemia after prolonged treatment. In contrast to DAs and SRLs, Pegvisomant does not have anti-tumor effects, but it is more effective at reducing GH and IGF-1 levels. The disadvantages of Pegvisomant are the possibility of irreversible liver damage and the overwhelming cost of treatment. Stereotactic radiosurgery (SRS) is another mode of treatment for acromegaly, however, there are many disadvantages to SRS including prolonged latency period, hypopituitarism, radio-necrosis of normal brain tissue, and secondary tumor formation. Novel therapies for acromegaly include antisense drugs and modified botulin neurotoxins. Despite the success of antisense drugs and modified botulin neurotoxins in animal models, greater research is required prior to application in human clinical trials. Gene therapy is an emerging treatment method for acromegaly and proper manipulation of viral immunogenic effects could prove as a successful treatment for large macroadenomas, invasive PAs, and recurrent PAs. Despite the success of surgery in treating microadenomas and noninvasive macroadenomas, therapeutic alternatives must be explored to treat invasive PAs, macroadenomas, and recurrent PAs. Future research in immunotherapies and gene therapies may provide greater insight into the development of more effective and less invasive treatment methods for acromegaly

Geography and exporting behavior : evidence from India

This paper examines locational factors that increase the odds of a firm's entry into export markets and affect the intensity of its participation. It differentiates between two different sources of spillovers: clustering of general economic activity and that of export-oriented activity. It also focuses on the effect of the business environment and that of institutions at the spatial unit of districts in India. The study disentangles the within-industry effect from the within-firm effect. A simple logit specification is used to model the probability of entry. The analysis is based on a panel of manufacturing firms in India, which allows for the introduction of firm-specific controls and a battery of fixed effects. The findings suggest that exporter-specific clustering, general economic agglomeration, and institutional factors affect firms'export behavior.Microfinance,Transport Economics Policy&Planning,Water and Industry,Economic Theory&Research,E-Business

Strain specific effects of low level lead exposure on associative learning and memory in rats.

Exposure to lead (Pb) remains a significant public health concern. Lead exposure in early life impairs the normal development of numerous cognitive and neurobehavioral processes. Previous work has shown that the effects of developmental Pb exposure on gene expression patterns in the brain are modulated by various factors including the developmental timing of the exposure, level of exposure, sex, and genetic background. Using gene microarray profiling, we previously reported a significant strain-specific effect of Pb exposure on the hippocampal transcriptome, with the greatest number of differentially expressed transcripts in Long Evans (LE) rats and the fewest in Sprague Dawley (SD) rats. The present study examined the extent to which this differential effect of Pb on hippocampal gene expression might influence behavior. Animals (males and females) were tested in a trace fear conditioning paradigm to evaluate effects of Pb exposures (perinatal (PERI; gestation to postnatal day 21) or early postnatal (EPN; postnatal day 1 to day 21)) on associative learning and memory. All animals (Pb-exposed and non-Pb-exposed controls) showed normal acquisition of the conditioned stimulus (tone)-unconditioned stimulus (footshock) association. Long Evans rats showed a significant deficit in short- and long-term recall, influenced by sex and the timing of Pb exposure (PERI or EPN). In contrast, Pb exposure had no significant effect on memory consolidation or recall in any SD rats. These results further demonstrate the important influence of genetic background to the functional outcomes from developmental Pb exposure

Evaluating Downside Risks in Reliable Networks

Reliable networks are those in which network elements have a positive probability of failing. Conventional performance measures for such networks concern themselves either with expected network performance or with the performance of the network when it is performing well. In reliable networks modeling critical functions, decision makers are often more concerned with network performance when the network is not performing well. In this paper, we study the single-source single-destination maximum flow problem through reliable networks and propose two risk measures to evaluate such downside performance. We propose an algorithm called COMPUTE-RISK to compute downside risk measures, and report our computational experience with the proposed algorithm.

Lexical stress constrains English-learning infants' segmentation in a non-native language.

Infants' ability to segment words in fluent speech is affected by their language experience. In this study we investigated the conditions under which infants can segment words in a non-native language. Using the Head-turn Preference Procedure, we found that monolingual English-learning 8-month-olds can segment bisyllabic words in Spanish (trochees and iambs) but not French (iambs). Our results are incompatible with accounts that rely on distributional learning, language rhythm similarity, or target word prosodic shape alone. Instead, we show that monolingual English-learning infants are able to segment words in a non-native language as long as words have stress, as is the case in English. More specifically, we show that even in a rhythmically different non-native language, English-learning infants can find words by detecting stressed syllables and treating them as word onsets or offsets

Speeding Up the Estimation of Expected Maximum Flows Through Reliable Networks

In this paper we present a strategy for speeding up the estimation of expected maximum flows through reliable networks. Our strategy tries to minimize the repetition of computational effort while evaluating network states sampled using the crude Monte Carlo method. Computational experiments with this strategy on three types of randomly generated networks show that it reduces the number of flow augmentations required for evaluating the states in the sample by as much as 52% on average with a standard deviation of 7% compared to the conventional strategy. This leads to an average time saving of about 71% with a standard deviation of about 8%.