Showing papers in "Discovery Medicine in 2005"

Macro trends in pharmaceutical innovation.

Abstract: Extract: A lately recycled criticism of the pharmaceutical industry is that it is failing in its mission to innovate. In particular, critics question the industry's incentives to innovate, and they deride those innovations the industry makes as imitative. Industry advocates contend the opposite. The truth is that there are no generally accepted measures of innovation that would conclusively prove either side's point. However, I have found trends in several measures that support both sides of the innovation debate. Overall, the bulk of evidence suggests that the pharmaceutical industry continues to regard pioneering innovations as important (evidenced by the motivation, effort and ability of the industry to create such innovations). However, like other mature manufacturing industries, the pharmaceutical industry relies heavily on incremental innovations (what critics call "me-too" drugs) to sustain its profits. To a large extent, these incremental innovations are themselves medically beneficial and should be encouraged rather than dismissed as merely imitative.

Memory dysfunction in clinical practice.

Abstract: Extract: Complaints of impaired memory are amongst the most common symptoms voiced by patients to physicians in the fields of neurology, psychiatry, medicine, and surgery Impairment of memory is one of the most disabling aspects of many neurological disorders, including neurodegenerative diseases, strokes, tumors, head trauma, hypoxia (reduced exposure of tissue to oxygen), cardiac surgery, malnutrition, attention deficit disorder, depression, anxiety, medication side-effects, and normal aging This memory loss often impairs the patient's normal daily activities, profoundly affecting both the patients and their families Research in memory began with neuropsychological studies of patients with focal brain lesions and now includes new methods such as PET (positron emission tomography, where the decay of an injected radioactive element or drug creates an image) and functional MRI (magnetic resonance imaging, where hydrogen atoms are polarized by a magnet and the summation of their spinning energy creates an image) Event-related methodologies have provided us with more refined and improved classification systems Rather than conceptualizing memory as "short-term" and "long-term," we now think of memory as a collection of mental abilities that use different systems within the brain In the present article we will summarize the four memory systems that are of clinical relevance: episodic memory, semantic memory, procedural memory, and working memory

How stress damages immune system and health.

Abstract: Extract: There is an extensive body of scientific literature related to the field of research called psychoneuroimmunology. Clinical studies, backed up by mechanism studies, have provided convincing evidence that the central nervous system (CNS) interacts with the endocrine and immune systems and that these interactions are bi-directional. Stress has been a focal point in this body of literature because it is known that stress can induce immune dysregulation across many aspects of the humoral and cellular immune responses. These studies have dated back to the 1960s and 1970s, and have included some very elegant studies involving animal models. The important outcome of this research is that stress-induced immune dysregulation can produce changes that are not only statistically significant but, most importantly, biologically significant in terms of health risk. It is now well established that there are very complex bi-directional interactions between the CNS and the immune system mediated by the endocrine system. Two important aspects of these interactions include the production of stress hormones by the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) axis. The interactions between immune cells also take place through the production of cytokines. Hormones can modulate immune function by binding to their receptors, which are expressed on virtually every type of immune cell. The modulation of cytokines has been shown to feedback to the brain, producing changes in the HPA axis, as well as inducing sickness behavior such as fever, loss of appetite, changes in sleep patterns and depression.

Therapeutic wisdom in traditional Chinese medicine: A perspective from modern science.

Abstract: Extract: Misunderstanding usually stems from ignorance. This is the case for comments directed at each other by western medicine and traditional Chinese medicine (TCM). Modern biomedical scientists insist that herbal remedies need quality control, rigorous clinical trials, and illumination of active ingredients and their action mechanisms. In fact, almost all ever-increasing number of research projects on herbal medicine are being conducted based on this belief. Researchers often disrespect those so-called unique, seemingly inaccessible and ridiculous theories in traditional medicine. While, in the eyes of TCM doctors, most published articles about TCM in Western medicine journals haven't felt TCM's "pulse" yet. They thought that such studies are also ridiculous to focus only on herbal drugs instead of the thinking which guides drug's usage. This is like studying Vincent van Gogh's paintbrush instead of his thoughts about art expression. TCM experts are disgruntled with the demand and rebuke from western medicine. They believe the real efficacy and toxicity of herbal agents will not be adequately demonstrated using the present evaluation paradigm for single chemical compounds, since TCM does not focus solely on the disease defined by specific pathological changes (e.g., the level of blood pressure or sugar, the identifying of tumor cells or microorganisms, etc.) but instead concentrates on the overall functional state of the patient. However, because of TCM's classic naming systems, they can not convey their notions effectively to the field of the mainstream medicine.

