The adverse effects of alcohol on the developing human represent a spectrum of structural anomalies and behavioral and neurocognitive disabilities, most accurately termed fetal alcohol spectrum ...disorders (FASD). The first descriptions in the modern medical literature of a distinctly recognizable pattern of malformations associated with maternal alcohol abuse were reported in 1968 and 1973. Since that time, substantial progress has been made in developing specific criteria for defining and diagnosing this condition. Two sets of diagnostic criteria are now used most widely for evaluation of children with potential diagnoses in the FASD continuum, ie, the 1996 Institute of Medicine (IOM) criteria and the Washington criteria. Although both approaches have improved the clinical delineation of FASD, both suffer from significant drawbacks in their practical application in pediatric practice.
The purpose of this report is to present specific clarifications of the 1996 IOM criteria for the diagnosis of FASD, to facilitate their practical application in clinical pediatric practice.
A large cohort of children who were prenatally exposed to alcohol were identified, through active case-ascertainment methods, in 6 Native American communities in the United States and 1 community in the Western Cape Province of South Africa. The children and their families underwent standardized multidisciplinary evaluations, including a dysmorphology examination, developmental and neuropsychologic testing, and a structured maternal interview, which gathered data about prenatal drinking practices and other demographic and family information. Data for these subjects were analyzed, and revisions and clarifications of the existing IOM FASD diagnostic categories were formulated on the basis of the results.
The revised IOM method defined accurately and completely the spectrum of disabilities among the children in our study. On the basis of this experience, we propose specific diagnostic criteria for fetal alcohol syndrome and partial fetal alcohol syndrome. We also define alcohol-related birth defects and alcohol-related neurodevelopmental disorder from a practical standpoint.
The 1996 IOM criteria remain the most appropriate diagnostic approach for children prenatally exposed to alcohol. The proposed revisions presented here make these criteria applicable in clinical pediatric practice.
Background
The prevalence and characteristics of fetal alcohol spectrum disorders (FASD) were determined in this fourth study of first‐grade children in a South African community.
Methods
Active case ...ascertainment methods were employed among 747 first‐grade pupils. The detailed characteristics of children within the continuum of FASD are contrasted with randomly selected, normal controls on (i) physical growth and dysmorphology; (ii) cognitive/behavioral characteristics; and (iii) maternal risk factors.
Results
The rates of specific diagnoses within the FASD spectrum continue to be among the highest reported in any community in the world. The prevalence (per 1,000) is as follows: fetal alcohol syndrome (FAS)—59.3 to 91.0; partial fetal alcohol syndrome (PFAS)—45.3 to 69.6; and alcohol‐related neurodevelopmental disorder (ARND)—30.5 to 46.8. The overall rate of FASD is therefore 135.1 to 207.5 per 1,000 (or 13.6 to 20.9%). Clinical profiles of the physical and cognitive/behavioral traits of children with a specific FASD diagnosis and controls are provided for understanding the full spectrum of FASD in a community. The spectral effect is evident in the characteristics of the diagnostic groups and summarized by the total (mean) dysmorphology scores of the children: FAS = 18.9; PFAS = 14.3; ARND = 12.2; and normal controls, alcohol exposed = 8.2 and unexposed = 7.1. Documented drinking during pregnancy is significantly correlated with verbal (r = −0.253) and nonverbal ability (r = −0.265), negative behaviors (r = 0.203), and total dysmorphology score (r = 0.431). Other measures of drinking during pregnancy are significantly associated with FASD, including binge drinking as low as 3 drinks per episode on 2 days of the week.
Conclusions
High rates of specific diagnoses within FASD were well documented in this new cohort of children. FASD persists in this community. The data reflect an increased ability to provide accurate and discriminating diagnoses throughout the continuum of FASD.
