Is there a basis for novel pharmacotherapy of autism?

No medication has yet been shown to consistently alter the symptoms or the course of autism in the majority of patients. The present pharmacotherapy is mainly palliative and sometimes effective in attenuating specific behaviors. The search for better treatment involves examination of the underlying pathophysiology, the genetic or environmental etiology (including possible iatrogenic causes), and assessment of the clinically-generated evidence of efficacy, including serendipitous or unexplained findings. Subtle neuroanatomic and neurochemical changes are being explored and there are anecdotal reports or limited clinical trials that suggest some therapy might be possible. Secretin is a surprising recent addition to the list of candidates. The pharmacologic mechanism by which these agents might provide such effect is not clear, but hypotheses are beginning to emerge. In addition, the prevention of some uncertain number of autism cases is being investigated by examination of certain vaccinations as putative causative or contributory factors. These topics are reviewed in this article, which has the additional purpose of stimulating novel drug discovery efforts for this enigmatic disorder.     

Microtubule-dependent reticulopodial motility: is there a role for actin?

We summarize our recent immunocytochemical characterization of the reticulopodial cytoskeleton of two allogromiid foraminifers and our pharmacologic dissection of its motility. The reticulopodial microtubule cytoskeleton stained with an antiserum to brain microtubule-associated protein 2. Polymeric actin was localized in the reticulopodia by rhodamine-phalloidin staining. Microtubule inhibitors reversibly inhibited all aspects of motility; cytochalasins induced altered morphology and disorganization of motility but did not inhibit pseudopodial movements or intracellular transport. Simultaneous application of KCN and salicylhydroxamic acid (an alternative oxidase inhibitor) rapidly blocked all movement, indicating that motility is dependent on metabolic energy and that an alternative oxidative pathway functions in allogromiids. Micromanipulation and laser microsurgical experiments revealed tension throughout the reticulopodium. Our results suggest that microtubules are active components of the reticulopodial motile machinery. Actin may mediate substrate adhesion, whole-cell locomotion, pseudopodial tension, and coordination of the microtubule-based motility.     

Microtubule-bundling studies revisited: is there a role for MAPs?

The molecular mechanism of microtubule bundling has been enveloped in controversy for the past few years. At the centre of the debate are MAPs: are they necessary for the formation of microtubule bundles? In this article, Gloria Lee and Roland Brandt weigh the evidence and propose that microtubule stability might be the crucial factor in microtubule bundling. Perhaps then MAPs might act as spacer molecules between microtubules.     

Hormonal therapies and meningioma: Is there a link?

Background: The aetiology of meningiomas is largely unknown although hormones have been suggested to play a role. Methods: A cohort study was performed to evaluate hormone-related factors associated with meningioma. Patients (12–89 years) with a first diagnosis of meningioma (January 1996–June 2008) were identified from The Health Improvement Network UK primary care database and age- and sex-matched to controls (n = 10 000) from the same cohort. Odds ratios (ORs) were calculated following a nested case control analysis using unconditional logistic regression. Results: In total, 745 patients with meningioma were identified from a study population of 2 171 287. No significantly increased risk of meningioma was found among female users of oral contraceptives (OR: 1.15; CI: 0.67–1.98), hormone replacement therapy (OR: 0.99; CI: 0.73–1.35) or low-dose cyproterone acetate (CPA; OR: 1.51; CI: 0.33–6.86) compared with non-users. There was a significantly increased risk of meningioma among male users of androgen analogues (OR: 19.09; CI: 2.81–129.74) and among users of high-dose CPA (OR: 6.30; CI: 1.37–28.94) compared with non-users, however there were only three cases currently using these drugs. No significant association was found between meningioma and prostate, breast, or genital cancers. Conclusions: Our results do not support a role for exogenous hormone use by females in meningioma development. The risk in males was only observed with high-dose, short-term (<1 year) therapy. Impact: While hormonal cancers and therapies are not associated with meningioma in females, the risk in males requires further investigation.     

Conventional culture for water quality assessment: is there a future?