Rediscovering natural products as a source of new drugs.

Abstract: Extract: Since the very beginnings of human medicine, physicians have relied on chemical compounds produced by animals, plants and microorganisms, so-called natural products, to treat diseases. Natural products are directly or indirectly responsible for roughly one-half of all drugs currently in use. Of the 877 small-molecule new drug molecules introduced between 1981 and 2002, 49% were natural products or natural product analogs. Despite the great success of the 70s and 80s, the pharmaceutical industry de-emphasized natural products research during the following decade. In this article, we examine the underlying reasons for the decline, and assess future prospects for natural products research in drug discovery. In the 1990s, major pharmaceutical companies moved to a lead-finding strategy based on High Throughput Screening (HTS) of very large collections (libraries) of synthetic compounds. The move arose from the belief that techniques such as combinatorial chemistry could produce larger, more cost-effective libraries with improved hit rates and quality. Additionally, advances in molecular biology, cellular biology and genomics dramatically increased the number of molecular targets, prompting shorter drug discovery timelines. In today's drug discovery environment, rapid screening and identification of potential drug molecules is essential for success. This puts traditional natural products-based programs, with their reliance on the lengthy processes of the screening of extracts library, bioassay-guided isolation of the active components, structure elucidation and subsequent production scale-up, at a competitive disadvantage.

Quantum Dots for Molecular Imaging and Cancer Medicine

Abstract: Extract: The past few decades have witnessed technical advances that have introduced cell biologists and physicians to a new, dynamic, subcellular world where genes and gene products can be visualized to interact in space and time and in health and disease. The accelerating field of molecular imaging has been critically dependent on indicator probes which show when and where genetically or biochemically defined molecules, signals or processes appear, interact and disappear, with high spatial and temporal resolution in living cells and whole organisms. For example, the use of radionuclide tracers combined with 3-dimensional (3-D) imaging systems such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) are now helping clinicians to characterize the molecular status of tumors deep within patients. Other types of imaging probes rely on the bioluminescence and fluorescence of genetically encoded proteins (originally found in fireflies and jellyfish, respectively) or entirely synthetic fluorochromes, or a combination of both. New powerful biological fluorescence microscopes provide the ability to study single molecules within single cells. Multiphoton confocal microscopy has been developed to allow for the capturing of high-resolution, 3-D images of living tissues that have been tagged with highly specific fluorophores.

Cancer stem cells: Implications for cancer causation and therapy resistance.

Abstract: Extract: The discovery that many cancers arise from alterations of the body's normal stem cells is changing our views of cancer causation as well as therapy. Stem cells have a unique capacity for self-renewal; with each division they give rise to cells with the same differentiation potential as the parental cell. The replication of stem cells is under tight control. Rapidly dividing tissues such as the hematopoietic (blood) system, the skin, and the gut require perpetually dividing cells, whereas in most tissues, the stem cells are quiescent (inactive) unless stimulated by damage or inflammation. Stem cells are long lived, and therefore have the potential to acquire successive mutations and pass these defects on to daughter cell populations. Normal stem cells possess innate properties that ensure their survival over the lifespan of the individual. This includes the expression of several transport proteins that protect cells against toxins, a low rate of cell division, and active DNA repair. To the extent that cancer stem cells retain these same properties, they will be relatively resistant to radiation and chemotherapy, and may survive to regenerate the tumor. A cancer patient's intestinal lining, white blood cell count, and hair growth recover after cytotoxic therapy because these tissues are renewed from stem cells. In a similar fashion, the patient's tumor may shrink or appear to be eliminated during therapy, but subsequently regress, due to the survival of cancer stem cells.