Tumours are abnormal growths of cells that reproduce by redirecting essential nutrients and resources from surrounding tissue. Changes to cell metabolism that trigger the growth of tumours are ...reflected in subtle differences between the chemical composition of healthy and malignant cells. We used LA-ICP-MS imaging to investigate whether these chemical differences can be used to spatially identify tumours and support detection of primary colorectal tumours in anatomical pathology. First, we generated quantitative LA-ICP-MS images of three colorectal surgical resections with case-matched normal intestinal wall tissue and used this data in a Monte Carlo optimisation experiment to develop an algorithm that can classify pixels as tumour positive or negative. Blinded testing and interrogation of LA-ICP-MS images with micrographs of haematoxylin and eosin stained and Ki67 immunolabelled sections revealed Monte Carlo optimisation accurately identified primary tumour cells, as well as returning false positive pixels in areas of high cell proliferation. We analysed an additional 11 surgical resections of primary colorectal tumours and re-developed our image processing method to include a random forest regression machine learning model to correctly identify heterogenous tumours and exclude false positive pixels in images of non-malignant tissue. Our final model used over 1.6 billion calculations to correctly discern healthy cells from various types and stages of invasive colorectal tumours. The imaging mass spectrometry and data analysis methods described, developed in partnership with clinical cancer researchers, have the potential to further support cancer detection as part of a comprehensive digital pathology approach to cancer care through validation of a new chemical biomarker of tumour cells.
Digital pathology and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging reveals a unique elemental signature of colorectal cancer.
The induction of beige adipocytes in s.c. white adipose tissue (WAT) depots of humans is postulated to improve glucose and lipid metabolism in obesity. The ability of obese, insulin-resistant humans ...to induce beige adipose tissue is unknown.
We exposed lean and obese research participants to cold (30-minute ice pack application each day for 10 days of the upper thigh) or treated them with the β3 agonist mirabegron. We determined beige adipose marker expression by IHC and quantitative PCR, and we analyzed mitochondrial bioenergetics and UCP activity with an Oxytherm system.
Cold significantly induced UCP1 and TMEM26 protein in both lean and obese subjects, and this response was not associated with age. Interestingly, these proteins increased to the same extent in s.c. WAT of the noniced contralateral leg, indicating a crossover effect. We further analyzed the bioenergetics of purified mitochondria from the abdominal s.c. WAT of cold-treated subjects and determined that repeat ice application significantly increased uncoupled respiration, consistent with the UCP1 protein induction and subsequent activation. Cold also increased State 3 and maximal respiration, and this effect on mitochondrial bioenergetics was stronger in summer than winter. Chronic treatment (10 weeks; 50 mg/day) with the β3 receptor agonist mirabegron induces UCP1, TMEM26, CIDEA, and phosphorylation of HSL on serine660 in obese subjects.
Cold or β3 agonists cause the induction of beige adipose tissue in human s.c. WAT; this phenomenon may be exploited to increase beige adipose in older, insulin-resistant, obese individuals.
Clinicaltrials.gov NCT02596776, NCT02919176.
NIH (DK107646, DK112282, P20GM103527, and by CTSA grant UL1TR001998).
Atrial fibrillation (AF) is the most common cardiac dysrhythmia and a source of considerable morbidity and mortality, but lifetime risk for AF has not been estimated.
We included all participants in ...the Framingham Heart Study who were free of AF at index ages of 40 years and older. We estimated lifetime risks for AF (including atrial flutter) to age 95 years, with death free of AF as a competing event. We followed 3999 men and 4726 women from 1968 to 1999 (176 166 person-years); 936 participants had development of AF and 2621 died without prior AF. At age 40 years, lifetime risks for AF were 26.0% (95% CI, 24.0% to 27.0%) for men and 23.0% (21.0% to 24.0%) for women. Lifetime risks did not change substantially with increasing index age despite decreasing remaining years of life because AF incidence rose rapidly with advancing age. At age 80 years, lifetime risks for AF were 22.7% (20.1% to 24.1%) in men and 21.6% (19.3% to 22.7%) in women. In further analyses, counting only those who had development of AF without prior or concurrent congestive heart failure or myocardial infarction, lifetime risks for AF were approximately 16%.
Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies.
