More surprises in the global greenhouse: Human health impacts from recent toxic marine aerosol formations, due to centennial alterations of world-wide coastal food webs.

Reductions of zooplankton biomasses and grazing pressures were observed during overfishing-induced trophic cascades and concurrent oil spills at global scales. Recent phytoplankton increments followed, once Fe-, P-, and N-nutrient limitations of commensal diazotrophs and dinoflagellates were also eliminated by respective human desertification, deforestation, and eutrophication during climate changes. Si-limitation of diatoms instead ensued during these last anthropogenic perturbations of agricultural effluents and sewage loadings. Consequently, ~15% of total world-wide annual asthma trigger responses, i.e. amounting to ~45 million adjacent humans during 2004, resulted from brevetoxin and palytoxin poisons in aerosol forms of western boundary current origins. They were denoted by greater global harmful algal bloom [HAB] abundances and breathing attacks among sea-side children during prior decadal surveys of asthma prevalence, compiled here in ten paired shelf ecosystems of western and eutrophied boundary currents. Since 1965, such inferred onshore fluxes of aerosolized DOC poisons of HABs may have served as additional wind-borne organic carriers of toxic marine MeHg, phthalate, and DDT/DDE vectors, traced by radio-iodine isotopes to potentially elicit carcinomas. During these exchanges, as much as 40% of mercury poisonings may instead have been effected by inhalation of collateral HAB-carried marine neurotoxic aerosols of MeHg, not just from eating marine fish. Health impacts in some areas were additional asthma and pneumonia episodes, as well as endocrine disruptions among the same adjacent humans, with known large local rates of thyroid cancers, physician-diagnosed pulmonary problems, and ubiquitous high indices of mercury in hair, pesticides in breast milk, and phthalates in urine.

The heterogeneity of ventral tegmental area neurons: Projection functions in a mood-related context.

The ventral tegmental area (VTA) in the brain's reward circuitry is composed of a heterogeneous population of dopamine, GABA, and glutamate neurons that play important roles in mediating mood-related functions including depression. These neurons project to different brain regions, including the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC), and the amygdala. The functional understanding of these projection pathways has been improved since the extensive use of advanced techniques such as viral-mediated gene transfer, cell-type-specific neurophysiology and circuit-probing optogenetics. In this article, we will discuss the recent progress in understanding these VTA projection-specific functions, focusing on mood-related disorders.

Tumour vasculature targeting agents in hybrid/conjugate drugs.

Tumour vasculature targeting has been a very active area of cancer drug discovery over the last decade. Growth of solid tumours beyond a certain point requires a sufficient blood supply in order for them to develop and metastasise. While novel anti-angiogenic and vascular disrupting agents represent an important contribution to the armoury of anti-cancer agents they nevertheless usually require combination with standard cytotoxic therapy in order to demonstrate positive clinical outcomes. In line with this consensus, a new concept has arisen, namely the design of functional hybrids where at least one component of the design targets a tumour angiogenic/vasculature pathway. This review will outline examples of such hybrid/conjugate-based approaches. Emphasis will be placed on their preclinical evaluation with particular focus on the RGD/NGR-conjugates, heparin-related hybrids and antibody-drug conjugates. In conclusion, the benefits and shortcomings of hybrids under development will be discussed in the context of future directions and applications.

Twenty-first century mast cell stabilizers.

Mast cell stabilizing drugs inhibit the release of allergic mediators from mast cells and are used clinically to prevent allergic reactions to common allergens. Despite the relative success of the most commonly prescribed mast cell stabilizer, disodium cromoglycate, in use for the preventative treatment of bronchial asthma, allergic conjunctivitis and vernal keratoconjunctivitis, there still remains an urgent need to design new substances that are less expensive and require less frequent dosing schedules. In this regard, recent developments towards the discovery of the next generation of mast cell stabilizing drugs has included studies on substances isolated from natural sources, biological, newly synthesized compounds and drugs licensed for other indications. The diversity of natural products evaluated range from simple phenols, alkaloids, terpenes to simple amino acids. While in some cases their precise mode of action remains unknown it has nevertheless sparked interest in the development of synthetic derivatives with improved pharmacological properties. Within the purely synthetic class of inhibitors, particular attention has been devoted to the inhibition of important signalling molecules including spleen TK and JAK3. The statin class of cholesterol-lowering drugs as well as nilotinib, a TK inhibitor, are just some examples of clinically used drugs that have been evaluated for their anti-allergic properties. Here, we examine each approach under investigation, summarize the test data generated and offer suggestions for further preclinical evaluation before their therapeutic potential can be realized.

