Free immunoglobulin light chains: A role in minimal change disease

Immunoglobulins are tetrameric molecules consisting of two heavy and two light chains linked by disulfide bonds. Single light chains are normally secreted in the plasma under soluble form. These immunoglobulin free light chains circulating in the blood may hold unexpected roles in diseases.Minimal change disease is defined as a renal disease with massive proteinuria and no obvious damage on light microscopy. We hypothesize that minimal change disease is not a primary renal disease but an immune disease due to a defect in B cells mediated by a special immunoglobulin chain. The efficiency of drugs targeting the immune system and the association to Hodgkin disease as well as: (1) the efficiency of B cell depletion to prevent relapse; (2) the association with B leukemia; and (3) the activation of CD23 during relapse point up a primary involvement of B cells. We hypothesize that an immunoglobulin chain with special polymorphism might be the link between the immune system and the dysfunction of the glomerular wall while immunoglobulin depletion leads to a transient remission of proteinuria in graft recurrence of the disease and nephropathy mediated by a monoclonal immunoglobulin chain may feature minimal change disease.Other diseases where free light chains may be involved include atopy, thromboembolism, glomerular inflammatory diseases and autoimmune diseases. We conclude that free circulating light chains, through infinite possibilities of polymorphisms determined by the variable domain are potential disturbing agents of many biological cascades or structures and could likely play the first role in multiple diseases.     

Climate change and vector-borne diseases: what are the implications for public health research and policy?

Vector-borne diseases continue to contribute significantly to the global burden of disease, and cause epidemics that disrupt health security and cause wider socioeconomic impacts around the world. All are sensitive in different ways to weather and climate conditions, so that the ongoing trends of increasing temperature and more variable weather threaten to undermine recent global progress against these diseases. Here, we review the current state of the global public health effort to address this challenge, and outline related initiatives by the World Health Organization (WHO) and its partners. Much of the debate to date has centred on attribution of past changes in disease rates to climate change, and the use of scenario-based models to project future changes in risk for specific diseases. While these can give useful indications, the unavoidable uncertainty in such analyses, and contingency on other socioeconomic and public health determinants in the past or future, limit their utility as decision-support tools. For operational health agencies, the most pressing need is the strengthening of current disease control efforts to bring down current disease rates and manage short-term climate risks, which will, in turn, increase resilience to long-term climate change. The WHO and partner agencies are working through a range of programmes to (i) ensure political support and financial investment in preventive and curative interventions to bring down current disease burdens; (ii) promote a comprehensive approach to climate risk management; (iii) support applied research, through definition of global and regional research agendas, and targeted research initiatives on priority diseases and population groups.     

Ontogenetic variation of the human genome

The human genome demonstrates variable levels of instability during ontogeny. Achieving the highest rate during early prenatal development, it decreases significantly throughout following ontogenetic stages. A failure to decrease or a spontaneous increase of genomic instability can promote infertility, pregnancy losses, chromosomal and genomic diseases, cancer, immunodeficiency, or brain diseases depending on developmental stage at which it occurs. Paradoxically, late ontogeny is associated with increase of genomic instability that is considered a probable mechanism for human aging. The latter is even more appreciable in human diseases associated with pathological or accelerated aging (i.e. Alzheimer's disease and ataxia-telangiectasia). These observations resulted in a hypothesis suggesting that somatic genomic variations throughout ontogeny are determinants of cellular vitality in health and disease including intrauterine development, postnatal life and aging. The most devastative effect of somatic genome variations is observed when it manifests as chromosome instability or aneuploidy, which has been repeatedly noted to produce pathologic conditions and to mediate developmental regulatory and aging processes. However, no commonly accepted concepts on the role of chromosome/genome instability in determination of human health span and life span are available. Here, a review of these ontogenetic variations is given to propose a new "dynamic genome" model for pathological and natural genomic changes throughout life that mimic those of phylogenetic diversity.     

Extracellular proteases and neuronal cell death.