Combining immunotherapy with chemotherapy to treat cancer.

Abstract: Extract: Cytotoxic chemotherapy remains one of the most widely available treatment options for cancer. Unfortunately, the efficacy of chemotherapy is limited and, for solid tumors in particular, cures are rarely achieved. Immunotherapy is a more experimental treatment method, aimed at mobilizing the body's immune cells to attack tumor cells, but it is also rarely curative. Few studies have investigated the options for combining chemotherapy and immunotherapy, largely because the two forms of treatment are considered to be antagonistic. Two assumptions have contributed to this view. First, most chemotherapies kill target cells by triggering a process of programmed cell death, or apoptosis, and this mode of cell death has been regarded as non-stimulatory or tolerogenic (induces tolerance). Thus, apoptosis-inducing chemotherapy would be expected to induce a state of non-responsiveness in the cytotoxic T lymphocytes that could otherwise potentially destroy tumor cells. Second, lymphocyte depletion (lymphopenia) is a common side effect of many anti-cancer drugs, and this too has been assumed to be detrimental to any potential immune response. However, recent advances in our thinking on immune regulation now challenge both of these assumptions. Here, we will review how recent data support the case for combining chemotherapy and immunotherapy in cancer treatment.

Reactivation of human cytomegalovirus in dendritic cells.

Abstract: Extract: Human cytomegalovirus (HCMV) is a member of the Herpesvirus family of viruses and is a ubiquitous human pathogen. Primary infection of immunocompetent individuals is rarely problematic, but congenital or neonatal infection, or infection in immunosuppressed individuals, can cause severe disease. An important biological characteristic of HCMV, with obvious clinical importance, is the ability of the virus to establish lifelong persistence in the host following the initial, normally asymptomatic, infection. A key strategy used by all herpesviruses to persist in the infected individual is the establishment of cellular sites of viral latency. Viral latency is operationally defined as the persistence of the viral genome in absence of the production of infectious virions, but with the ability of the viral genome to reactivate under certain conditions. HCMV can remain latent in peripheral blood cells throughout the host's lifetime and sporadic reactivation events are generally well controlled by cell-mediated immunosurveillance, particularly virus-specific CD4+ and CD8+ T lymphocytes. However, in immunocompromised AIDS patients or immunosuppressed transplant patients, HCMV replication becomes uncontrolled and can cause serious morbidity and mortality, due to disease in the eye (retinitis), lung, nervous system and other organs. Analyses of virus strains during HCMV infection of organ transplant patients have shown that infection is predominantly due to reactivation of the transplant recipient's own HCMV, although it can also result from virus transferred from the donor. Consequently, an understanding of the cellular sites of latency and reactivation, and the mechanisms that control latency in these cells, are of major importance for further understanding of HCMV pathogenesis, as it follows reactivation.

Seasonal variation of rheumatic diseases.

Abstract: Extract: Seasonal variation has been shown in a number of rheumatic diseases (diseases involving the joints and related structures). The incidence of acute gouty attacks (an inflammatory arthritis) is highest in the spring. The onset or exacerbation of rheumatoid arthritis, the onset of Wegener's granulomatosis (chronic tissue inflammation and cellular clumping in the nasal passages, lungs and kidneys), anti-neutrophil cytoplasmic antibodies (ANCA) associated kidney inflammation (glomerulonephritis) and systemic vasculitis are all seen more commonly in the winter. There is a significant increase in the incidence of positive biopsies in giant cell arteritis (vascular inflammation of the temple) in late winter and autumn. In systemic lupus erythematosus (SLE, an autoimmune disease in which antibodies to self components are found in the blood stream and in tissues) there may be a tendency for different organs to be affected during different seasons. In SLE patients, there is an increased incidence of photosensitive skin rashes in the summer and of joint pain in the winter and spring. A significantly higher prevalence in the winter and spring was observed among SLE patients with class V lupus nephritis (LN, inflammation of the kidneys), as compared with the summer and fall. A similar trend was seen for seasonal variation of the percentage of class III lupus nephritis patients.