Tubulin-targeting agents in hybrid drugs.

The targeting of tubulin is an important mechanism for cancer chemotherapy. However, limitations such as resistance, toxicity and incomplete tumour elimination associated with individual anti-cancer drugs have led to a need for combination therapy in cancer. It is therefore relevant to ask whether two or more drugs might be combined in a single hybrid molecule to advantageous effect. This review provides an overview of the hybrid drugs thus far investigated, in which at least one component targets tubulin. The rationale behind this approach is that the hybrid drug may have activity enhanced above and beyond that of the equivalent drug combination, or have an otherwise improved clinical outcome. Particular emphasis is placed on the investigation of activity in multidrug-resistant cancer cell lines. Attention is drawn to the difficulties encountered when developing hybrid drugs, with respect to in vivo metabolism-tracking, increased molecular bulk, and optimisation of the drug dosage ratio. The actual and potential advantages and disadvantages of such hybrid drugs when compared to single drugs or drug combinations are discussed critically and promising directions for future research is highlighted.

A series of 1, 2-coupled indane dimers with mast cell stabilisation and smooth muscle relaxation properties.

Asthma is characterised by bronchoconstriction and inflammation, with infiltration and activation of inflammatory cells such as eosinophils and mast cells, and subsequent release of inflammatory mediators. Much of the therapy directed at the treatment of asthma is either to provide symptomatic relief through bronchodilation or to reduce inflammation to prevent or delay airway remodelling. In an attempt to address both of these issues, a novel series of 1,2-indane dimers has been synthesized and evaluated for smooth muscle relaxant and mast cell stabilising activities. We have identified two lead compounds, 5 and 15, which have substantial mast cell stabilisation activity.

Hybrid drugs for malaria.

Malaria continues to devastate much of the tropics and sub-tropics in spite of the availability of a number of antimalarial drugs. Part of this problem is due to the disadvantages of the drugs in use, which include (depending on the drug) side effects, reduced efficacy due to resistance, and high cost. Multiple traditional and novel approaches to the discovery and design of new antimalarial agents are likely to be required to furnish the new drugs necessary for improved malaria control. This review will address one novel and emerging approach, namely the development of hybrid antimalarial agents composed of two distinct antimalarial moieties joined covalently. Particular emphasis will be placed on the properties of the hybrids' design, including biological activity, advantages over other approaches, and the potential to address issues relating to resistance, solubility and formulation/delivery. The review will discuss the synthetic methodology used to form the hybrid and the ease by which it may be cleaved to form the independent components in vivo. The molecules discussed include hybrids of (i) artemisinins or other endoperoxide-based agents and quinolines (e.g. trioxaquines), (ii) chloroquine or other aminoquinolines and resistance-reversing or other agents, and (iii) peptidase inhibitors and other agents. The actual and potential advantages and disadvantages of such hybrids in relation to established single drugs or drug combinations will be discussed critically and promising future directions highlighted.

Synthesis and pharmacological activity of aminoindanone dimers and related compounds.

A series of N-substituted 3-aminoindanones were synthesised and evaluated for smooth muscle relaxant activity and mediator release inhibition effects. A low level of smooth muscle relaxant activity has been identified in all derivatives. Data have revealed that the significant mediator release inhibition effects observed are related to the nature of the amine substituents. A structure activity relationship is proposed.

Red tides in the Gulf of Mexico: Where, when, and why?