Conventional culture for the detection, enumeration and identification of micro-organisms has been the traditional tool of the microbiologist. It is, however, time-consuming and labour-intensive and confirmed results often require several days of analysis. Culture may not grow the organisms being sought and for enumeration may only detect a small proportion of the total population. However, it does have the advantage of being simple to use and relatively inexpensive. It is also a direct means of assessing cell viability. Novel fluorogenic dyes and fluorgenic and chromogenic substrates have overcome some of these problems by providing a means of rapid and specific detection and enumeration whilst removing the need for subculture and confirmation tests. Immunological tests such as ELISA have significantly reduced analysis time by providing specific target organism detection. Molecular techniques have removed the need for culture. Improvements in sensitivity, and removal of the inhibitory nature of sample matrices, have allowed analysts to detect low levels of micro-organisms but the questions of viability and comparability with cultural techniques still remain. Are we about to see a change of culture in water quality assessment, or can cultural techniques be developed that reduce analysis time to a few hours and can rapid methods be used for detecting the presence and viability of organisms?     

Is there a physical chemical basis for the present genetic code?

Summary Recent experiments on the interaction of amino acids with homopolyribonucleic acids as measured by proton magnetic resonance spectroscopy and on the interactions of ribonucleoside 5-monophosphates with immobilized amino acids give relative binding strengths that are not reconcilable with the present genetic code in any simple way.     

Sequence-specific binding of single-stranded RNA: is there a code for recognition?

A code predicting the RNA sequence that will be bound by a certain protein based on its amino acid sequence or its structure would provide a useful tool for the design of RNA binders with desired sequence-specificity. Such de novo designed RNA binders could be of extraordinary use in both medical and basic research applications. Furthermore, a code could help to predict the cellular functions of RNA-binding proteins that have not yet been extensively studied. A comparative analysis of Pumilio homology domains, zinc-containing RNA binders, hnRNP K homology domains and RNA recognition motifs is performed in this review. Based on this, a set of binding rules is proposed that hints towards a code for RNA recognition by these domains. Furthermore, we discuss the intermolecular interactions that are important for RNA binding and summarize their importance in providing affinity and specificity.     

Minimum viable populations: is there a 'magic number' for conservation practitioners?

Establishing species conservation priorities and recovery goals is often enhanced by extinction risk estimates. The need to set goals, even in data-deficient situations, has prompted researchers to ask whether general guidelines could replace individual estimates of extinction risk. To inform conservation policy, recent studies have revived the concept of the minimum viable population (MVP), the population size required to provide some specified probability of persistence for a given period of time. These studies conclude that long-term persistence requires ≥5000 adult individuals, an MVP threshold that is unaffected by taxonomy, life history or environmental conditions. Here, we re-evaluate this suggestion. We find that neither data nor theory supports its general applicability, raising questions about the utility of MVPs for conservation planning.     

Symmetrical breast reconstruction: is there a role for three-dimensional digital photography?

Clinical applications of three-dimensional digital photography include assessments of breast volume and contour. It was hypothesized that knowledge of preoperative and postoperative breast volumes might facilitate obtaining symmetry after reconstructions with autologous tissue or implants. Breast reconstruction was performed for 382 women during a 4-year period. Of those women, 334 completed all phases of the reconstruction and underwent symmetry analysis. Reconstructive procedures included the use of pedicle transverse rectus abdominis musculocutaneous flaps, free transverse rectus abdominis musculocutaneous flaps, deep inferior epigastric perforator flaps, superior gluteal artery perforator flaps, or latissimus dorsi flaps or expanders/implants. Three-dimensional digital photographic images were obtained for 33 women, whereas the remaining 301 women were not digitally photographed. The differences in symmetry after the initial reconstruction and after the secondary procedures were compared for all women and for the groups with and without three-dimensional photographic images. For the group with three-dimensional imaging, initial volume symmetry was obtained for 73 percent, initial contour symmetry was obtained for 27 percent, secondary procedures were necessary for 70 percent, final volume symmetry was obtained for 88 percent, and final contour symmetry was obtained for 79 percent. For the group without three-dimensional photographic images, initial volume symmetry was obtained for 57 percent, initial contour symmetry was obtained for 34 percent, secondary procedures were necessary for 50 percent, final volume symmetry was obtained for 80 percent, and final contour symmetry was obtained for 71 percent. The results demonstrated that there was no significant difference in final contour and volume symmetry between women who had or did not have three-dimensional digital photographic images taken. However, the results demonstrated that autologous tissue reconstructions resulted in improved contour and volume symmetry, compared with implant reconstructions.     