The role of CD8 T cell replicative senescence in human aging.

Abstract: Extract: Normal somatic cells are strictly limited in the number of times they can divide. This intrinsic barrier to unlimited proliferation, a process known as replicative senescence, was first described by Hayflick and colleagues nearly fifty years ago in cell cultures of normal fibroblasts (connective tissue cells), and has since been documented for a variety of human cell types, including epithelial cells (cells which make up the inner and outer surface of vessels, organs, etc.), keratinocytes (cells that produce keratin which becomes hair, skin and nails), endothelial cells (cells that line, for instance, the circulatory system) and hepatocytes (liver cells) cultured in vitro. Ironically, it was only recently that this cell culture model was adapted to the so-called CD8 (cytotoxic) T cell, the immune cell type that is actually required to undergo extensive proliferation in order to function effectively in controlling infections. The reason that clonal expansion is so crucial for proper immune function is that each lymphocyte expresses a unique antigen receptor, i.e., recognizes one specific "substance." During a viral infection, the few T cells that recognize that particular virus must undergo extensive cell division to produce sufficient effector cells to clear the infection. Once an infection is cleared, most of the CD8 T cells die by apoptosis (programmed cell death), leaving just a few memory cells with the same antigen receptor to deal with possible future encounters with the same pathogen, at which time the process of clonal expansion is repeated.

"Mendel in the Kitchen: A Scientist's View of Genetically Modified Foods".

Abstract: SUMMARY: Is genetically modified food safe? Are concerns over genetically modified food warranted? What is the difference between introducing genes into plants by grafting and by molecular engineering? These and other questions are answered in the book "Mendel in the Kitchen" written by plant biology expert Dr. Nina Fedoroff.

A Biobehavioral Perspective of Tumor Biology

Abstract: Extract: The perspective that cancer may be causally linked to stress has a long history. In 200 AD, Galen proposed that melancholic women were more susceptible to cancer than women who were sanguine. Rigorous examinations of related observations have lagged over the ensuing centuries. More recently, epidemiologic studies have shown that psychologic and social characteristics (e.g., chronic stress and negative life events, social isolation and support, socioeconomic burden, and emotional processes) might be associated with differential cancer incidence, progression, and mortality. The biologic mechanisms (e.g., signaling pathways) that may account for such observations are being discovered through the convergence of relevant molecular, cellular, and clinical data. In this article, we review the clinical and experimental evidence regarding the effects of stress on tumor development, growth, and progression. Within this context, we define "stress" as an external event ("stressor") or perception of such events that engender psychologic and physiologic changes ("stress responses") designed to approach, avoid, or defend against the external event.

Pharmacokinetics of drugs administered in nanosuspension.

Abstract: Extract: Nanosuspensions are submicron-sized crystalline drug particles that are stabilized by coatings of surfactant (a surface-active agent which reduces surface tension) to produce stable pharmaceutical formulations. Their development arose in response to the evolving needs of the medicinal chemist over the last twenty years. During this period, the implementation of high throughput screening tests has enabled the identification of molecular drug candidates with greater affinity for protein receptor targets. In general, such lead compounds have proved to be larger and more hydrophobic (water-hating) than previous candidates, thus permitting the exclusion of water from the receptor surface and increasing the hydrophobic interaction with the target. While effective, as demonstrated in in-vitro binding assays, such compounds often lack sufficient water solubility, a parameter required for successful, subsequent development.

Psoriasis: Clinical manifestations, pathogenesis and therapeutic perspectives.