[1] Independent data from the Gulf of Mexico are used to develop and test the hypothesis that the same sequence of physical and ecological events each year allows the toxic dinoflagellate Karenia brevis to become dominant. A phosphorus-rich nutrient supply initiates phytoplankton succession, once deposition events of Saharan iron-rich dust allow Trichodesmium blooms to utilize ubiquitous dissolved nitrogen gas within otherwise nitrogen-poor sea water. They and the co-occurring K. brevis are positioned within the bottom Ekman layers, as a consequence of their similar diel vertical migration patterns on the middle shelf. Upon onshore upwelling of these near-bottom seed populations to CDOM-rich surface waters of coastal regions, light-inhibition of the small red tide of ~1 ug chl l(-1) of ichthytoxic K. brevis is alleviated. Thence, dead fish serve as a supplementary nutrient source, yielding large, self-shaded red tides of ~10 ug chl l(-1). The source of phosphorus is mainly of fossil origin off west Florida, where past nutrient additions from the eutrophied Lake Okeechobee had minimal impact. In contrast, the P-sources are of mainly anthropogenic origin off Texas, since both the nutrient loadings of Mississippi River and the spatial extent of the downstream red tides have increased over the last 100 years. During the past century and particularly within the last decade, previously cryptic Karenia spp. have caused toxic red tides in similar coastal habitats of other western boundary currents off Japan, China, New Zealand, Australia, and South Africa, downstream of the Gobi, Simpson, Great Western, and Kalahari Deserts, in a global response to both desertification and eutrophication.

Induction of the mammalian node requires Arkadia function in the extraembryonic lineages.

The early mammalian embryo is patterned by signals emanating from extraembryonic and embryonic signalling centres, most notably the anterior visceral endoderm (AVE) and the node, respectively. The AVE is responsible for anterior development, whereas further axis specification depends on the node, the equivalent of Spemann's organizer. Formation of the node, at the anterior primitive streak, depends on expression of the transcription factor HNF3beta (ref. 4). However, both the source and the nature of the signals responsible for inducing the node have been unknown. Here we describe a recessive lethal mutation, arkadia, generated using gene-trap mutagenesis. Mutant embryos establish an AVE but fail to maintain anterior embryonic structures and lack a node. The mutation has disrupted the Arkadia gene, which encodes a putative intracellular protein containing a RING domain. Arkadia is essential for HNF3beta expression in the anterior primitive streak. Analysis with chimaeras, however, shows that Arkadia functions within extraembryonic tissues, revealing that these are required to induce the node. Furthermore, our experiments show that Arkadia interacts genetically with the transforming growth factor (TGF)beta-like factor Nodal, implying that Nodal mediates the function of Arkadia in node induction.

Arkadia enhances nodal-related signalling to induce mesendoderm.

Nodal-related members of the transforming growth factor (TGF)-beta family regulate the induction of mesoderm, endoderm, and mesendoderm, a tissue specific to the Spemann organizer. How these different tissues form in response to the same signalling molecules is not completely understood. It has been suggested that concentration-dependent effects, mediated by extracellular cofactors and antagonists, are responsible for the differences. Here we show that the nuclear protein Arkadia specifically potentiates the mesendoderm-inducing activity of a subset of TGF-beta family members. The combined activities of Arkadia and Xenopus nodal-related-1 are sufficient to induce mesendoderm and suppress mesoderm. Arkadia dorsalizes ventral tissues, resulting in the induction of organizer-specific gene expression. Blocking nodal signalling extracellularly inhibits these effects. Arkadia influences nodal activity when co-expressed and can function in cells adjacent to those producing the nodal signal. Our findings, together with the observation that Arkadia mutant mice lack a node and node-derived mesendoderm, identify Arkadia as an essential modulator of the nodal signalling cascade that leads to induction of Spemann's organizer.

Diagnosis and management of hamate hook fractures.

Hamate hook fractures, although uncommon, are now recognized with increasing frequency because of the increase in popularity of racket sports and golf. Careful clinical evaluation and adjunctive radiologic investigation help establish the diagnosis. Acute nondisplaced fractures can heal with immobilization, while displaced fractures and nonunions typically require open reduction and internal fixation (acute fractures) or hook excision.