AIDS-associated Kaposi's sarcoma: is there still a role for interferon alfa?

Interferon alfa (IFN) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFN in KS treatment, little is currently known about the mechanism(s) by which IFN causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFN activities. To a large extent other agents have supplanted IFN as treatments for KS, but there may still remain a therapeutic role for IFN, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling.     

Metabolism and longevity: is there a role for membrane fatty acids?

More than 100 years ago, Max Rubner combined the fact that both metabolic rate and longevity of mammals varies with body size to calculate that "life energy potential" (lifetime energy turnover per kilogram) was relatively constant. This calculation linked longevity to aerobic metabolism which in turn led to the "rate-of-living" and ultimately the "oxidative stress" theories of aging. However, the link between metabolic rate and longevity is imperfect. Although unknown in Rubner's time, one aspect of body composition of mammals also varies with body size, namely the fatty acid composition of membranes. Fatty acids vary dramatically in their susceptibility to peroxidation and the products of lipid peroxidation are very powerful reactive molecules that damage other cellular molecules. The "membrane pacemaker" modification of the "oxidative stress" theory of aging proposes that fatty acid composition of membranes, via its influence on peroxidation of lipids, is an important determinant of lifespan (and a link between metabolism and longevity). The relationship between membrane fatty acid composition and longevity is discussed for (1) mammals of different body size, (2) birds of different body size, (3) mammals and birds that are exceptionally long-living for their size, (4) strains of mice that vary in longevity, (5) calorie-restriction extension of longevity in rodents, (6) differences in longevity between queen and worker honeybees, and (7) variation in longevity among humans. Most of these comparisons support an important role for membrane fatty acid composition in the determination of longevity. It is apparent that membrane composition is regulated for each species. Provided the diet is not deficient in polyunsaturated fat, it has minimal influence on a species' membrane fatty acid composition and likely also on it's maximum longevity. The exceptional longevity of Homo sapiens combined with the limited knowledge of the fatty acid composition of human tissues support the potential importance of mitochondrial membranes in determination of longevity.     

Coenzyme Q10: is there a clinical role and a case for measurement?

Coenzyme Q(10) (CoQ(10)) is an essential cofactor in the mitochondrial electron transport pathway, and is also a lipid-soluble antioxidant. It is endogenously synthesised via the mevalonate pathway, and some is obtained from the diet. CoQ(10) supplements are available over the counter from health food shops and pharmacies. CoQ(10) deficiency has been implicated in several clinical disorders, including but not confined to heart failure, hypertension, Parkinson's disease and malignancy. Statin, 3-hydroxy-3- methyl-glutaryl (HMG)-CoA reductase inhibitor therapy inhibits conversion of HMG-CoA to mevalonate and lowers plasma CoQ(10) concentrations. The case for measurement of plasma CoQ(10) is based on the relationship between levels and outcomes, as in chronic heart failure, where it may identify individuals most likely to benefit from supplementation therapy. During CoQ(10) supplementation plasma CoQ(10) levels should be monitored to ensure efficacy, given that there is variable bioavailability between commercial formulations, and known inter-individual variation in CoQ(10) absorption. Knowledge of biological variation and reference change values is important to determine whether a significant change in plasma CoQ(10) has occurred, whether a reduction for example following statin therapy or an increase following supplementation. Emerging evidence will determine whether CoQ(10) does indeed have an important clinical role and in particular, whether there is a case for measurement.