Exposure to alcohol in utero can cause birth defects, including face and brain abnormalities, and is the most common preventable cause of intellectual disabilities. Here we use structural magnetic ...resonance imaging to measure cortical volume change longitudinally in a cohort of human children and youth with prenatal alcohol exposure (PAE) and a group of unexposed control subjects, demonstrating that the normal processes of brain maturation are disrupted in individuals whose mothers drank heavily during pregnancy. Trajectories of cortical volume change within children and youth with PAE differed from those of unexposed control subjects in posterior brain regions, particularly in the parietal cortex. In these areas, control children appear to show a particularly plastic cortex with a prolonged pattern of cortical volume increases followed by equally vigorous volume loss during adolescence, while the alcohol-exposed participants showed primarily volume loss, demonstrating decreased plasticity. Furthermore, smaller volume changes between scans were associated with lower intelligence and worse facial morphology in both groups, and were related to the amount of PAE during each trimester of pregnancy in the exposed group. This demonstrates that measures of IQ and facial dysmorphology predict, to some degree, the structural brain development that occurs in subsequent years. These results are encouraging in that interventions aimed at altering "experience" over time may improve brain trajectories in individuals with heavy PAE and possibly other neurodevelopmental disorders.
Atrial fibrillation (AF) is the most common cardiac dysrhythmia in the United States. Whereas rare cases of familial AF have been reported, it is unknown if AF among unselected individuals is a ...heritable condition.
To determine whether parental AF increases the risk for the development of offspring AF.
Prospective cohort study (1983-2002) within the Framingham Heart Study, a population-based epidemiologic study. Participants were 2243 offspring (1165 women, 1078 men) at least 30 years of age and free of AF whose parents had both been evaluated in the original cohort.
Development of new-onset AF in the offspring was prospectively examined in association with previously documented parental AF.
Among 2243 offspring participants, 681 (30%) had at least 1 parent with documented AF; 70 offspring participants (23 women; mean age, 62 range, 40-81 years) developed AF in follow-up. Compared with no parental AF, AF in at least 1 parent increased the risk of offspring AF (multivariable-adjusted odds ratio OR, 1.85; 95% confidence interval CI, 1.12-3.06; P =.02). These results were stronger when age was limited to younger than 75 years in both parents and offspring (multivariable-adjusted OR, 3.23; 95% CI, 1.87-5.58; P<.001) and when the sample was further limited to those without antecedent myocardial infarction, heart failure, or valve disease (multivariable-adjusted OR, 3.17; 95% CI, 1.71-5.86; P<.001).
Parental AF increases the future risk for offspring AF, an observation supporting a genetic susceptibility to developing this dysrhythmia. Further research into the genetic factors predisposing to AF is warranted.
The cancer stem cell hypothesis suggests that malignant growth depends on a subset of tumor cells with stem cell-like properties of self-renewal. Because hedgehog (Hh) signaling regulates progenitor ...cell fate in normal development and homeostasis, aberrant pathway activation might be involved in the maintenance of such a population in cancer. Indeed, mutational activation of the Hh pathway is associated with medulloblastoma and basal cell carcinoma; pathway activity is also critical for growth of other tumors lacking such mutations, although the mechanism of pathway activation is poorly understood. Here we study the role and mechanism of Hh pathway activation in multiple myeloma (MM), a malignancy with a well defined stem cell compartment. In this model, rare malignant progenitors capable of clonal expansion resemble B cells, whereas the much larger tumor cell population manifests a differentiated plasma cell phenotype that pathologically defines the disease. We show that the subset of MM cells that manifests Hh pathway activity is markedly concentrated within the tumor stem cell compartment. The Hh ligand promotes expansion of MM stem cells without differentiation, whereas the Hh pathway blockade, while having little or no effect on malignant plasma cell growth, markedly inhibits clonal expansion accompanied by terminal differentiation of purified MM stem cells. These data reveal that Hh pathway activation is heterogeneous across the spectrum of MM tumor stem cells and their more differentiated progeny. The potential existence of similar relationships in other adult cancers may have important biologic and clinical implications for the study of aberrant Hh signaling.
Decades of research have suggested that all positive affective states broaden attention. Recent studies have found that positive affects high in approach motivation narrow attention, whereas positive ...affects low in approach motivation broaden attention. However, these studies were limited because they used only affective pictures to manipulate positive affect. The pictures, rather than the affective states created by them, may have caused individuals to focus on the emotional details of the picture, and this attentional focus may have caused the narrowing of attentional scope. Moreover, no experiment has yet to examine both low and high approach-motivated positive affect within the same individuals in the same study. The current experiments manipulated pregoal (high approach) and postgoal (low approach) positive states by giving participants the opportunity to win money on a game. Results revealed that pregoal positive affect caused a narrowing of attention, whereas postgoal positive affect caused a broadening of attention.
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