Binding of the alpha 2 integrin I domain to extracellular matrix ligands: structural and mechanistic differences between collagen and laminin binding.

The alpha 2 beta 1 integrin functions as a cell surface receptor for collagen on some cells and as both a collagen and laminin receptor on a more restricted subset of cell types including endothelial and epithelial cells. The alpha 2 integrin subunit I domain binds collagen in a divalent cation-dependent manner. In contrast, I domain binding to laminin occurs via both divalent cation-dependent and -independent mechanisms. Saturable binding was observed in the presence of either Mn2+ or EDTA, although the extent of binding in Mn2+ was twice that observed in EDTA. Half-maximal binding occurred at about 22 nM I domain in either case. Whereas laminin binding was significantly enhanced by Mn2+, with half-maximal binding occurring at 1.9 mM Mn2+, Mg2+ was much less effective. Deletion of the N-terminal 35 residues of the I domain, including the DXSXS portion of the MIDAS motif, caused a significant diminution of laminin binding activity. Laminin binding by the I domain was significantly inhibited by the alpha 2 beta 1 function-blocking antibody 6F1 in the presence of either EDTA or Mn2+. The non-function-blocking antibody 12F1 had no effect. In contrast to the binding of the alpha 2 integrin I domain to collagen, the laminin binding activity of the I domain was not enhanced by the addition of the first EF hand motif of the integrin.

MR imaging of ulnar nerve entrapment secondary to an anomalous wrist muscle.

MR imaging of an anomalous hypothenar adductor muscle causing isolated deep ulnar nerve branch compression and producing a purely motor neuropathy is presented. The muscle appears to represent a type 1 variant of the intrinsic anomalous hypothenar adductor muscle.

Torticollis and hip dislocation.

Reports in the literature suggest that there is an association between two childhood disorders: torticollis, an easily recognized clinical deformity, and developmental dislocation or dysplasia of the hip, an occult disorder. The identification of the obvious disease, torticollis, may prompt a search for the occult disease, developmental dislocation of the hip. If the association of these two disorders is common, it may be justified to expend resources to diagnose the occult disorder in all cases in which the more obviously noticed disorder is recognized. The reported association varies between 2 and 29%. We retrospectively reviewed 70 patients with the diagnosis of congenital muscular torticollis to determine the incidence of hip dislocation or subluxation in these patients. Fifty-four patients had radiographs of their hips. Forty-one patients were available for follow-up at an average of age 3+4 years. Six patients were noted to have hip subluxation or dislocation, all at presentation. Of these, four had been referred for diagnosed hip disease, whereas two were referred for torticollis, and the hip disease was then diagnosed by the pediatric orthopaedist. No patient had abnormal radiographs or physical findings at follow-up. We conclude that the rate of hip disease in those with torticollis is approximately 8% and is lower than the 20% often quoted.

The alpha 2 beta 1 integrin binds to the CB4 peptide of the alpha 2(I) collagen chain.

The adhesion of platelets and other cells to type I collagen is mediated by the alpha 2 beta 1 integrin. A binding site for the alpha 2 beta 1 integrin within the alpha 1(I) collagen chain has previously been localized to the cyanogen bromide fragment alpha 1(I)-CB3. We noe show by use of inhibitory monoclonal antibodies against the alpha 2 beta 1 integrin, that platelets also adhere to purified alpha 2(I) collagen chains by a mechanism mediated by the alpha 2 beta 1 integrin. Moreover, following isolation of cyanogen bromide fragments of the alpha 2(I) collagen chain by HPLC, we demonstrate that alpha 2 beta 1 integrin-mediated adhesion is restricted to the CB4 fragment of the alpha 2(I) collagen polypeptide. These findings indicate the presence of at least two spatially distinct binding sites for the alpha 2 beta 1 integrin on the native type I collagen triple helix.

Contributions of the I and EF hand domains to the divalent cation-dependent collagen binding activity of the alpha2beta1 integrin.

