Immunohistochemical characterization of lymphosarcoma in two alpacas (Lama pacos)

Species cross-reactive anti-peptide antibodies were assessed in formalin-fixed tissue for use in immunophenotyping of lymphosarcoma in two alpacas. Diagnosis of lymphosarcoma was made by routine histopathological examination. Primary antibodies used for immunophenotyping were anti-human CD3 and anti-human CD5 for T cells; and anti-human CD79a and anti-human CD79b for B cells/plasma cells. In one case, most of the neoplastic cells were labelled with both anti-CD3 and anti-CD79b, and smaller numbers were labelled with anti-CD79a. The other case was classified as a B-cell tumour on the basis of labelling of the majority of neoplastic cells with anti-CD79b and anti-CD79a. This is the first recorded attempt at immunophenotyping lymphosarcoma in alpacas and, to our knowledge, the first record of presumptive co-expression of T- and B-cell-associated molecules in lymphosarcoma in the veterinary literature.     

Heterogeneity for congenital generalized lipodystrophy in seventeen patients from Oman

Seventeen children with congenital generalized lipodystrophy or Berardinelli-Seip Congenital Lipodystrophy (BSCL) from 12 consanguineous sibships were observed in Oman. All children had widespread absence of adipose tissue from infancy together with apparent muscle hypertrophy and hepatomegaly. They did not appear to represent a single homogenous entity, and it was possible to subclassify the cases into two distinct groups. In the first group of seven cases, the features were similar to other published cases with acanthosis nigricans, raised insulin levels, and insulin resistance. In this group, there was an association between the degree of acanthosis nigricans and the severity of the disorder. Molecular analysis of these cases showed homozygosity at the BSCL2 locus on chromosome 11q13 in four of the seven cases. In the second group of ten cases, there were striking abnormalities in both skeletal and nonskeletal muscle. Reduced exercise tolerance and percussion myoxedema were observed in skeletal muscle, while infantile hypertrophic pyloric stenosis, prominent veins (phlebomegaly), disturbance of cardiac rhythm, and cardiomyopathy were observed in nonskeletal muscle. There was evidence against homozygosity in some cases for the known loci for BSCL, and this group may represent a new clinical syndrome with lipodystrophy at a different genetic location.     

Dirofilaria immitis encodes Di-nhr-7, a putative orthologue of the Drosophila ecdysone-regulated E78 gene

Filarial parasites are responsible for several serious human diseases with symptoms such as lymphoedema, elephantiasis, and blindness. An understanding of how these parasites pass through developmental checkpoints may elucidate the general mechanisms of these illnesses and suggest potential targets for intervention. A useful model system for the study of human filariasis is the related nematode Dirofilaria immitis, the causative agent of dog heartworm disease. In D. immitis, molting from the third to the fourth larval stage can be induced in vitro by the insect hormone 20-OH ecdysone, suggesting that ecdysone, or some related hormone, may play a similar role in the development of D. immitis. Ecdysone has a well-characterized developmental role in insects, where it is involved in the control of molting and metamorphosis. We have identified a D. immitis orthologue of the Drosophila ecdysone response early gene E78, a member of the nuclear receptor (NR) superfamily. The D. immitis gene, Di-nhr-7 (NR1E1) encodes at least three isoforms, including two potential negative regulatory isoforms, and is expressed in a sex-specific manner. An MBP/Di-NHR-7 fusion protein is able to bind to DNA response elements that are recognized by the closely related mammalian NR Rev-erb(alpha).     

Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype

Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause an autosomal recessive fatal disorder called Lafora's disease (LD) classically described as an adolescent-onset stimulus-sensitive myoclonus, epilepsy and neurologic deterioration. Here we related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified two subsyndromes: (i) classical LD with adolescent-onset stimulus-sensitive grand mal, absence and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (P = 0.0007); (ii) atypical LD with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (P = 0.0015). To understand the two subsyndromes better, we investigated the effect of five missense mutations in the carbohydrate-binding domain (CBD-4; coded by exon 1) and three missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's intracellular localization in HeLa cells. Expression of three mutant proteins (T194I, G279S and Y294N) in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the three CBD-4 mutants showed cytoplasmic clumping. However, CBD-4 mutants W32G and R108C targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. Our data, thus, represent the first report of a novel childhood syndrome for LD. Our results also provide clues for distinct roles for the CBD-4 and DSP domains of laforin in the etiology of two subsyndromes of LD.     