Abstract: Extract: Psoriasis, a common inflammatory skin disorder, has recently moved into the limelight of both basic and clinical research. On the one hand, research into its pathogenesis has furthered our general understanding of T cell-mediated autoimmune disorders, and, on the other hand, psoriasis is used increasingly as a primary target disorder for novel therapies that are pathogenesis-oriented. Given that psoriasis affects approximately 2% of the population, it is a truly common skin disease. It is, therefore, somewhat surprising that the first description of psoriasis as a distinct entity dates back only to the year 1841. Geographic and ethnic factors appear to have a significant influence on the prevalence of psoriasis: ranges from 0% in the population of the Pacific islands of Samoa to 12% in the Arctic Kasach'ye have been reported. Ethnic influence is particularly evident when looking at the prevalence in African Americans, which is less than half that of the United States in general. Numerous family studies have provided compelling evidence for a genetic predisposition to develop psoriasis, although the inheritance pattern is still unclear. Genome-wide linkage studies have identified several putative psoriasis susceptibility loci, one of which located in the MHC (major histocompatibility complex, a cluster/locus of genes involved in the immune response of rejection) region on chromosome 6 was found to be present in several populations. This locus, termed "PSORiasis Susceptibility 1" (PSORS1), can thus be considered the major susceptibility locus and is associated with up to 50% of psoriasis cases.

"A change of heart: how the people of framingham, massachusetts, helped unravel the mysteries of cardiovascular disease".

Abstract: SUMMARY For more than 50 years, Framingham Heart Study has produced over 1,000 scientific papers and identified major risk factors associated with heart disease, stroke, and others. It changed America's heart. Cigarettes were no longer advertised as "your doctor's favorite brands." We knew, from the Study, that LDL is a "bad" cholesterol and HDL is a good one.

Pharmacogenomics: Bench to bedside.

Abstract: Extract: Pharmacogenetics is the study of how genetic inheritance affects a person's response to drugs. A major goal for pharmacogenetic research has been the individualization of drug therapy, by which doctors could more precisely cater to an individual's physiological particularities when prescribing drugs, which would both maximize efficacy and minimize toxicity. Advances in pharmacogenetics have converged with rapid developments in human genomics; as a result, pharmacogenetics has evolved into pharmacogenomics. We will briefly review the development of pharmacogenetics and pharmacogenomics, and outline factors that have influenced the "translation" of pharmacogenomics from the research bench to the patients' bedside. The end of the 20th and beginning of the 21st centuries saw the "therapeutic revolution" (which had resulted in the development of drugs to treat diseases ranging from hypertension to childhood leukemia) converge with the "genomic revolution."

Not all Staphylococcus aureus strains are equally pathogenic.

Abstract: Extract: Members of the bacterial species Staphylococcus aureus are considered important human pathogens by all microbiologists and infectious disease specialists. A significant number of humans are persistently colonized in the nose with S. aureus strains, and long term colonization, up to years, has been observed. For 80% of all severe staphylococcal infections, the source seems to be endogenous, so ecological balance during colonization seems to be a key concept. During lifetime, many of the colonized individuals may suffer from mild infections, usually limited to the skin. The occasional furuncle is not a life-threatening disease, neither is impetigo or eczema (related to S. aureus carriage). However, once a person becomes severely ill and hospitalized, the opportunities for the Staphylococcus to manifest itself as a dangerous and invasive threat to human life are greater. It has been demonstrated recently that bacteremia (bacteria entered the blood circulation) caused by S. aureus is more frequent among nasal carriers than among non-carriers. The risk for the staphylococcal carriers increases threefold. In contrast, the risk of dying from an S. aureus bacteremic period is significantly higher in non-carriers. So carriage predisposes individuals to the development of infections but the sequels of these infections are less severe than in the case of infection in a non-carrier.

Lactobacilli as natural enhancer of cellular immune response.

Abstract: Extract: Dendritic cells (DCs), widely distributed in lymphoid (containing lymphocytes) and non-lymphoid tissue, are a complex, heterogeneous group of multifunctional antigen-presenting cells that comprise an essential component of the immune system. For well over a decade, dendritic cells have been recognized as an essential component of both the host innate and adaptive immune responses. DCs, due to their differential regulation and initiation of acquired immune responses, are at the forefront of current research in immunobiology and vaccinology. Recent reports suggest that certain types of antigens (a substance capable of inducing an immune response) differentially govern DC activation and maturation, which ultimately influence the entire immune response. Various species of Lactobacillus (a bacterium found ubiquitously in the mouth, intestinal tract, and vagina) have been shown to differentially regulate dendritic cells and enhance their ability to prime specific immune responses and, thus, they may have great utility as future vaccine adjuvants.

