Issues of preserving fertility, preventing early menopause, and predicting reproductive ability have become crucial for many adult thalassemia major females.
LH/FSH and estardiol, commonly used for assessment of fertility potential in thalassemia, have a poor predictive value. Current reproductive practice utilizes markers of ovarian reserve testing (ORT), which were not yet studied in thalassemia women. We explored the relationship between liver iron concentration (LIC) and fertility status in 26 females (mean 30 years old). Seventeen (65%) of them experienced primary or secondary amenorrhea. Levels of LH/FSH and estradiol were low or undetectable in 48% and 35% of patients, respectively and did not correlate with age, presence of amenorrhea and LIC. This further addresses the need for utilization of current available methods for assessment of fertility capacity in thalassemia, which will also allow future correlation with pituitary iron measures by MRI as well as early intervention for fertility preservation.
Thalassemia major; infertility in thalassemia; ovarian reserve testing (ORT)
One of the fundamental goals in human genetics is to link gene function to phenotype, yet the function of the majority of the genes in the human body is still poorly understood. This is especially true for the developing human brain. The study of human phenotypes that result from inherited, mutated alleles is the most direct evidence for the requirement of a gene in human physiology. Thus, the study of Mendelian central nervous system(CNS) diseases can be an extremely powerful approach to elucidate such phenotypic/genotypic links and to increase our understanding of the key components required for development of the human brain. In this review, we highlight examples of how the study of inherited neurodevelopmental disorders contributes to our knowledge of both the “normal” and diseased human brain, as well as elaborate on the future of this type of research. Mendelian disease research has been, and will continue to be, key to understanding the molecular mechanisms that underlie human brain function, and will ultimately form a basis for the design of intelligent, mechanism-specific treatments for nervous system disorders.
genetics; inherit; brain; development; CNS; disease; Mendelian
The elderly, often defined as those 65 years or older, are the most rapidly growing segment of the population, and onset of epilepsy is higher in this age group than in any other. This paper reviews recent developments, including: a new proposed definition of epilepsy, a transgenic mouse model of Alzheimer's disease which exhibits complex partial seizures, evidence that the highest incidence of epilepsy may occur after admission to a nursing home, a challenge to the vitamin D hypothesis of osteoporosis associated with antiepileptic drugs (AEDs), evidence that the genetic complement of hepatic isoenzymes is more predictive of metabolic rate than age, and data showing that there is considerable variability in antiepileptic drug (AED) levels in many nursing home residents during constant dosing conditions.
epilepsy; elderly; nursing homes; treatment
Glucocorticoid (GC) use results in rapid bone loss and an elevated risk of fracture. The excess bone fragility from GC treatment is multifactorial. GCs increase bone remodeling through reductions in gonadal hormones, elevations in PTH from negative calcium balance, early stimulation of osteoclast maturation and activity, and delayed, sustained reduction in osteogenesis and osteoblast activity. GCs also alter the metabolism of osteocytes so that increased osteocyte lacunae size, with demineralization around the osteocyte and reduced elastic modulus, is observed in a mouse model of GC-induced bone loss. In summary, GC effects on bone fragility are multifactorial, and additional studies are now under way to clarify how GCs alter osteocyte metabolism and result in reduction in localized bone strength.
glucocorticoids; osteoporosis; bone fragility
The National Institutes of Health’s Clinical and Translational Science Award (CTSA) program has had a profound impact on clinical research and training methods at the University of California, Davis (UC Davis). UC Davis was among the first 12 institutions to receive NIH funding for this award, and created its Clinical and Translational Science Center (CTSC) in 2006. The funding accelerated and further integrated an existing conscientious and careful planning effort for translational research with a stepwise approach to gradually increase our institutional competencies, capabilities, and resources in this area. The development of our CTSC has led us to develop new ways of bringing together a diverse faculty and facilitating research. The CTSC has impacted virtually every area and infrastructure resource involved in promoting clinical and translational research at our institution.