Neuronal cell death occurs during development of the central nervous system as well as in pathological situations such as acute injury and progressive degenerative diseases. For instance, granule cells in the developing cerebellum and neuronal precursor cells in the cortex undergo programmed cell death, or apoptosis. There is currently strong debate conceming the mechanism of death in many degenerative events such as ischemia, blunt head trauma, excitotoxicity and neurodegenerative diseases, i.e. Alzheimer's disease. Neurons can die a necrotic death when the initial insult is too great; apoptosis requires "planning." For example, the cell death seen in the core of an ischemic infarct is necrotic, while in the surrounding penumbra region the death is probably apoptotic. Regardless of the degenerative pathway, damaged or dead neurons are a hallmark of many diseases including Alzheimer's, Parkinson's, glaucoma, ischemia and multiple sclerosis. Molecules such as cytokines, chemokines, reactive nitrogen/oxygen species, and proteases play an important role in promoting and/or mediating neurodegeneration. Proteases have been implicated in both physiological and pathological events, suggesting their intervention in key points when things go awry. In this review we will summarize recent findings linking extracellular proteases with neuronal cell death in both human diseases and their animal models.     

Molecular interactions between prions as seeds and recombinant prion proteins as substrates resemble the biological interspecies barrier in vitro

Prion diseases like Creutzfeldt-Jakob disease in humans, Scrapie in sheep or bovine spongiform encephalopathy are fatal neurodegenerative diseases, which can be of sporadic, genetic, or infectious origin. Prion diseases are transmissible between different species, however, with a variable species barrier. The key event of prion amplification is the conversion of the cellular isoform of the prion protein (PrP(C)) into the pathogenic isoform (PrP(Sc)). We developed a sodiumdodecylsulfate-based PrP conversion system that induces amyloid fibril formation from soluble α-helical structured recombinant PrP (recPrP). This approach was extended applying pre-purified PrP(Sc) as seeds which accelerate fibrillization of recPrP. In the present study we investigated the interspecies coherence of prion disease. Therefore we used PrP(Sc) from different species like Syrian hamster, cattle, mouse and sheep and seeded fibrillization of recPrP from the same or other species to mimic in vitro the natural species barrier. We could show that the in vitro system of seeded fibrillization is in accordance with what is known from the naturally occurring species barriers.     

Amyloid fibrils of mammalian prion protein induce axonal degeneration in NTERA2-derived terminally differentiated neurons

Defects in axonal transport and synaptic dysfunctions are associated with early stages of several neurodegenerative diseases including Alzheimer's, Huntington's, Parkinson's, and prion diseases. Here, we tested the effect of full-length mammalian prion protein (rPrP) converted into three conformationally different isoforms to induce pathological changes regarded as early subcellular hallmarks of prion disease. We employed human embryonal teratocarcinoma NTERA2 cells (NT2) that were terminally differentiated into neuronal and glial cells and co-cultured together. We found that rPrP fibrils but not alpha-rPrP or soluble beta-sheet rich oligomers caused degeneration of neuronal processes. Degeneration of processes was accompanied by a collapse of microtubules and aggregation of cytoskeletal proteins, formation of neuritic beads, and a dramatic change in localization of synaptophysin. Our studies demonstrated the utility of NT2 cells as valuable human model system for elucidating subcellular events of prion pathogenesis, and supported the emerging hypothesis that defects in neuronal transport and synaptic abnormalities are early pathological hallmarks associated with prion diseases.     

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.     

