It is well known that microbes, zooplankton, and fish are important sources of recycled nitrogen in coastal waters, yet marine mammals have largely been ignored or dismissed in this cycle. Using ...field measurements and population data, we find that marine mammals can enhance primary productivity in their feeding areas by concentrating nitrogen near the surface through the release of flocculent fecal plumes. Whales and seals may be responsible for replenishing 2.3×10(4) metric tons of N per year in the Gulf of Maine's euphotic zone, more than the input of all rivers combined. This upward "whale pump" played a much larger role before commercial harvest, when marine mammal recycling of nitrogen was likely more than three times atmospheric N input. Even with reduced populations, marine mammals provide an important ecosystem service by sustaining productivity in regions where they occur in high densities.
Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired ...human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C′) inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C′ inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.
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•Antibodies function with complement to inhibit P. falciparum replication•Antibodies fix C1q to block invasion and lyse merozoites•Complement-fixing antibodies are strongly associated with immunity in children•Antibody-complement inhibition can be induced by human vaccination
Antibodies are important in immunity to malaria, but their protective function has been unclear. Boyle and colleagues report that acquired and vaccine-induced human antibodies recruit complement to block infection of erythrocytes and blood-stage replication of Plasmodium falciparum.
Controlled human malaria infection (CHMI) entails deliberate infection with malaria parasites either by mosquito bite or by direct injection of sporozoites or parasitized erythrocytes. When required, ...the resulting blood-stage infection is curtailed by the administration of antimalarial drugs. Inducing a malaria infection via inoculation with infected blood was first used as a treatment (malariotherapy) for neurosyphilis in Europe and the United States in the early 1900s. More recently, CHMI has been applied to the fields of malaria vaccine and drug development, where it is used to evaluate products in well-controlled early-phase proof-of-concept clinical studies, thus facilitating progression of only the most promising candidates for further evaluation in areas where malaria is endemic. Controlled infections have also been used to immunize against malaria infection. Historically, CHMI studies have been restricted by the need for access to insectaries housing infected mosquitoes or suitable malaria-infected individuals. Evaluation of vaccine and drug candidates has been constrained in these studies by the availability of a limited number of
isolates. Recent advances have included cryopreservation of sporozoites, the manufacture of well-characterized and genetically distinct cultured malaria cell banks for blood-stage infection, and the availability of
-specific reagents. These advances will help to accelerate malaria vaccine and drug development by making the reagents for CHMI more widely accessible and also enabling a more rigorous evaluation with multiple parasite strains and species. Here we discuss the different applications of CHMI, recent advances in the use of CHMI, and ongoing challenges for consideration.
The soil transmitted helminths are a group of parasitic worms responsible for extensive morbidity in many of the world's most economically depressed locations. With growing emphasis on disease ...mapping and eradication, the availability of accurate and cost-effective diagnostic measures is of paramount importance to global control and elimination efforts. While real-time PCR-based molecular detection assays have shown great promise, to date, these assays have utilized sub-optimal targets. By performing next-generation sequencing-based repeat analyses, we have identified high copy-number, non-coding DNA sequences from a series of soil transmitted pathogens. We have used these repetitive DNA elements as targets in the development of novel, multi-parallel, PCR-based diagnostic assays.
Utilizing next-generation sequencing and the Galaxy-based RepeatExplorer web server, we performed repeat DNA analysis on five species of soil transmitted helminths (Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Ascaris lumbricoides, and Strongyloides stercoralis). Employing high copy-number, non-coding repeat DNA sequences as targets, novel real-time PCR assays were designed, and assays were tested against established molecular detection methods. Each assay provided consistent detection of genomic DNA at quantities of 2 fg or less, demonstrated species-specificity, and showed an improved limit of detection over the existing, proven PCR-based assay.
The utilization of next-generation sequencing-based repeat DNA analysis methodologies for the identification of molecular diagnostic targets has the ability to improve assay species-specificity and limits of detection. By exploiting such high copy-number repeat sequences, the assays described here will facilitate soil transmitted helminth diagnostic efforts. We recommend similar analyses when designing PCR-based diagnostic tests for the detection of other eukaryotic pathogens.
The association between hygiene and prevalence of autoimmune disease has been attributed in part to enteric helminth infection. A pilot study of experimental infection with the hookworm Necator ...americanus was undertaken among a group of otherwise healthy people with celiac disease to test the potential of the helminth to suppress the immunopathology induced by gluten.
In a 21-week, double-blinded, placebo-controlled study, we explored the effects of N. americanus infection in 20 healthy, helminth-naïve adults with celiac disease well controlled by diet. Staged cutaneous inoculations with 10 and 5 infective 3(rd) stage hookworm larvae or placebo were performed at week-0 and -12 respectively. At week-20, a five day oral wheat challenge equivalent to 16 grams of gluten per day was undertaken. Primary outcomes included duodenal Marsh score and quantification of the immunodominant α-gliadin peptide (QE65)-specific systemic interferon-γ-producing cells by ELISpot pre- and post-wheat challenge.
Enteric colonisation with hookworm established in all 10 cases, resulting in transiently painful enteritis in 5. Chronic infection was asymptomatic, with no effect on hemoglobin levels. Although some duodenal eosinophilia was apparent, hookworm-infected mucosa retained a healthy appearance. In both groups, wheat challenge caused deterioration in both primary and several secondary outcomes.
