Dengue infection - mechanisms, epidemiology, pathogenesis, diagnosis and management !

DENGUE:

"Dengue is the leading mosquito-borne viral illness infecting humans !"

Dengue is caused by infection with any of the four dengue virus serotypes. This review highlights the mechanisms underlying the clinical course of a dengue infection, which can range from mild febrile illness through to hemorrhagic fever and circulatory shock. It also outlines the epidemiology, pathogenesis, diagnosis and management of dengue infection.

Key phases of dengue infection

Dengue is a mosquito-borne disease caused by infection with dengue virus (DENV). Clinically, the disease can range from a mild febrile illness (previously called dengue fever) through to dengue with warning signs and severe dengue, which includes what were previously called dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).

 

DENVs belong to the genus Flavivirus of the Flaviviridae family. The four serotypes are enveloped, spherical viral particles with a diameter of approximately 500 Å20. The genome of each serotype comprises approximately 11 kb of positive-sense, single-stranded RNA that encodes ten proteins. The three structural proteins encoded by the genome are the membrane (M) protein, envelope (E) protein and capsid (C) protein; the non-structural (NS) proteins are NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5.

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Mechanism how SARS-CoV-2 causes COVID-19 progression !

COVID-19:

"The viral receptor on human cells plays a critical role in disease progression !"

Viruses enter cells and initiate infection by binding to their cognate cell surface receptors. The expression and distribution of viral entry receptors therefore regulates their tropism, determining the tissues that are infected and thus disease pathogenesis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus known to co-opt the peptidase angiotensin-converting enzyme 2 (ACE2) for cell entry. The interaction between SARS-CoV-2 and ACE2 is critical to determining both tissue tropism and progression from early SARS-CoV-2 infection to severe coronavirus disease 2019 (COVID-19). Understanding the cellular basis of SARS-CoV-2 infection could reveal treatments that prevent the development of severe disease, and thus reduce mortality.

Key phases of disease progression

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2). Initial infection of cells in the upper respiratory tract may be asymptomatic, but these patients can still transmit the virus. For those who develop symptoms, up to 90% will have pneumonitis, caused by infection of cells in the lower respiratory tract. Some of these patients will progress to severe disease, with disruption of the epithelial-endothelial barrier, and multi-organ involvement.

 

As with all coronaviruses, SARS-CoV-2 cell entry is dependent on its 180-kDa spike (S) protein, which mediates two essential events: binding to ACE2 by the amino-terminal region, and fusion of viral and cellular membranes through the carboxyl-terminal region. Infection of lung cells requires host proteolytic activation of spike at a polybasic furin cleavage site. To date, this cleavage site is found in all spike proteins from clinical SARS-CoV-2 isolates, as well as some other highly pathogenic viruses (e.g., avian influenza A), but it is absent from SARS-CoV and is likely to have been acquired by recombination between coronaviruses in bats. Cleavage by the furin protease therefore expands SARS-CoV-2 cell tropism and may have facilitated transmission from bats to humans. Membrane fusion also requires cleavage by additional proteases, particularly transmembrane protease serine 2 (TMPRSS2), a host cell surface protease that cleaves spike shortly after binding ACE2. SARS-CoV-2 tropism is therefore dependent on expression of cellular proteases, as well as ACE2.

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What are proteins and how much do you need?

Proteins:

Proteins are large molecules that our cells need to function properly. They consist of amino acids. The structure and function of our bodies depend on proteins. The regulation of the body's cells, tissues, and organs cannot happen without them.

Muscles, skin, bones, and other parts of the human body contain significant amounts of protein, including enzymes, hormones, and antibodies.

Proteins also work as neurotransmitters. Hemoglobin, a carrier of oxygen in the blood, is a protein.

What are proteins?

Proteins are long chains of amino acids that form the basis of all life. They are like machines that make all living things, whether viruses, bacteria, butterflies, jellyfish, plants, or human function.

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Hormonal Dysfunction in Male Infertility -Diagnosis and Treatment !

Male Infertility:

Treatment of infertility-related hormonal dysfunction in men requires an understanding of the hormonal basis of spermatogenesis. The best method for accurately determining male androgenization status remains elusive. Treatment of hormonal dysfunction can fall into two categories — empirical and targeted. Empirical therapy refers to experience-based treatment approaches in the absence of an identifiable etiology. Targeted therapy refers to the correction of a specific underlying hormonal abnormality.