The alpha2beta1 integrin binds collagen in a Mg2+-dependent manner that is inhibited by Ca2+. Like the intact integrin, purified recombinant proteins containing the alpha2 integrin I domain, either alone or with variable numbers of alpha2 integrin EF hand metal binding sites, bound collagen in a Mg2+-dependent manner, and Ca2+ did not support binding. However, unlike the intact integrin, Ca2+ did not inhibit the Mg2+-dependent binding of any of the fusion proteins to collagen. Binding to collagen was saturable and blocked by the alpha2beta1 function blocking antibody 6F1. Deletional analysis demonstrated that residues present within the amino-terminal 35 amino acids contribute to the 6F1 epitope and are required for Mg2+-dependent collagen binding. The results indicate that the I domain contains a Mg2+ binding site that is essential for collagen binding and that the I domain alone is sufficient for collagen binding. Binding is markedly enhanced in a divalent cation-dependent manner by the addition of the first EF hand motif. Mutation of the EF hand to an inactive form completely abrogated the effect. The sites necessary for Ca2+ inhibition are not present within the I domain or the adjacent region containing the three EF hand sites.

Platelet interactions with fibronectin: divalent cation-independent platelet adhesion to the gelatin-binding domain of fibronectin.

Divalent cation-dependent platelet adhesion to fibronectin (FN) is mediated by the integrin receptors alpha 5 beta 1 (GP Ic-IIa) and alpha IIb beta 3 (GP IIb-IIIa), which recognize the RGD (Arg-Gly-Asp) sequence in the cell-binding domain. However, FN can also support divalent cation-independent platelet adhesion. To determine which domain of FN mediates divalent cation-independent adhesion, proteolysis with thermolysin and affinity chromatography were used to isolate the cell-binding, gelatin-binding, and heparin-binding domains of FN. Unactivated and thrombin-activated platelets adhered to intact FN and the 45-Kd gelatin-binding domain in the presence of either Ca2+ or EDTA. Platelet spreading was mediated only by the 105-Kd cell-binding domain and required divalent cations. The heparin-binding domains did not support platelet adhesion. Reduction of intrachain disulfide bonds or removal of carbohydrate side chains on the gelatin-binding domain did not alter the ability to support platelet adhesion. Divalent cation-independent adhesion to the 45-Kd gelatin-binding domain was not inhibited by RGDS (Arg-Gly-Asp-Ser) synthetic peptides or monoclonal antibodies (MoAbs) directed against known platelet receptors. We conclude that platelets can adhere but not spread on the gelatin-binding domain of FN by a novel divalent cation-independent mechanism.

Auto-induction of transforming growth factor-beta in human lung fibroblasts.

The type beta transforming growth factors (TGF-beta s) are a family of potent cytokines with diverse effects on proliferation, differentiation, turnover of extracellular matrix components, oncogene expression, and other aspects of cellular phenotype. Unlike lung fibroblasts of certain species, unstimulated human lung fibroblast lines produce little or no TGF-beta in culture. However, TGF-beta has been reported to autoregulate its own production in certain human tumor cells and in rodent cell lines. To test whether this phenomenon is operative in fibroblasts from normal human lung tissue, confluent cultures of IMR90 normal fetal lung fibroblasts were exposed to TGF-beta. Cultures were exposed briefly to purified TGF-beta 1 under serum-free conditions and secretion of newly synthesized TGF-beta over the ensuing 72 h was determined by immunoblotting and bioassays made specific with the use of neutralizing antibodies. Steady-state levels of mRNA for TGF-beta 1 were detected by Northern and slot blot hybridization analysis of total cellular RNA. The 2.5 kb TGF-beta 1 mRNA species rose within 1.5 h of exposure of IMR90 cells to TGF-beta 1 and reached maximal levels after 16 h. Increased levels of TGF-beta were detected in conditioned medium 9 h after the start of the exposure. Thereafter, TGF-beta continued to accumulate at an elevated rate (90 +/- 7 versus < or = 15 pg/10(6) cells/h in uninduced cells) for up to 72 h. As little as 1 ng/ml TGF-beta 1 auto-induced TGF-beta secretion.(ABSTRACT TRUNCATED AT 250 WORDS)