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An asymmetric synthetic route to (−)-galanthamine (1), a pharmacologically active Amaryllidaceaealkaloid used for the symptomatic treatment of early onset Alzheimer’s disease, was successfully established with very high levels of stereocontrol. The key to achieving high chemo- and stereo-selectivity in this approach was the use of transition-metal-mediated reactions, namely, enyne ring-closing metathesis, Heck coupling, and titanium-based asymmetric allylation.

Cattle pastoralism plays a central role in human livelihood in Africa. However, the genetic history of its success remains unknown. Here, through whole-genome sequence analysis of 172 indigenous African cattle from 16 breeds representative of the main cattle groups, we identify a major taurine × indicine cattle admixture event dated to circa 750–1,050 yr ago, which has shaped the genome of today’s cattle in the Horn of Africa. We identify 16 loci linked to African environmental adaptations across crossbred animals showing an excess of taurine or indicine ancestry. These include immune-, heat-tolerance- and reproduction-related genes. Moreover, we identify one highly divergent locus in African taurine cattle, which is putatively linked to trypanotolerance and present in crossbred cattle living in trypanosomosis-infested areas. Our findings indicate that a combination of past taurine and recent indicine admixture-derived genetic resources is at the root of the present success of African pastoralism.

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Painful terminal neuromas resulting from nerve injury following amputation are common. However, there is currently no universally accepted gold standard of treatment for this condition. A comprehensive literature review is presented on the treatment of terminal neuromas. Four categories of terminal neuroma surgical procedures are assessed: epineurial closure; nerve transposition with implantation; neurorrhaphy, and alternate target reinnervation. Significant patient and case studies are highlighted in each section, focusing on surgical technique and patient outcome metrics. Studies presented consisted of a PubMed search for “terminal neuromas,” without year limitation. The current available research supports the use of implantation into muscle for the surgical treatment of terminal neuromas. However, this technique has several fundamental flaws that limit its utility, as it does not address the underlying physiology behind neuroma formation. Regenerative peripheral nerve interfaces and targeted muscle reinnervation are 2 techniques that seem to offer the most promise in preventing and treating terminal neuroma formation. Both techniques are also capable of generating control signals which can be used for both motor and sensory prosthetic control. Such technology has the potential to lead to the future restoration of lost limb function in amputees. Further clinical research employing larger patient groups with high-quality control groups and reproducible outcome measures is needed to determine the most effective and beneficial surgical treatment for terminal neuromas. Primary focus should be placed on investigating techniques that most closely approximate the theoretically ideal neuroma treatment, including targeted muscle reinnervation and regenerative peripheral nerve interfaces.

The history of African indigenous cattle and their adaptation to environmental and human selection pressure is at the root of their remarkable diversity. Characterization of this diversity is an essential step towards understanding the genomic basis of productivity and adaptation to survival under African farming systems. We analyze patterns of African cattle genetic variation by sequencing 48 genomes from five indigenous populations and comparing them to the genomes of 53 commercial taurine breeds. We find the highest genetic diversity among African zebu and sanga cattle. Our search for genomic regions under selection reveals signatures of selection for environmental adaptive traits. In particular, we identify signatures of selection including genes and/or pathways controlling anemia and feeding behavior in the trypanotolerant N’Dama, coat color and horn development in Ankole, and heat tolerance and tick resistance across African cattle especially in zebu breeds. Our findings unravel at the genome-wide level, the unique adaptive diversity of African cattle while emphasizing the opportunities for sustainable improvement of livestock productivity on the continent.

Anaphylaxis is an acute and potentially lethal multisystem allergic reaction that occurs in a variety of clinical scenarios and is almost unavoidable. Immunologic reactions to medications, foods, and insect stings cause most episodes, but virtually any substance capable of inducing systemic degranulation of mast cells and basophils can produce anaphylaxis. All health care professionals must be able to recognize anaphylaxis promptly, be prepared to treat it appropriately, and be able to provide preventive recommendations. Similarly, at-risk individuals must be prepared to self-treat anaphylaxis promptly if prevention fails.

Allergic rhinitis is a common pediatric problem with significant comorbidities and potential complications. This article is an overview of the epidemiology, pathophysiology, and current therapeutic strategies. Allergic rhinitis management in a specific child is age dependent and influenced by the severity and frequency of the symptoms and the presence of any concurrent conditions. Current strategies permit symptomatic control and improved quality of life for most patients.