Bipolar disorder: Neurochemistry and drug mechanisms.

Abstract: Extract: The alternating states of mania, depression and mood moderation (euthymia) are so distinct that biological research in psychiatry was attracted to the study of bipolar disorders very early on. Moreover, the discovery of lithium as a simple metal ion that had a strong mood-stabilizing effect suggested that a simple biological pathophysiology might be easily discovered in manic-depressive illness and that this might lead the way to major biological discoveries in other mental disorders and human behavior in general. Overall this story has been heroic and exciting but it has left us in 2005 still without any biological diagnostic test or clear pathophysiological abnormality in manic-depressive illness. Early studies looked for urinary or spinal fluid abnormalities of metabolites of the major monoamine neurotransmitters (chemicals that contain an amino group attached to a carbon backbone in the nervous system, which carry signals between neurons), noradrenaline, serotonin and dopamine. Often, early findings were not replicated, or if replicated they turned out to be secondary to the hyperactivity that occurs in mania or the hypoactivity and weight loss observed in depression.

Mechanism of disease: Pulmonary hypertension.

Abstract: Extract: Pulmonary hypertension (PH) was previously termed primary (idiopathic or of unknown origin, i.e., spontaneous) or secondary (as a result of another disorder) pulmonary hypertension. It is now clear, however, that many of the entities labeled as secondary pulmonary hypertension resemble primary pulmonary hypertension in both their histopathological features and their response to treatment. For this reason, the World Health Organization (WHO) has recently classified PH into five groups on the basis of their proposed underlying mechanism. Group I in this classification, designated pulmonary arterial hypertension, is the focus of this overview. Pulmonary arterial hypertension (PAH) is defined as a sustained elevation of the pulmonary arterial pressure to greater than 25 mmHg at rest or greater than 30 mmHg following exercise, with a mean pulmonary-capillary wedge pressure (an indirect measure of left atrial pressure) of less than 15 mmHg. The entities within the category of PAH include idiopathic pulmonary arterial hypertension (IPAH; formerly, primary pulmonary hypertension), PAH associated with collagen vascular disease (e.g., in limited systemic sclerosis), portal hypertension (high pressure in the vessel that carries blood from the intestines to the liver), congenital left-to-right intra-cardiac shunts, infection with the human immunodeficiency virus (HIV), and persistent pulmonary hypertension of the newborn. The histological appearance of lung vessels in each of these conditions is similar: intimal fibrosis (formation of fibrous material in the inner lining of the blood vessel), increased medial thickness, pulmonary arteriolar occlusion (block of arterioles [the vessels that join the arteries and capillaries] in the lung), and plexiform (web-like) lesions predominate.

What determines longevity: Metabolic rate or stability?

Abstract: Extract: The conventional wisdom about why species age and live as long as they do is based in part on the modern version of the very old and now discredited "rate of living" (ROL) theory of aging. According to the old ROL theory, aging is caused by the loss of some vital substance such as water or hormones - the more rapid the vital substance is used up the shorter the lifespan. The modern and more plausible version of ROL is based on a hypothesis formulated by Raymond Pearl (1921) in the early 20th century where it was suggested that the primary determinant of how long species live is influenced by the relative speed of their resting metabolism. That is, metabolic rate is thought to be inversely proportional to maximum lifespan, which means that species that live fast will die young while those that have a slower metabolic rate live slower and longer. The evolutionary theory of why aging occurs that arose in the 20th century conceptually supports predictions from the metabolic rate theory, although the evolutionary line of reasoning is silent about the mechanisms involved. According to evolution theory, animals that face high extrinsic mortality such as predation and infectious diseases must develop quickly (i.e., live fast) in order to pass their genes onto the next generation before death occurs, while animals that face low extrinsic mortality delay development and reproduction, and thus live slower and longer.