Experimental N. americanus infection proved to be safe and enabled testing its effect on a range of measures of the human autoimmune response. Infection imposed no obvious benefit on pathology.
ClinicalTrials.gov NCT00671138.
On the Physiology of the Sensory-Collapse Test McCarthy, James E.; Attaluri, Pradeep; Nicksic, Peter
The Journal of hand surgery (American ed.),
06/2024, Letnik:
49, Številka:
6
Journal Article
Recenzirano
The sensory-collapse test (formerly the scratch-collapse test) is a physical examination finding describing a momentary inhibition of external shoulder rotation following light stimulation of an ...injured nerve in the ipsilateral limb. Similar to other physical examination tests designed to interrogate nerve compression, such as the Phalen or Tinel tests, its test characteristics demonstrate variation. There remains speculation about the test’s existence and anatomic basis. The literature of mammalian reflex physiology was reviewed with an emphasis on the sensory pathways from the upper extremity, the extrapyramidal system, and newly discovered pathways and concepts of nociception. A clear reflex pathway is described connecting the stimulus within an injured nerve through the afferent pathways in the fasciculus cuneatus in the spinal cord directly to the lateral reticulospinal tract, resulting in the inhibition of extensor muscles in the proximal limb (eg, shoulder) and activation of the limb flexors by acting upon alpha and gamma motor neurons. The sensory-collapse test represents a reflex pathway that teleologically provides a mechanism to protect an injured nerve by withdrawal toward the trunk and away from the noxious environment.
As malaria transmission continues to decrease, an increasing number of countries will enter pre-elimination and elimination. To interrupt transmission, changes in control strategies are likely to ...require more accurate identification of all carriers of Plasmodium parasites, both symptomatic and asymptomatic, using diagnostic tools that are highly sensitive, high throughput and with fast turnaround times preferably performed in local health service settings. Currently available immunochromatographic lateral flow rapid diagnostic tests and field microscopy are unlikely to consistently detect infections at parasite densities less than 100 parasites/µL making them insufficiently sensitive for detecting all carriers. Molecular diagnostic platforms, such as PCR and LAMP, are currently available in reference laboratories, but at a cost both financially and in turnaround time. This review describes the recent progress in developing molecular diagnostic tools in terms of their capacity for high throughput and potential for performance in non-reference laboratories for malaria elimination.
In 1896, a serendipitous laboratory accident led to the understanding that hookworms propagate infection by penetrating skin, a theory that was then confirmed with the first experimental human ...infection, reported in 1901. Experimental human infections undertaken in the 20th century enabled understanding of the natural history of infection and the immune response. More recently, experimental hookworm infection has been performed to investigate the immunomodulatory potential of hookworm infection and for the evaluation of hookworm vaccines and chemotherapeutic interventions. Experimental human hookworm infection has been proven to be safe, with no deaths observed in over 500 participants (although early reports predate systematic adverse event reporting) and no serious adverse events described in over 200 participants enrolled in contemporary clinical trials. While experimental human hookworm infection holds significant promise, as both a challenge model for testing anti-hookworm therapies and for treating various diseases of modernity, there are many challenges that present. These challenges include preparation and storage of larvae, which has not significantly changed since Harada and Mori first described their coproculture method in 1955. In vitro methods of hookworm larval culture, storage, and the development of meaningful potency or release assays are required. Surrogate markers of intestinal infection intensity are required because faecal egg counts or hookworm faecal DNA intensity lack the fidelity required for exploration of hookworm infection as a vaccine/drug testing platform or as a regulated therapy.
A disproportionate burden of helminthiases in human populations occurs in marginalised, low-income, and resource-constrained regions of the world, with over 1 billion people in developing areas of ...sub-Saharan Africa, Asia, and the Americas infected with one or more helminth species. The morbidity caused by such infections imposes a substantial burden of disease, contributing to a vicious circle of infection, poverty, decreased productivity, and inadequate socioeconomic development. Furthermore, helminth infection accentuates the morbidity of malaria and HIV/AIDS, and impairs vaccine efficacy. Polyparasitism is the norm in these populations, and infections tend to be persistent. Hence, there is a great need to reduce morbidity caused by helminth infections. However, major deficiencies exist in diagnostics and interventions, including vector control, drugs, and vaccines. Overcoming these deficiencies is hampered by major gaps in knowledge of helminth biology and transmission dynamics, platforms from which to help develop such tools. The Disease Reference Group on Helminths Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. In this review, we provide an overview of the forces driving the persistence of helminthiases as a public health problem despite the many control initiatives that have been put in place; identify the main obstacles that impede progress towards their control and elimination; and discuss recent advances, opportunities, and challenges for the understanding of the biology, epidemiology, and control of these infections. The helminth infections that will be discussed include: onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, food-borne trematodiases, and taeniasis/cysticercosis.
A second is that small sections of the population usually remain out of reach of chemotherapy programmes, subgroups that frequently have a disproportionately heavy burden of infection, thereby ...serving as a reservoir for reinfection. ...longer-term effectiveness of chemotherapy in interrupting transmission is dependent on maintenance of regular retreatment. Other issues that are not yet resolved with regards to chemotherapy include potential teratogenic effects of benzimidazole drugs and associations with eczema in children following maternal chemotherapy during pregnancy 24. ...whilst chemotherapy is necessary to rapidly reduce the burden and morbidity of helminth infections, we argue that by itself it is an unsustainable strategy for helminth control and for reaching control and elimination targets.
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