This review aims to provide an evidence-based overview of several pharmacotherapeutic options available for refractory anaphylaxis when intramuscular epinephrine, the drug of choice, fails to provide resolution of signs and symptoms.

Despite the inherent capability for axonal regeneration, recovery following severe peripheral nerve injury remains unpredictable and often very poor. Surgeons typically use autologous nerve grafts taken from the patient's own body to bridge long nerve gaps. However, the amount of suitable nerve available from a given patient is limited, and using autologous grafts leaves the patient with scars, numbness, and other forms of donor-site morbidity. Therefore, surgeons and engineers have sought off-the-shelf alternatives to the current practice of autologous nerve grafting. Decellularized nerve allografts have recently become available as an alternative to traditional nerve autografting. In this review, we provide a critical analysis comparing the advantages and limitations of the three major experimental models of decellularized nerve allografts: cold preserved, freeze-thawed, and chemical detergent based. Current tissue engineering-based techniques to optimize decellularized nerve allografts are discussed. We also evaluate studies that supplement decellularized nerve grafts with exogenous factors such as Schwann cells, stem cells, and growth factors to both support and enhance axonal regeneration through the decellularized allografts. In examining the advantages and disadvantages of the studies of decellularized allografts, we suggest that experimental methods, including the animal model, graft length, follow-up time, and outcome measures of regenerative progress and success be consolidated. Finally, all clinical studies in which decellularized nerve allografts have been used to bridge nerve gaps in patients are reviewed.

This review aims to provide an overview of the evolving understanding of the pathophysiology of anaphylaxis.

This article explores the educational concept of experiential learning, particularly in terms of service learning and situated learning. It proposes an alternative definition of an academic learning community, namely the role of primary social relationships as God-given contexts for learning It concludes with practical application of the enormous potential for accomplishment of educational objectives through situated learning.

AbstractBackground/Aims:Determine (1) frequency of attention-deficit hyperactivity disorder (ADHD) treatment and (2) growth responses in growth hormone (GH)-treated children who are receiving ADHD medication versus GH alone. Methods:Prepubertal children with idiopathic short stature (ISS) or GH deficiency (IGHD) enrolled in Genentech’s National Cooperative Growth Study. ADHD treatment was determined by documentation of psycho-stimulant medication use at enrollment. Results:ADHD medication use increased from 0.8 (7/850) in 1985 to 5.8 (752/12,113) in 2005. First-year GH treatment response for ADHD + IGHD versus IGHD: 8.5 ± 2.0 vs. 9.4 ± 2.6 cm/year, but when adjusted for age, sex, and enrollment body mass index, the difference is clinically insignificant (–0.4 cm/year). First-year growth was similar in all ISS: 8.1 ± 1.9 versus 8.6 ± 2.1 cm/year (ADHD + ISS vs. ISS, an adjusted –0.2-cm/year difference). Conclusion:Increasing numbers of GH-treated children are taking ADHD medications and their growth responses during the first year of GH therapy are similar to those not taking ADHD medications.Copyright © 2009 S. Karger AG, Basel

Peripheral nerve regeneration within guidance conduits involves a critical association between regenerating axons, Schwann cells (SCs), and neovascularization. However, it is currently unknown if there is a greater association between these factors in nonpermeable versus semipermeable nerve guide conduits. We therefore examined this collaboration in both silicone- and collagen-based nerve conduits in both 5- and 10-mm-injury gaps in rat sciatic nerves. Results indicate that collagen conduits promoted enhanced axonal and SC regeneration and association when compared to silicone conduits in the shorter 5-mm-gap model. In addition, collagen tubes displayed enhanced neovascularization over silicone conduits, suggesting that these three factors are intimately related in successful peripheral nerve regeneration. At later time points (1- and 2-month analysis) in a 10-mm-gap model, collagen tubes displayed enhanced axonal regeneration, myelination, and vascularization when compared to silicone-based conduits. Results from these studies suggest that regenerating cables within collagen-based conduits are revascularized earlier and more completely, which in turn enhances peripheral nerve regeneration through these nerve guides as compared to silicone conduits.