Regulation of intracellular pH

The approach that most animal cells employ to regulate intracellular pH (pH(i)) is not too different conceptually from the way a sophisticated system might regulate the temperature of a house. Just as the heat capacity (C) of a house minimizes sudden temperature (T) shifts caused by acute cold and heat loads, the buffering power (beta) of a cell minimizes sudden pH(i) shifts caused by acute acid and alkali loads. However, increasing C (or beta) only minimizes T (or pH(i)) changes; it does not eliminate the changes, return T (or pH(i)) to normal, or shift steady-state T (or pH(i)). Whereas a house may have a furnace to raise T, a cell generally has more than one acid-extruding transporter (which exports acid and/or imports alkali) to raise pH(i). Whereas an air conditioner lowers T, a cell generally has more than one acid-loading transporter to lower pH(i). Just as a house might respond to graded decreases (or increases) in T by producing graded increases in heat (or cold) output, cells respond to graded decreases (or increases) in pH(i) with graded increases (or decreases) in acid-extrusion (or acid-loading) rate. Steady-state T (or pH(i)) can change only in response to a change in chronic cold (or acid) loading or chronic heat (or alkali) loading as produced, for example, by a change in environmental T (or pH) or a change in the kinetics of the furnace (or acid extrudes) or air conditioner (or acid loaders). Finally, just as a temperature-control system might benefit from environmental sensors that provide clues about cold and heat loading, at least some cells seem to have extracellular CO(2) or extracellular HCO(3)(-) sensors that modulate acid-base transport.     

Fatal neurological disease in scrapie-infected mice induced for experimental autoimmune encephalomyelitis

During the years or decades of prion disease incubation, at-risk individuals are certain to encounter diverse pathological insults, such as viral and bacterial infections, autoimmune diseases, or inflammatory processes. Whether prion disease incubation time and clinical signs or otherwise the pathology of intercurrent diseases can be affected by the coinfection process is unknown. To investigate this possibility, mice infected with the scrapie agent at both high and low titers were subsequently induced for experimental autoimmune encephalomyelitis, an immune system-mediated model of central nervous system (CNS) inflammation. We show here that co-induced mice died from a progressive neurological disease long before control mice succumbed to classical scrapie. To investigate the mechanism of the co-induced syndrome, we evaluated biochemical and pathological markers of both diseases. Brain and spleen PrP(Sc) levels in the dying co-induced mice were comparable to those observed in asymptomatic scrapie-infected animals, suggesting that co-induced disease is not an accelerated form of scrapie. In contrast, inflammatory markers, such as demyelination, immune cell infiltrates, and gliosis, were markedly increased in co-induced mouse spinal cords. Activated astrocytes were especially elevated in the medulla oblongata. Furthermore, PrP(sc) depositions were found in demyelinated white matter areas in co-induced mouse spinal cords, suggesting the presence of activated infected immune cells that infiltrate into the CNS to facilitate the process of prion neuroinvasion. We hypothesize that inflammatory processes affecting the CNS may have severe clinical implications in subjects incubating prion diseases.     

The activity of the high-affinity K+ uptake system Kdp sensitizes cells of Escherichia coli to methylglyoxal.

Expression of the Kdp system sensitizes cells to methylglyoxal (MG) whether this electrophile is added externally or is synthesized endogenously. The basis of this enhanced sensitivity is the maintenance of a higher cytoplasmic pH (pHi) in cells expressing Kdp. In such cells, MG elicits rapid cytoplasmic acidification via KefB and KefC, but the steady-state pHi attained is still too high to confer protection Lowering pHi further by incubation with acetate increases the sensitivity of cells to MG.     

A survey of the pathology of marmosets (Callithrix jacchus) under experiment

A survey of the pathology of 567 laboratory-bred cotton-eared marmosets (Callithrix jacchus) is presented. There were few significant pathological changes in animals used in studies up to 6 months in duration, suggesting that the marmoset can be a useful non-human primate species for routine toxicology. The most common pathological changes encountered were chronic colitis, chronic thyroiditis and interstitial mononuclear infiltration in the kidney. No internal parasites were encountered, nor were any viral or bacterial diseases identified. Fungal disease was confined to a few cases of oesophageal mycoses. In a long term study a variety of pathological changes have been observed, including a 'wasting' syndrome, not related to skeletal muscle myopathy, with atrophy of the gastrointestinal tract, salivary glands and gonads, haemosiderosis and fatty change in the liver and osteoporosis. It is suggested that these changes may be related to protein deficiency and that the nutritional requirements of the marmoset require further investigation.     