Can infections prevent or cure allergy and autoimmunity

Abstract: Extract: In western countries the prevalence and incidence of allergic and autoimmune diseases have been increasing dramatically over the last 50 years. In the last two decades, significant progress has been made towards understanding the genetic basis for susceptibility to autoimmunity or allergy. Genetic factors, however, cannot explain abrupt changes in disease incidence. It is therefore likely that environmental factors, specifically environmental factors that have changed over the last two generations, are critical for the increasing incidence of allergies and autoimmune diseases. Traditionally, autoimmune diseases such as multiple sclerosis (MS), type I diabetes, or rheumatoid arthritis (RA) are believed to have resulted from aberrant immune response to pathogens. In contrast, the "hygiene hypothesis," first postulated some 20 years ago, proposes that a lack of infections, especially during early childhood, predisposes one to the aberrant immune responses against harmless foreign antigens that cause allergic diseases such as rhinitis, atopic dermatitis, and allergic asthma. Several lines of epidemiological, clinical and experimental research point to more complex connections, either protective or pathogenic, between infection, allergy and autoimmunity.

Crypticity of self antigenic determinants is the cornerstone of a theory of autoimmunity.

Abstract: Extract: The immune system is designed to keep in check, to kill, and to clear from the body any invading disease-causing microbial agents such as bacteria and viruses. This immunity against foreign pathogens is mediated primarily through T lymphocytes and antibodies. Furthermore, there are in-built regulatory mechanisms that monitor the activity of these immune effector components. However, under certain constellations of genetic predisposition and environmental triggers, the same immune system can turn against the host and cause damage to the body's own ("self") cells and tissues (autoimmunity). Diseases like multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and thyroiditis represent a spectrum of autoimmune diseases caused by a dysregulated immune system. Although the autoimmune nature of many of these disorders is clear, their precise etiology is far from evident. Both the genetic composition of an individual [represented, for example, by the major histocompatibility complex (MHC), which in humans is termed HLA (human leukocyte antigens)] and environmental influences (e.g., microbial agents, stress, etc.) are believed to be the major factors that determine outcome of an immune response against self components.

Learning from BCG: Designing a better tuberculosis vaccine.

Abstract: Extract: Prior to the advent of vaccination, disease caused by M. tuberculosis had two age-related peaks: one in the first few 2-3 years of life characterized by a very high incidence of mortality and a later peak in adult life starting in the late teens or early twenties. Today, where most of the global population is vaccinated with BCG, TB mainly manifests as a pulmonary disease in the adult population. The first clinical studies with Mycobacterium bovis bacille Calmette-Guerin (BCG) -- an attenuated pathogen and still the only vaccine available -- started in 1921 and demonstrated that BCG was highly efficient in protecting against TB in children. After the Second World War, the vaccine was offered to children throughout Europe, and today WHO recommends that infants should be immunized as soon after birth as possible with a single, intradermal dose of BCG in all countries at high risk of TB infection. To date, more than 3 billion people have received BCG, which makes BCG one of the most widely used vaccines in the world. The current consensus is that neonatal vaccination with BCG protects children efficiently against the early (and often severe) manifestations of TB, such as TB meningitis, regardless of settings. In contrast, its efficacy against pulmonary disease in adults has varied from 0% to 80% in different studies.

Receptor tyrosine kinases as therapeutic targets in cancer.

Abstract: Extract: Tyrosine kinases are a large and diverse family of proteins found only in Metazoans. The ERBB receptor tyrosine kinases (RTK), the main focus of this article, belong to the sub-group encompassing the cell surface proteins. All receptor tyrosine kinases have an extracellular domain that binds peptide ligands, span the membrane once, and have an intracellular portion with protein tyrosine kinase activity. Ligand binding to receptor tyrosine kinases induces the formation of receptor dimers and activates the kinase domain of the receptor, which transfers a phosphate group from the bound ATP to specific tyrosine side chains on the receptor proteins and on intracellular signaling proteins that bind the active receptor tyrosine kinases. In many types of human tumors, ERBB (erythroblastosis group B) receptor tyrosine kinases are aberrantly activated and contribute to cancer development. Accordingly, these receptors have been intensely studied both to understand their roles in cancer biology and to employ them as therapeutic targets. Many ERBB targeted inhibitors are now in clinical use.