Since the first case reports in 1910 of testicular atrophy after canine hypophysectomy, the hormonal basis of human reproduction has been an area of evolving investigation. An array of treatment modalities are available for hormonal dysfunction in the setting of male infertility, but the diagnosis of such dysfunction and its treatment is often empirical, or guided by the clinician's judgement, and can be open to interpretation. Our ability to understand the intra testicular hormonal environment and its effect on spermatogenesis is limited by current methods of routine clinical investigation.

Investigations into female infertility benefit from reliance on objective, verifiable outcomes such as ovulation, biochemical pregnancy, and clinical pregnancy. Meanwhile, the male counterpart has been hampered by the necessary dependence on bulk seminal parameters, which are notoriously poor predictors of fertility potential. Perhaps the only truly reliable semen analysis is one indicating azoospermia and that is where the most exciting clinical outcomes research has focused.

This review article describes and discusses the pathophysiology, diagnosis, and treatment of fertility-associated male hormonal dysfunction.

• Oestradiol is the principal mediator of negative feedback on the hypothalamic–pituitary axis, which illustrates the influence of selective oestrogen receptor modulators and aromatase inhibitors on male hormonal parameters

• Serum hormonal assays are unreliable indicators of intratesticular androgen levels, and the best approach for determining male androgen status remains elusive

• Follicle-stimulating hormone and inhibin B are markers of spermatogenesis and their relative values in the setting of an intact hypothalamic–pituitary–gonadal axis provide important information about testicular function

• Targeted hormonal therapy corrects specific hormonal dysfunctions, empirical hormonal therapy is employed when no underlying cause is identified and the evidence for empirical therapy is dependent on the type of medication used

• A return of sperm to the ejaculate or successful surgical sperm retrieval among men with azoospermia owing to spermatogenic dysfunction are the most objective indicators of outcomes of hormonal therapy

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Molecular Basis of Tolerance and Immunity to Antigens.

Molecular Immunology

The intestinal immune system has to discriminate between harmful and beneficial antigens. Although strong protective immunity is essential to prevent invasion by pathogens, equivalent responses against dietary proteins or commensal bacteria can lead to chronic disease. These responses are normally prevented by a complex interplay of regulatory mechanisms. This article reviews the unique aspects of the local microenvironment of the intestinal immune system and discuss how these promote the development of regulatory responses that ensure the maintenance of homeostasis in the gut.

The intestinal immune system is the largest and most complex part of the immune system. Not only does it encounter more antigen than any other part of the body, but it must also discriminate clearly between invasive organisms and harmless antigens, such as food proteins and commensal bacteria. Most human pathogens enter the body through a mucosal surface, such as the intestine, and strong immune responses are required to protect this physiologically essential tissue. In addition, it is important to prevent further dissemination of such infections. By contrast, active immunity against non-pathogenic materials would be wasteful, and hypersensitivity responses against dietary antigens or commensal bacteria can lead to inflammatory disorders such as Coeliac Disease and Crohn's Disease, respectively. As a result, the usual response to harmless gut antigens is the induction of local and systemic immunological tolerance, known as oral tolerance. In addition to its physiological importance, this phenomenon can be exploited for the immunotherapy of autoimmune and inflammatory diseases, but it is also an obstacle to the development of recombinant oral vaccines. For these reasons, there is great interest in the processes that determine the immunological consequences of oral administration of antigen. To some extent, this discrimination between harmful and harmless antigens also occurs in other parts of the immune system, as it partly results from inherent properties of the antigen and associated adjuvants. Nevertheless, it has been proposed that there are also specific features of mucosal tissues that favour the induction of tolerance, the production of immunoglobulin A antibodies and, to a lesser extent, T helper 2 (TH2)-cell responses. Several features of mucosal tissues might contribute to these effects, including a unique ontogeny and anatomical patterning, specialized cells and organs that are involved in the uptake of antigen, distinctive subsets of antigen-presenting cells (APCs) and several unusual populations of B and T cells. In addition, the migration of lymphocytes to the intestine is controlled by a series of unique adhesion molecules and chemokine receptors.