LineageSpecificSeqgen: generating sequence data with lineage-specific variation in the proportion of variable sites

Background  

Commonly used phylogenetic models assume a homogeneous evolutionary process throughout the tree. It is known that these homogeneous models are often too simplistic, and that with time some properties of the evolutionary process can change (due to selection or drift). In particular, as constraints on sequences evolve, the proportion of variable sites can vary between lineages. This affects the ability of phylogenetic methods to correctly estimate phylogenetic trees, especially for long timescales. To date there is no phylogenetic model that allows for change in the proportion of variable sites, and the degree to which this affects phylogenetic reconstruction is unknown.     

Risk and disease

The way that diseases such as high blood pressure (hypertension), high cholesterol, and diabetes are defined is closely tied to ideas about modifiable risk. In particular, the threshold for diagnosing each of these conditions is set at the level where future risk of disease can be reduced by lowering the relevant parameter (of blood pressure, low-density lipoprotein, or blood glucose, respectively). In this article, I make the case that these criteria, and those for diagnosing and treating other "risk-based diseases," reflect an unfortunate trend towards reclassifying risk as disease. I closely examine stage 1 hypertension and high cholesterol and argue that many patients diagnosed with these "diseases" do not actually have a pathological condition. In addition, though, I argue that the fact that they are risk factors, rather than diseases, does not diminish the importance of treating them, since there is good evidence that such treatment can reduce morbidity and mortality. For both philosophical and ethical reasons, however, the conditions should not be labeled as pathological. The tendency to reclassify risk factors as diseases is an important trend to examine and critique.     

Peripheral pathogenesis of prion diseases

Prions are infectious pathogens that cause a group of neurodegenerative diseases characterized by spongiform degeneration of the central nervous system. Prions appear to lack any informational nucleic acid. The most notable prion diseases include bovine spongiform encephalopathy, scrapie in sheep and Creutzfeldt-Jakob disease of humans. Transmission is thought to be achieved through conversion of a normal host protein into a pathological isoform. Although the main pathological changes during the course of the disease occur in the brain, the infectious agent accumulates early in lymphoid tissue. The subsequent development of clinical disease depends on the presence of an intact immune system including mature B-cells. In this article we review the state of knowledge on the routes of neuroinvasion used by the infectious agent in order to gain access to the central nervous system upon entry into extracerebral sites.     

白介素1β对培养的大鼠皮层神经元钙通道电流的抑制作用

白细胞介素1β（IL-1β）是重要的促炎细胞因子,在中枢神经系统（CNS）中发挥广泛的生物学功能。在病理条件下,细胞膜上电压门控钙通道的变化与疾病发展过程密切相关。虽然IL-1β和钙通道都在脑损伤和脑疾病过程中发挥重要作用,但目前还很少有两者之间相互关系的研究报道。该研究使用了培养的大鼠胎鼠皮层神经元和膜片钳记录技术,研究了长时间的IL-1β处理对电压门控钙通道电流的作用。结果表明,IL-1β在10和50 ng/mL剂量下都可以抑制钙电流,这种抑制作用具有时间和剂量依赖性的模式,并且不改变钙通道的激活性质。     

Unaltered susceptibility to scrapie in serotonin transporter deficient mice

The serotonergic system has been hypothesized to play an important role in prion diseases. Specifically, hyperactivity of the serotonergic system in prion diseases is suggested by an increase in the turnover rate of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) in human and experimental prion diseases. The 5-HT transporter (5-HTT) determines the duration of serotonergic neurotransmission by way of reuptake of 5-HT from the extracellular space. 5-HTT availability is reduced in brains of patients with the human prion disease familial fatal insomnia. To further clarify a possible role of the 5-HTT in prion diseases we investigated whether mice lacking the 5-HTT display an altered susceptibility to experimental scrapie infection. Surprisingly, 5-HTT knockout mice developed mouse scrapie in a time course similar to wildtype control mice with accumulation of the pathological prion protein, PrP(Sc) and with typical pathological hallmarks of the disease. These findings argue against a major role of the 5-HTT in the pathogenesis of prion diseases in mice.