Nutrition; Translation; Clinical research
Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) causes the most common form of kidney cancer. pVHL is part of a complex that polyubiquitinates the alpha subunit of the heterodimeric transcription factor HIF. In the presence of oxygen HIFa is prolyl hydroxylated by EglN1 (also called PHD2). This modification recruits pVHL, which then targets HIFa for proteasomal degradation. In hypoxic, or pVHL-defective, cells HIFa accumulates, binds to HIFb, and transcriptionally activates genes such as VEGF. VEGF inhibitors and mTOR inhibitors, which indirectly affect HIF, are now approved for the treatment of kidney cancer. EglN1 is a 2-oxoglutarate-dependent dioxygenase. Such enzymes can be inhibited with drug-like small molecules. EglN1 inhibitors are currently being tested for the treatment of anemia. EglN2 (PHD1) and EglN3 (PHD3), which are EglNs paralogs, appear to play HIF-independent roles in cell proliferation and apoptosis, respectively, and are garnering interest as potential cancer targets. A number of JmjC-containing proteins, including RBP2 and PLU-1, are 2-oxoglutarate-dependent dioxygenases that demethylate histones. Preclinical data suggest that inhibition of RBP2 or PLU-1 would suppress tumor growth.
cancer; tumor suppressor protein; transcription factor
The enzyme catalase converts solar radiation into reactive oxidant species (ROS). In this study, we report that several bacterial catalases (hydroperoxidases, HP), including Escherichia coli HP-I and HP-II also generate reactive oxidants in response to ultraviolet B light (UVB). HP-I and HP-II are identical except for the presence of NADPH. We found that only one of the catalases, HPI, produces oxidants in response to UVB light, indicating a potential role for the nucleotide in ROS production. This prompts us to speculate that NADPH may act as a cofactor regulating ROS generation by mammalian catalases. Structural analysis of the NADPH domains of several mammalian catalases revealed that the nucleotide is bound in a constrained conformation and that UVB irradiation induces NADPH oxidation and positional changes. Biochemical and kinetic analysis indicate that ROS formation by the enzyme is enhanced by oxidation of the cofactor. Conformational changes following absorption of UVB light by catalase NADPH have the potential to facilitate ROS production by the enzyme.
catalase; UVB; ROS; NADPH; light
In preparation for designing and undertaking trials of strategies that can modulate “innate inflammation” to improve outcomes of ischemic injury, consideration of approaches that have managed cellular inflammation in ischemic stroke are instructive. Robust experimental work has demonstrated the efficacy (and apparent safety) of targeting PMN leukocyte–endothelial cell interactions in the early moments following focal ischemia onset in model systems. Four clinical trial programs were undertaken to assess the safety and efficacy of inhibitors to PMN leukocyte interactions with the endothelial cell during ischemic stroke. Experiences in those clinical trial programs indicate specific limitations that halted progress in this line of investigation before an adequate hypothesis test could be achieved. Although innate inflammation is a central part of injury evolution following focal ischemia, great care in the translation from experimental studies to Phase I/II clinical safety assessments and to the design and conduct of Phase III trials is needed.
PMN leukocytes; ischemic stroke; inflammation; clinical studies; treatment
In the central nervous system, microvessel–neuron interactions appear highly coordinated. The rapid simultaneous responses of the microvasculature, neurons, and glia to focal ischemia in experimental ischemic stroke suggest that these responses could be viewed in a unitary fashion, rather than as individual components. The “neurovascular unit” consists of microvessels (endothelial cells–basal lamina matrix–astrocyte end-feet [and pericytes]), astrocytes, neurons and their axons, and other supporting cells that are likely to modulate the function of the “unit.” Each cell component generates an inflammatory response to ischemia. Matrix metalloproteinase (MMP)-9 was first associated with hemorrhagic transformation following focal ischemia in an experimental model. A series of studies of ischemic stroke patients also suggests a relationship between MMP-9 levels and several consequences of ischemic injury, including hemorrhagic transformation. Recent experimental work suggests specific cell sources for MMP-9 generation and for matrix proteases from four distinct families that could impact neurovascular unit integrity.
