A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit ...double-digit-picomolar binding affinities for the α4β2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure−activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds.
Whole-genome association studies are predicted to be especially powerful in isolated populations owing to increased linkage disequilibrium (LD) and decreased allelic diversity, but this possibility ...has not been empirically tested. We compared genome-wide data on 113,240 SNPs typed on 30 trios from the Pacific island of Kosrae to the same markers typed in the 270 samples from the International HapMap Project. The extent of LD is longer and haplotype diversity is lower in Kosrae than in the HapMap populations. More than 98% of Kosraen haplotypes are present in HapMap populations, indicating that HapMap will be useful for genetic studies on Kosrae. The long-range LD around common alleles and limited diversity result in improved efficiency in genetic studies in this population and augments the power to detect association of 'hidden SNPs'.
Decitabine produced responses in patients with acute myeloid leukemia or myelodysplastic syndromes who had cytogenetic abnormalities associated with a poor prognosis, including 21 of 21 patients with ...tumors that contained
TP53
mutations.
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are clonal disorders of myeloid hematopoiesis.
1
Adult patients with AML who have karyotypes that are associated with unfavorable risk and older patients with AML (≥60 years of age) have poor outcomes, with a median survival of approximately 1 year.
2
,
3
Patients with AML and
TP53
mutations tend to be older (median age, 61 to 67 years), and almost all have karyotypes that are associated with unfavorable risk; if they receive standard cytotoxic chemotherapy, these patients have especially poor outcomes (median survival, 4 to 6 months).
3
–
6
Decitabine (5-aza-2′-deoxycytidine) is commonly used as . . .
Background Ischemic mitral regurgitation, a complication of myocardial infarction and coronary artery disease more generally, is associated with a high mortality rate and is estimated to affect 2.8 ...million Americans. With 1-year mortality rates as high as 40%, recent practice guidelines of professional societies recommend repair or replacement, but there remains a lack of conclusive evidence supporting either intervention. The choice between therapeutic options is characterized by the trade-off between reduced operative morbidity and mortality with repair versus a better long-term correction of mitral insufficiency with replacement. The long-term benefits of repair versus replacement remain unknown, which has led to significant variation in surgical practice. Methods and Results This article describes the design of a prospective randomized clinical trial to evaluate the safety and effectiveness of mitral valve repair and replacement in patients with severe ischemic mitral regurgitation. This trial is being conducted as part of the Cardiothoracic Surgical Trials Network. This article addresses challenges in selecting a feasible primary end point, characterizing the target population (including the degree of mitral regurgitation) and analytical challenges in this high mortality disease. Conclusions The article concludes by discussing the importance of information on functional status, survival, neurocognition, quality of life, and cardiac physiology in therapeutic decision making.
Multiple myeloma is a neoplastic plasma cell dyscrasia that on a yearly basis affects nearly 17,000 individuals and kills more than 11,000. Although no cure exists, many effective treatments are ...available that prolong survival and improve the quality of life of patients with this disease. The purpose of this consensus is to offer a simplified, evidence-based algorithm of decision making for patients with newly diagnosed myeloma. In cases in which evidence is lacking, our team of 18 Mayo Clinic myeloma experts reached a consensus on what therapy could generally be recommended. The focal point of our strategy revolves around risk stratification. Although a multitude of risk factors have been identified throughout the years, including age, tumor burden, renal function, lactate dehydrogenase, β2 -microglobulin, and serum albumin, our group has now recognized and endorsed a genetic stratification and patient functional status for treatment.
“U” curve association of blood pressure and mortality in hemodialysis patients.
Hypertension may play an important role in the pathogenesis of the excess cardiovascular and cerebrovascular (CV) ...morbidity observed in hemodialysis patients (HD). However, the optimal blood pressure (BP) range for HD patients has not been defined. We postulated that there is a “U” curve relationship between BP and CV mortality. To explore this hypothesis we studied 5,433 HD patients in Dialysis Clinic Inc., a large not-for-profit chain, over a five year period.
Cox regression, with fixed and time-varying covariates, was used to assess the effect of systolic blood pressure (SBP) and diastolic blood pressure (DBP), pre- and post-dialysis, on CV mortality, while adjusting for age, gender, ethnicity, primary cause of end-stage renal disease, Kt/V, serum albumin, and antihypertensive medications.
The overall impact of BP on CV mortality was modest. Pre-dialysis, neither systolic nor diastolic hypertension were associated with an increase in CV mortality. Post-dialysis, SBP ≥ 180mm Hg (RR = 1.96, P < 0.015) and DBP ≥ 90mm Hg (RR = 1.73, P < 0.05) were associated with increased CV mortality. Low SBP (SBP < 110mm Hg) was associated with increased CV mortality, pre- and post-dialysis.
The results suggest the presence of a “U” curve relationship between SBP post-dialysis and CV mortality in HD patients.
ABSTRACT
KIF1A is a neuron‐specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic ...paraparesis or sensory and autonomic neuropathy type‐2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.
De novo (genetic changes not transmitted from the parents) missense mutations targeting conserved residues in the motor domain of the neuron‐specific motor protein KIF1A alters its activity and cause a complex neurologic phenotype characterized by severe developmental delay and/or intellectual disability, as well as variable cerebellar atrophy, visual loss, spastic paraparesis, peripheral neuropathy and epilepsy.
The current generation of coupled climate models run at the Geophysical Fluid Dynamics Laboratory (GFDL) as part of the Climate Change Science Program contains ocean components that differ in almost ...every respect from those contained in previous generations of GFDL climate models. This paper summarizes the new physical features of the models and examines the simulations that they produce. Of the two new coupled climate model versions 2.1 (CM2.1) and 2.0 (CM2.0), the CM2.1 model represents a major improvement over CM2.0 in most of the major oceanic features examined, with strikingly lower drifts in hydrographic fields such as temperature and salinity, more realistic ventilation of the deep ocean, and currents that are closer to their observed values. Regional analysis of the differences between the models highlights the importance of wind stress in determining the circulation, particularly in the Southern Ocean. At present, major errors in both models are associated with Northern Hemisphere Mode Waters and outflows from overflows, particularly the Mediterranean Sea and Red Sea.
The immaturity of the immune system increases the susceptibility of young infants to infectious diseases and prevents the induction of protective immune responses by vaccines. We previously reported ...that Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination induces a potent Th1 response to mycobacterial Ags in newborns. In this study, we evaluated the influence of BCG on the response to unrelated vaccines given in early life. Newborns were randomly allocated to one of three study groups receiving BCG at birth, when infants received their first dose of hepatitis B and oral polio vaccines; at 2 mo of age, when infants received their first dose of diphtheria and tetanus vaccines; or at 4.5 mo of age, when immune responses to vaccines were measured. Administration of BCG at the time of priming markedly increased the cellular and Ab responses to the hepatitis B vaccine, but had only a limited influence on the cytokine response to tetanus toxoid and no effect on the Ab responses to tetanus and diphtheria toxoids. Although BCG induced a potent Th1-type response to mycobacterial Ags, it promoted the production of both Th1- and Th2-type cytokines in response to unrelated vaccines. The effect of BCG was apparent at the systemic level, as it increased the Ab response to oral polio vaccine. These results demonstrate that BCG influences the immune response to unrelated Ags in early life, likely through its influence on the maturation of dendritic cells.
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