Anaphylaxis, an acute and potentially lethal multi-system clinical syndrome resulting from the sudden, systemic degranulation of mast cells and basophils, occurs in a variety of clinical scenarios and is almost unavoidable inmedical practice. Healthcare professionalsmust be able to recognize its features, treat an episode promptly and appropriately, and be able to provide recommendations to prevent future episodes. Epinephrine, administered immediately, is the drug of choice for acute anaphylaxis. The discussion provides an overview of one set of evidence-based and consensus parameters for the diagnosis and management of anaphylaxis.

To examine differences in cytokine profiles that may confer tolerance/susceptibility to bovine African trypanosomiasis, N'Dama (trypanotolerant, n= 8) and Boran (trypanosusceptible, n= 8) cattle were experimentally challenged with Trypanosoma congolense. Blood samples were collected over a 34-day period, and RNA was extracted from peripheral blood mononuclear cells. The expression levels of a panel of 14 cytokines were profiled over the time course of infection and between breeds. Messenger RNA (mRNA) transcript levels for the IL2, IL8, and IL1RNgenes were significantly downregulated across the time course of infection in both breeds. There was an early increase in transcripts for genes encoding proinflammatory mediators (IFNG, IL1A, TNF, and IL12) in N'Dama by 14 days postinfection (dpi) compared with preinfection levels that was not detected in the susceptible Boran breed. By the time of peak parasitemia, a type 2 helper T cells (TH2)-like cytokine environment was prevalent that was particularly evident in the Boran. Increases in transcripts for the IL6(29 and 34 dpi) and IL10(21, 25, and 29 dpi) genes were detected that were higher in the Boran compared with N'Dama. These findings highlight the implications for using murine models to study the bovine immune response to trypanosomiasis, where in some cases cytokine expression patterns differ. Overall, these data suggest that the trypanotolerant N'Dama are more capable of responding very early in infection with proinflammatory and TH1 type cytokines than the trypanosusceptible Boran and may explain why N'Dama control parasitemia more efficiently than Boran during the early stages of infection.

There has been interest in using recombinant human (rh) insulin-like growth factor (IGF)-I (rhIGF-I) to treat short stature, either alone or in combination with its binding protein (insulin-like growth factor binding protein [IGFBP]-3). IGF-I has been shown to increase growth velocity in children with IGF deficiency, either as a result of growth hormone insensitivity syndrome (GHIS) or IGF gene deletion. However, there have been adverse events, particularly hypoglycaemia, reported with administration of unbound rhIGF-I. In addition, the serum half-life of unbound rhIGF-I is shorter when administered to patients with GHIS, who have low serum concentrations of its binding proteins IGFBP-3 and acid-labile subunit (ALS), than when administered to normal volunteers or to the patient with an IGF-I gene deletion (who had normal levels of IGFBP-3). iPlex™ (mecasermin rinfabate), an equimolar mixture of IGF-I and its binding protein IGFBP-3, was developed to prolong the half-life and to counteract acute adverse events (particularly hypoglycaemia) associated with administration of IGF-I. Although there are no published data on the efficacy of mecasermin rinfabate in treating growth disorders, it does appear that mecasermin rinfabate has a longer half-life in patients with GHIS than unbound IGF-I, and fewer reports of adverse events (including hypoglycaemia) when administered to patients with diabetes.

Growth hormone-insensitivity syndrome (GHIS) is usually caused by mutations in the growth hormone receptor. Recombinant IGF-I has been used to treat GHIS either alone (mecasermin) or in combination with IGF-binding protein (IGFBP)-3 (mecasermin rinfabate). IGF-I increases the growth velocity of children with IGF deficiency, which is either as a result of GHIS or an IGF-I gene deletion. Hypoglycaemia has been reported with administration of unbound IGF-I and, in addition, the serum half-life of unbound IGF-I is shorter when administered to patients with GHIS (who have low serum concentrations of its binding protein IGFBP-3) than when administered to normal volunteers or to patients with an IGF-I gene deletion (but normal IGFBP-3 levels). The IGF-I–IGFBP-3 combination was developed to prolong the half-life and counteract the acute adverse events (particularly hypoglycaemia) that are associated with administration of IGF-I. It seems that the IGF-I–IGFBP-3 combination has a longer half-life in patients with GHIS than unbound IGF-I, with fewer reports of adverse events (including hypoglycaemia) when administered to patients with diabetes. There are no studies comparing the efficacy of mecasermin with mecasermin rinfabate; both drugs have been shown to be effective but cannot be differentiated in terms of efficacy.