matrix metalloproteinases; ischemic stroke; inflammation; matrix proteins; neurovascular unit
SHIP1 is at the nexus of intracellular signaling pathways in immune cells that mediate BM graft rejection, production of inflammatory and immunosuppressive cytokines, immunoregulatory cell formation, the BM niche that supports development of the immune system and immune cancers. Here I summarize how SHIP participates in normal immune physiology and the pathologies that result when SHIP is mutated. I also put forward a proposal that SHIP can have either inhibitory and activating roles in cell signaling that are determined by whether signaling pathways distal to PI3K are promoted by SHIP's substrate (PI(3,4,5)P3) or its product (PI(3,4)P2) I also propose the “Two PIP Hypothesis” that postulates both SHIP's product and its substrate are necessary for a cancer cell to achieve and sustain a malignant state. Finally, due to the recent discovery of small molecule antagonists and agonists for SHIP, I discuss potential therapeutic settings where chemical modulation of SHIP might be of benefit.
SHIP; PI(3,4,5)P3; PI(3,4)P2; Treg cells; NK cells; MIR cells; antigen presentation; osteoblasts; s-SHIP; cancer; Crohn's Disease
Chronic and intermittent ischemic vascular disorders represent a burgeoning clinical challenge. Previous studies have focused on the idea that therapeutic angiogenesis strategies could alleviate tissue ischemia; however, it is now appreciated that vascular disease is not simply limited to vascular wall cells but also influenced by simultaneously occurring inflammatory responses. Our laboratory has discovered that pharmacological treatment of permanent tissue ischemia with dipyridamole significantly augments ischemic tissue reperfusion, angiogenesis, and arteriogenesis over time. We have found that the beneficial effects of dipyridamole therapy are due to its ability to increase tissue nitric oxide bioavailability that corrects tissue redox imbalance. Importantly, we have also discovered that dipyridamole treatment invoking nitric oxide (NO) production significantly downregulates various innate immune response genes during chronic ischemic tissue injury. These findings demonstrate that dipyridamole induced production of nitrite/NO significantly decreases inflammatory responses while increasing vascular growth in ischemic tissues.
inflammation; angiogenesis; interleukin 10; toll like receptors nitric oxide
Stroke in general, and ischemic stroke in particular, are routinely defined using clinical criteria. Incorporating brain imaging and neuropathological findings into an expanded conceptual definition of stroke will result in a vastly increased prevalence of the disease. The resultant category of mixed cerebrovascular disease thus may include subclinical infarct, cerebral white matter disease, and cerebral microbleeds. Subclinical brain infarcts occur five times more frequently than does clinical ischemic stroke. Abnormalities of cerebral white matter are present in more than 95% of the population over the age of 65 years, and magnetic resonance imaging evidence of cerebral microbleeds is found in at least 18% of the population, beginning at the age of 60 years. Pathologic evidence supports at least a partial microvascular origin for cerebral white matter disease and cerebral microbleeds. Emphasizing mixed cerebrovascular disease as a conceptual framework allows for a focus on common underlying mechanisms and new therapeutic strategies.
stroke; blood–brain barrier; ischemia; hemorrhage
Scientific interest in the relationship between cognition and action has increased markedly in the past several years, fueled by the discovery of mirror neurons in monkey prefrontal and parietal cortex and by the emergence of a movement in cognitive psychology, termed the embodied cognition framework, which emphasizes the role of simulation in cognitive representations. Guided by a functional neuroanatomic model called the Two Action Systems account, which posits numerous points of differentiation between structure- and function-based actions, we focus on two of the major issues under recent scrutiny: the relationship between representations for action production and recognition, and the role of action in object representations. We suggest that mirror neurons in humans are not critical for full action understanding, and that only function-based (and not structure-based) action is a component of embodied object concepts.