Malignancy risk in autoimmune rheumatic diseases.

Abstract: Extract: All domains of medical knowledge are rapidly increasing. For example, we now understand more about the fascinating collection of "autoimmune diseases" that share one common feature: an overactive immune system that reacts against normal tissue, causing inflammation and often damage. Simultaneously, there has been an explosion of knowledge in the field of oncology, particularly related to hematological malignancies, including lymphomas. It is in part because of this increased understanding of both autoimmune disorders and malignancy that we have begun to appreciate the links between autoimmune rheumatic disease and cancer risk. In the world of rheumatology (the speciality responsible, in large part, for autoimmune rheumatic conditions), a large body of evidence has been accumulating regarding cancer risk in rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, and scleroderma/systemic sclerosis. A more detailed description of this topic was published elsewhere.

HMGB1: An immmune odyssey.

Abstract: Extract: Survival has always been a challenge in nature and fast adaptation is the key. To adapt to new situations during evolution, cells learned to reuse available molecules for different purposes. One example of a molecule recruited from an extant cellular pathway into new functions is the high mobility group box 1 (HMGB1) protein. Over the years, HMGB1 has been known by many names (amphoterin, differentiation enhancing factor, sulphoglucuronyl carbohydrate binding protein-1, p30) and relatively recently has been discovered to have a double identity from a functional point of view. When it resides in the nucleus, HMGB1 binds and bends the DNA helix facilitating the formation of protein complexes (multiple proteins binding to the same stretch of DNA) that regulate nuclear biochemical transactions. Once outside the cell it acts as a potent signal of inflammation, which is a fast response set in motion following injury or infection. The inflammatory reaction is mediated by the innate immune system, which constitutes the first line of defense to tissue damage and microbial agents. Processes like elimination of dead cells, protection against invading microorganisms and tissue repair intersect at the level of innate immunity. We will summarize recently published data that point towards HMGB1 as a common signal of tissue injury and infection used by the innate immune system, and highlight its involvement in disease.

"Curing MS: How Science Is Solving the Mysteries of Multiple Sclerosis".

Abstract: SUMMARY On a grander scale, multiple sclerosis is a battle between a patient's will to fight and the disease's vicious attack on central nerve cells. On a cellular scale, it's between the T helper 1 (Th1) cell, which attacks and destroys the myelin sheath that protects nerve cells, and the Th2 and Th3 cells, which try to bring Th1 cells under control.

Death of lymphocytes: A clue to immune deficiency in human aging.

Abstract: Extract: There is only one way to conceive; however, there are multiple ways to die. The latter is particularly true with each and every cell in our body. One of the ways to die is by programmed cell death or apoptosis (a suicidal form of cell death), which is a natural form of cell death. Apoptosis is critical in embryogenesis, metamorphosis, cellular homeostasis, and removal of unwanted and mutated cells. In the immune system, apoptosis plays an important role in the development of thymocytes (immature T lymphocytes in the thymus), selection of T cell repertoire, deletion of self-reactive lymphocytes, cytotoxicity towards target cells by natural killer and cytotoxic T lymphocytes, and termination of effector lymphocytes at the end of an immune response. Apoptosis is tightly regulated by a set of genes, which either promote or inhibit apoptosis. There are several signaling pathways that mediate apoptosis, namely the death receptor (extrinsic) pathway, mitochondrial (intrinsic) pathway, and the endoplasmic reticulum (ER) pathway. Common to these pathways is the recruitment of adaptor proteins to form a scaffold complex that activates initiator caspases (cysteine proteases), which in-turn activate effector caspases. These effector caspases act as a molecular chainsaw and cleave a large number of cytoplasmic and nuclear substrates, resulting in the morphological and biochemical changes characteristic of apoptosis.