Malaria and trypanosomiasis are vector-borne protozoal diseases which disproportionately affect the poor. Both give rise to immense human suffering; malaria exerts its effect directly on human health, while trypanosomiasis causes damage largely though its effect on the health and productivity of the livestock on which so many poor people depend. These diseases both have multifaceted and poorly understood mechanisms of pathogenesis, combined with relatively complex life cycles characterised by multiple stages in both insect vector and mammalian host. In both cases, there is a dramatic effect of host genotype on disease progression. This effect is apparent in both the human and cattle hosts and among inbred mouse strains. This provides an opportunity to use the mouse to probe the mechanisms underlying resistance or susceptibility to pathology. The availability of high-density linkage maps, the genome sequence and transcriptomics tools has transformed the power of the mouse to illuminate such fundamental aspects of the host-parasite interaction.

The relationship between sleep-disordered breathing (SDB) and nasal obstruction is unclear. In order to better understand, we performed an extensive computer-assisted review and analysis of the medical literature on this topic. Data were grouped into reports of normal control subjects, patients with isolated nasal obstruction, and those with SDB. We conclude that SDB can both result from and be worsened by nasal obstruction. Nasal breathing increases ventilatory drive and nasal occlusion decreases pharyngeal patency in normal subjects. Nasal congestion from any cause predisposes to SDB. Although increased nasal resistance does not always correlate with symptoms of congestion, nasal congestion typically results in a switch to oronasal breathing that compromises the airway. Moreover, oral breathing in children may lead to the development of facial structural abnormalities associated with SDB. We postulate that the switch to oronasal breathing that occurs with chronic nasal conditions is a final common pathway for SDB.

Anaphylaxis is a life-threatening syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation. Foods and medications cause most anaphylaxis for which a cause can be identified, but virtually any agent capable of directly or indirectly activating mast cells or basophils can cause this syndrome. This review discusses the pathophysiologic mechanisms of anaphylaxis, its causes, and its treatment. (J Allergy Clin Immunol 2002;110:341-8.)

1. No allergenic vaccine should be considered completely safe for an individual allergic to its contents.

Residents in the southeastern United States would hardly describe life with the aggressive imported fire ant as peaceful coexistence. The continued spread of these insects has produced agricultural problems, changes in the ecosystem, and increasing numbers of subjects with sting sequelae, including hypersensitivity reactions, secondary infections, and rare neurologic sequelae. Evolutionary changes have facilitated their expansion northward into Virginia and westward into California, and increasing urbanization will likely permit further expansion. Recent reports of building invasion with sting attacks inside occupied dwellings, including health care facilities, heighten public health concerns. This article reviews the medically important entomology, clinical aspects of stings, and the current approaches to chemical control of fire ants. We also propose directions for future research and treatment.(J Allergy Clin Immunol 2000;105:683-91.)

The relative effects of growth hormone (GH) on GH-deficient (GHD) children with and without severely delayed skeletal maturation prior to treatment are unclear. Methods: Pre-pubertal GHD children enrolled in the National Cooperative Growth Study were divided into two groups: severe pretreatment BA delay (BA Z-score ≤–2, group 1) and mild to moderate delay (BA Z-score between –2 and 0, group 2). BA Z-scores (BAZ), height Z-scores and predicted adult height (PAH) Z-scores at pubertal onset were determined after initiation of recombinant human GH (rhGH) therapy. Results: Height Z-scores increased from baseline to the start of puberty in both groups (group 1: mean difference of +0.99, males and +1.02, females; group 2: +0.68, males and +0.75, females). Mean BAZ also increased in all group 1 children (+1.62, males and +1.08, females) with no corresponding change in mean BAZ in group 2. PAH Z-scores increased in both groups. There was no evidence of undue advance in BA since mean BAZ remained well below zero in group 1 and was unchanged in group 2. Conclusion: rhGH has a beneficial effect on growth in prepubertal GHD children at all levels of pretreatment BA delay.