This review article discusses the anatomical factors which determine the special nature of small intestinal immune responses, and the unique processes and cells involved in the uptake and presentation of antigen to T cells in the gut. In particular, it focuses on the local factors that determine the behaviour of APCs and T cells in the gut and discuss recent evidence that challenges the conventional dogma that Peyer’s patches are the only site for the initiation of mucosal immunity and tolerance.

It also focuses on the small intestine, as this tissue has been studied in most detail and it contains the largest proportion of immune cells in the gut. However, the reader should be aware that each compartment of the intestine, from the oropharynx to the stomach and to the rectum, has its own specializations, which might have individual effects on immune regulation in response to local antigens.

• The intestinal immune system is an anatomically and functionally distinct compartment, in which a careful distinction must be made between harmful antigens, such as invasive pathogens, and harmless antigens, such as dietary proteins or commensal bacteria.

• The default response to harmless antigens is the induction of tolerance. A breakdown in this physiological process can lead to disease.

• Immune responses and tolerance in the gut are initiated in organized lymphoid organs, such as the Peyer's patches and mesenteric lymph nodes (MLNs). The mucosa contains effector or regulatory cells that migrate there selectively, from the MLNs, in the lymph and bloodstream under the control of α4β7 integrins and the chemokine receptor CCR9.

• Pathogens might enter the intestinal immune system through M cells in the follicle-associated epithelium of the Peyer's patches, whereas soluble antigens might gain access predominantly through the normal epithelium that covers the villus mucosa.

• Peyer's patches, lamina propria and MLNs contain unusual populations of dendritic cells (DCs), some of which are characterized by the production of interleukin-10 (IL-10) and which polarize T cells to an IL-4-, IL-10- and transforming growth factor-β (TGF-β)-producing 'regulatory' phenotype.

• Genetically determined factors, together with luminal bacteria, might act on epithelial and stromal components of the intestinal mucosa to produce a local microenvironment that is dominated by the constitutive production of prostaglandin E2 (PGE2), TGF-β and IL-10. Under physiological conditions, this favours the differentiation of regulatory DCs and T cells, which leads to systemic tolerance and/or immunoglobulin-A production.

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Causes of High PSA that are not Cancer !

The prostate-specific antigen test is a blood test that measures levels of a protein the prostate gland produces. Men with prostate cancer usually have elevated levels of this protein, but heightened levels do not always mean cancer.

Other health conditions may also cause prostate-specific antigen (PSA) levels to rise. In some cases, an elevated PSA is temporary and not a sign of a health problem at all.

Cells in the prostate gland produce PSA and levels typically remain below 4 nanograms per milliliter (ng/mL).

Most men with prostate cancer have PSA levels above 4 ng/mL, but about 15 percent of men with a PSA level below 4 ng/mL are also diagnosed with prostate cancer. This means that a PSA test alone cannot rule out or diagnose prostate cancer but can identify whether a man is at higher risk of having or developing the disease.

Initial testing may include both a PSA test and a digital rectal exam (DRE). During this examination, a doctor inserts a finger into the rectum to check the prostate for abnormalities. Together, if these two tests suggest prostate cancer, then the doctor will arrange for a biopsy to confirm the diagnosis.

False positives - a high PSA level, but no cancer - on the PSA test are common. PSA levels rise with age and other factors. Men with high PSA levels should follow up with a doctor, but should not assume they have cancer.

A high PSA level may not always indicate prostate cancer.

Read more: Causes of High PSA that are not Cancer !

Source: MedicalNewsToday

Video: Prostate Cancer - Essential Facts

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Heterogeneity in Tuberculosis.

Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as a clinically asymptomatic, contained state that is termed latent TB infection (LTBI); a smaller subset of infected individuals present with symptomatic, active TB. Within these two seemingly binary states, there is a spectrum of host outcomes that have varying symptoms, microbiologies, immune responses and pathologies. Recently, it has become apparent that there is diversity of infection even within a single individual. A good understanding of the heterogeneity that is intrinsic to TB — at both the population level and the individual level — is crucial to inform the development of intervention strategies that account for and target the unique, complex and independent nature of the local host–pathogen interactions that occur in this infection. In this Review, we draw on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease.

Read more: Heterogeneity in Tuberculosis.

Figure 1: A classical tuberculosis granuloma. The hallmark tuberculosis
granuloma is a highly organized collection of immune cells that aggregate
around a central necrotic core.

Source: NATURE REVIEWS IMMUNOLOGY

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