apraxia; praxis; objects; attention; dorso-dorsal; dorso-ventral
The immune toxicity of the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to as dioxin, has been studied for over 35 years but only recently has the profound immune suppression induced by TCDD exposure been linked to induction of regulatory T cells (Tregs). The effects of TCDD are mediated through its binding to the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. The subsequent AHR-dependent effects on immune responses are determined by the cell types involved, their activation status, and the type of antigenic stimulus. Collectively, studies indicate that TCDD inhibits CD4+ T cell differentiation into T helper (Th)1, Th2, and Th17 effector cells, while inducing Foxp3-negative and/or preserving Foxp3+ Tregs. Although it is not yet clear how activation of AHR by TCDD induces Tregs, there is a potential therapeutic role for alternative AHR ligands in the treatment of immune-mediated disorders.
2,3,7,8 tetrachlorodibenzo-p-dioxin; aryl hydrocarbon receptor; regulatory T cells; dendritic cells; indoleamine 2,3-dioxygenase; Foxp3; NF-κB
Signaling by H2O2, α,β-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (HNE) and related chemical species, is thought to differ from signaling by other second messengers because the oxidants and other electrophiles can readily undergo nonenzymatic reactions and are therefore classified as “reactive.” This brief review will describe how and when the chemistry of signaling is similar or differs from classic second messengers, such as cyclic AMP, or posttranslational signaling, such as farnesylation or ubiquitination. The chemistry of cysteine provides a common factor that underlies signaling by H2O2 and HNE. Nonetheless, as H2O2 and HNE are rapidly metabolized in vivo, spatial considerations are extremely important in their actions. Therefore, the locations of sources of H2O2 and α,β-unsaturated aldehydes, the NADPH oxidases, mitochondria, membrane lipids, and redox cycling toxicants, as well as their targets, are key factors. The activation of the JNK pathway by HNE and endogenously generated H2O2 illustrates these principles.
hydrogen peroxide; superoxide; 4-hydroxynonenal; thiol; thiolate; protein tyrosine phosphatase; glutathionylation; thioredoxin
Epigenetics holds promise to explain some puzzles concerning the risk and course of psychiatric disorders. Epigenetic information is essential as a set of operating instructions for the genome, which is heritable with DNA. The epigenetic regulation of gene expression can plausibly be influenced by the environment of one’s ancestors, prenatal exposures, and by early life events. Some epigenetic mechanisms may alter neurophysiology throughout life by programming gene expression, perhaps in anticipation of certain life experiences. These epigenetic signals are only meta-stable and may be perturbed by stochastic events, errors, or by environmental toxins. This introduction considers the possibility that epigenetic change that may occur as paternal age advances or during fetal adversity may be causally related to the susceptibility for schizophrenia.
epigenetics; reproduction; genetics; paternal age; schizophrenia
A wide range of parameters influence allosteric communications between the α- and β-subunits of the Trp synthase α2β2 multienzyme complex with L-Ser, including monovalent cations, pH, temperature, ligands, organic solvents, and hydrostatic pressure. The conformational change from closed to open can be monitored either by absorbance at 423 nm or fluorescence at 495 nm from the pyridoxal-5′-phosphate-L-Ser complex. Pressure perturbation was used to quantify the effects of monovalent cations, ligands, and mutations on the conformational equilibrium of Trp synthase. P-jump kinetics in the presence of Na+, NH4+, and Na+ together with benzimidazole were also examined. The plots of lnk versus P are nonlinear and require a compressibility (β‡o) term to obtain a good fit. β‡o is positive for the Na+ enzyme but negative for NH4+ and Na+ with benzimidazole. These results suggest that there is a large contribution of solvation to the kinetics of the conformational change of Trp synthase. The relaxation kinetics are also different if the P-jumps are made by increasing or decreasing pressure, suggesting that the enzyme conformations are ensembles of microstates.