For stimulation of growth velocity in children with growth hormone (GH) deficiency the ideal GH dose should result in catch-up growth, provide realization of adult height potential, allow puberty to occur at a normal time, and avoid adverse events. During the years 1958–1985, the standard replacement dose for GH deficiency was limited by GH supply. After the introduction of recombinant GH, the mean dose increased from 0.1 to 0.3 mg/kg/week, which appears to be about three times the normal GH production rate. First year growth velocity response to GH replacement in GH deficiency is positively correlated to the logarithm of the GH dose. Slightly higher doses are commonly used in the treatment of other causes of growth failure such as Turner's syndrome and chronic renal insufficiency (currently 0.375 and 0.35 mg/kg, respectively), although there have been no studies to establish that these doses are ideal.

1,9‐Dideoxyforskolin inhibits proteoglycan synthesis and xyloside‐initiated glycosaminoglycan (GAG) synthesis in chick embryo chondrocytes. Dideoxyforskolin does not affect the length of xyloside‐initiated GAG chains secreted into the medium but chains from the dense proteoglycan secreted into the medium appear slightly longer. Incorporation of labeled serine into the dense proteoglycan and subsequent digestion with Pronase revealed a dramatic decrease in percent of total radioactivity associated with GAG chains in the proteoglyean from cultures treated with forskolin or dideoxyforskolin. These observations suggest that these diterpenes have a specific inhibitory effect on chain initiation reactions and thus may be useful tools in the study of proteoglycan synthesis and processing.

1,9-Dideoxyforskolin inhibits proteoglycan synthesis and xyloside-initiated glycosaminoglycan (GAG) synthesis in chick embryo chondrocytes. Dideoxyforskolin does not affect the length of xyloside-initiated GAG chains secreted into the medium but chains from the dense proteoglycan secreted into the medium appear slightly longer. Incorporation of labeled serine into the dense proteoglycan and subsequent digestion with Pronase revealed a dramatic decrease in percent of total radioactivity associated with GAG chains in the proteoglyean from cultures treated with forskolin or dideoxyforskolin. These observations suggest that these diterpenes have a specific inhibitory effect on chain initiation reactions and thus may be useful tools in the study of proteoglycan synthesis and processing.

Synthesis of a calcium-binding amino acid, gamma-carboxyglutamic acid, is a vitamin K–dependent enzymatic process. Warfarin inhibits gamma-carboxyglutamic acid synthesis and, therefore, might diminish the calcification of porcine bioprosthetic valves. To evaluate this, we studied 40 porcine bioprosthetic valves removed because of spontaneous degeneration; 17 patients were treated with warfarin (prothrombin time ≥1.5 control) and 23 were untreated. Gross visualization of calcification corresponded closely to x-ray visualization of calcification in explanted valves. No grossly visible calcification or only a single localized nodule was shown in 11 of 17 valves (65%) in treated patients and in only five of 23 valves (22%) in untreated patients (p < 0.02). Histologic examination showed no calcium or only fine specks of calcium in nine of 13 valves (69%) among warfarin-treated patients and three of 19 valves (16%) from untreated patients. Warfarin, therefore, administered in usual clinical doses, appeared to diminish calcification in spontaneously degenerated porcine bioprosthetic valves.

Abstract. We determined albumin, total protein, somatomedin C, retinol binding protein (RBP), transferrin, prealbumin, and complement (C3) concentrations in serum, and vitamin A concentrations in plasma before initiation of growth hormone (GH) therapy and 13 h after each of 4 daily injections of GH (0.1 U/kg) in 6 GH deficient children. Levels of total protein, albumin, and transferrin did not change during the first week of GH administration, however, transferrin levels rose after 6 weeks of GH therapy. Initial somatomedin C levels were below the normal range (0.19 ± 0.03 U/ml), and rose with GH administration in 4 of the 6 subjects, resulting in a post-treatment mean of 0.56 ± 0.23 U/ml. With GH administration vitamin A and RBP concentrations decreased from initial values (P< 0.05), and reached a plateau after 2 injections of GH, while there was no change in concentrations of other proteins. There was a significant linear correlation (P< 0.05) between the levels of vitamin A and RBP before and after GH administration. We conclude that GH administration results in a selective and marked reduction in the concentrations of plasma vitamin A and serum RBP.