tryptophan synthase; allostery; pyridoxal-5′-phosphate; compressibility; solvation
CXCL12/SDF-1 dynamically regulates hematopoietic stem cell (HSC) attraction in the bone marrow (BM). Circadian regulation of bone formation and HSC traffic is relayed in bone and BM by β-adrenergic receptors (β-AR) expressed on HSCs, osteoblasts and mesenchymal stem / progenitor cells. Circadian HSC release from the BM follows rhythmic secretion of norepinephrine (NE) from nerve terminals, β3-AR activation and Cxcl12 downregulation, possibly due to reduced Sp1 nuclear content. Here, we show that β-AR stimulation in stromal cells causes Sp1 degradation, partially mediated by 26S proteasome. Inverted trends of circulating hematopoietic progenitors and BM Cxcl12 mRNA levels change acutely after light onset, shown to induce sympathetic efferent activity. In BM stromal cells, activation of β3-AR downregulates Cxcl12, whereas β2-AR stimulation induces clock gene expression. Double-deficiency in β2- and β3-ARs compromises enforced mobilization. Therefore, β2- and β3-ARs have specific roles in stromal cells and cooperate during progenitor mobilization.
β-adrenergic receptors; bone marrow stromal cells; circadian; clock; CXCL12/SDF-1; hematopoietic progenitor mobilization
Reactive species derived from oxygen and nitric oxide are produced during inflammation and promote oxidation and nitration of biomolecules, including unsaturated fatty acids. Among the products of these reactions are α,β-unsaturated carbonyl and nitro derivatives of fatty acids, electrophilic species whose reactivity with nucleophilic amino acids provides a means of posttranslational protein modification and signaling. These electrophilic fatty acids activate cytosolic and nuclear stress–response pathways (through Nrf2/Keap1 and PPARγ, for example). There is also growing evidence that mitochondria generate electrophilic species. This appreciation, when combined with the role of mitochondrial dysfunction in conditions where exogenously delivered electrophiles exhibit therapeutic benefit, suggests that mitochondrial electrophile targets are also important in the resolution and prevention of inflammatory injury. Cardioprotective signaling pathways in particular appear to converge on mitochondria, with nitro-fatty acids recently shown to protect against cardiac ischemia/reperfusion injury in a murine model. Although numerous mitochondrial proteins are subject to modification by electrophiles, defining the targets most relevant to cytoprotection during inflammatory stress remains a clinically relevant goal.
electrophiles; mitochondria; redox signaling; ischemia-reperfusion
The hematopoietic stem cell (HSC) niche is currently defined as the specific microenvironment in the bone marrow (BM) which anatomically harbors HSCs and governs their fate. It plays a pivotal role in regulating the survival and self-renewal ability of HSCs, protecting them from exhaustion while preventing their excessive proliferation. Many different stromal cell types have been proposed as putative constituents of the niche, but their integrated function is still unrevealed. Mechanisms by which stem/progenitor cell behavior is regulated in the niche include cell-to-cell interaction and the production of growth factors, cytokines, and extracellular matrix proteins. The HSC niche is a dynamic entity reflecting and responding to the needs of the organism. An understanding of how the niche participates in the maintenance of tissue homeostasis and repair offers new opportunities for the development of novel therapeutic tools.
HSC niche; stem cells; microenvironment; osteoblastic cells; perivascular cells; regeneration
Ambient air pollution has been linked to cardiovascular and respiratory morbidity and mortality in epidemiology studies. Frequently, oxidative and nitrosative stress are hypothesized to mediate these pollution effects, however precise mechanisms remain unclear. This paper describes the methodology for a major panel study to examine air pollution effects on these and other mechanistic pathways. The study took place during the drastic air pollution changes accompanying the 2008 Olympics in Beijing, China. After a general description of air pollution health effects, we provide a discussion of panel studies and describe the unique features of this study that make it likely to provide compelling results. This study should lead to a clearer and more precise definition of the role of oxidative and nitrosative stress, as well as other mechanisms, in determining acute morbidity and mortality from air pollution exposure.
panel study; oxidative stress; exhaled breath condensate; 2008 Olympics
Epidemiological studies have linked exposure to traffic-related air pollutants to increased respiratory and cardiovascular morbidity and mortality. Evidence from human, animal, and in vitro studies supports an important role for oxidative stress in the pathophysiological pathways underlying the adverse health effects of air pollutants. In controlled-exposure studies of animals and humans, emissions from diesel engines, a major source of traffic-related air pollutants, cause pulmonary and systemic inflammation that is mediated by redox-sensitive signaling pathways. Assessment of human responses to traffic-related air pollution under realistic conditions is challenging due to the complex, dynamic nature of near-roadway exposure. Noninvasive measurement of biomarkers in breath and breath condensate may be particularly useful for evaluating the role of oxidative stress in acute responses to exposures that occur in vehicles or during near-roadway activities. Promising biomarkers include nitric oxide in exhaled breath, and nitrite/nitrate, malondialdehyde, and F2-isoprostanes in exhaled breath condensate.
air pollution; traffic; oxidative stress; exhaled breath; airways; biomarkers
Two kinds of evidence suggest that female fertility may end at an earlier age in modern people than in ancestral populations or in our closest living relatives, chimpanzees. We investigate both to see whether fertility schedules or ovarian follicle counts falsify the alternative hypothesis that the age of terminal fertility changed little in the human lineage while greater longevity evolved due to grandmother effects. We use 19th century Utah women to represent non-contracepting humans, and compare their fertility by age with published records for wild chimpanzees. Then we revisit published counts of ovarian follicular stocks in both species. Results show wide individual variation in age at last birth and oocyte stocks in both humans and chimpanzees. This heterogeneity, combined with interspecific differences in adult mortality, has large and opposing effects on fertility schedules. Neither realized fertility nor rates of follicular atresia stand as evidence against the hypothesis that ages at last birth changed little while greater longevity evolved in our lineage.
grandmother hypothesis; fertility decline; menopause; heterogeneity; follicular depletion; chimpanzee comparisons
Sulfur mustard (SM) is a chemical weapon that targets the skin, eyes, and lung. It was first employed during World War I and it remains a significant military and civilian threat. As a bifunctional alkylating agent, SM reacts with a variety of macromolecules in target tissues including nucleic acids, proteins and lipids, as well as small molecular weight metabolites such as glutathione. By alkylating subcellular components, SM disrupts metabolism, a process that can lead to oxidative stress. Evidence for oxidative stress in tissues exposed to SM or its analogs include increased formation of reactive oxygen species, the presence of lipid peroxidation products and oxidized proteins, and increases in antioxidant enzymes such as superoxide dismutase, catalase, and glutathione-S-transferase. Inhibition of antioxidant enzymes including thioredoxin reductase by SM can also disrupt cellular redox homeostasis. Consistent with these findings, SM-induced toxicity has been shown to be reduced by antioxidants in both in vitro and in vivo models. These data indicate that drugs that target oxidative stress pathways may represent important candidates for reducing SM-induced tissue injury.
oxidative stress; reactive oxygen species; nitric oxide; vesicants; dermatotoxicity
Despite an increasing number of military service members in need of mental health treatment following deployment to Iraq and Afghanistan, numerous psychological and practical barriers limit access to care. Perceived stigma about admitting psychological difficulties as well as frequent long distances to treatment facilities reduce many veterans' willingness and ability to receive care. Telemedicine and virtual human technologies offer a unique potential to expand services to those in greatest need. Telemedicine-based treatment has been used to address multiple psychiatric disorders, including posttraumatic stress disorder, depression, and substance use, as well as to provide suicide risk assessment and intervention. Clinician education and training has also been enhanced and expanded through the use of distance technologies, with trainees practicing clinical skills with virtual patients and supervisors connecting with clinicians via videoconferencing. The use of these innovative and creative vehicles offer a significant and as yet unfulfilled promise to expand delivery of high quality psychological therapies, regardless of clinician and patient location.
telemedicine; virtual reality; videoconferencing; barriers to care; OIF/OEF veterans