Decision making in health care: limitations of the substituted judgement principle

The substituted judgement principle is often recommended as a means of promoting the self-determination of an incompetent individual when proxy decision makers are faced with having to make decisions about health care. This article represents a critical ethical analysis of this decision-making principle and describes practical impediments that serve to undermine its fundamental purpose. These impediments predominantly stem from the informality associated with the application of the substituted judgement principle. It is recommended that the principles upon which decisions are made about health care for another person should be transparent to all those involved in the process. Furthermore, the substituted judgement principle requires greater rigour in its practical application than currently tends to be the case. It may be that this principle should be subsumed as a component of advance directives in order that it fulfils its aim of serving to respect the self-determination of incompetent individuals.     

Percentage of body fat and body mass index are associated with mobility limitations in people aged 70 and older from NHANES III

OBJECTIVES: To assess the association between functional limitations and body composition indices, including percentage of body fat, muscle mass, and body mass index (BMI). DESIGN: A cross-sectional, population-representative sample. SETTING: All noninstitutionalized people living in the United States (National Health and Nutrition Examination Survey). Data were collected between 1988 and 1994. PARTICIPANTS: One thousand five hundred twenty-six women and 1,391 men aged 70 and older. MEASUREMENTS: Independent variables included BMI, muscle mass, and percentage of body fat; the latter two were assessed using predictive equations. The dependent variable, functional limitations, was defined as difficulty in performing at least three of five functional living tasks, such as carrying a 10-pound bag of groceries. RESULTS: Women in the highest quintile for percentage of body fat and women with a BMI of 30 or greater were two times more likely to report functional limitations than women in the comparison groups. Similar, but weaker, relationships were found among men; men in the highest quintile for body fat and men with a BMI of 35 or greater were 1.5 times more likely to report limitations. Low muscle mass (sarcopenia) and sarcopenia in combination with high percentage of body fat (sarcopenic obesity) were not associated with a greater likelihood of reporting functional limitations. CONCLUSIONS: Prevention of excessive accumulation of body fat and maintenance of a BMI in the normal range may reduce the likelihood of functional limitations in old age.     

Association of forced expiratory volume with disease duration and sputum neutrophils in chronic asthma

Some patients with chronic asthma develop irreversible airflow obstruction. Our aim was to assess whether reported duration of asthma and induced sputum cell counts were associated with pulmonary function in patients with asthma who did not smoke.Maximal forced expiratory volume in the first second (FEV(1)) was determined following a steroid trial (oral prednisolone, 30 mg/d [n = 92 patients]; or inhaled fluticasone, 2000 microg/d [n = 5]; for 2 weeks) and 2.5 mg of nebulized albuterol. Asthma history was recorded with duration from first diagnosis. All subjects were nonsmokers, or were to have stopped smoking > or =5 years previously and smoked < or =5 pack-years (n = 12). Induced sputum was obtained from 59 subjects for analysis of airway cell counts.Maximal FEV(1) was inversely associated with asthma duration (r = -0.47, P <0.0001), age (r = -0.40, P <0.0001), and the proportion of sputum neutrophils (r(s) = -0.50, P = 0.00004). After adjusting for age, both duration of disease and sputum neutrophils were independently associated with maximal FEV(1). Neutrophil activation, as measured by sputum myeloperoxidase levels, was positively associated with the proportion of sputum neutrophils (r(s) = 0.45, P = 0.0004) and inversely associated with maximal FEV(1) (r(s) = -0.59, P <0.0001).Long disease duration may be a predisposing factor for the development of irreversible airflow obstruction in patients with chronic asthma. The negative associations of sputum neutrophil count and activation with maximal FEV(1) suggest that neutrophils may be involved in the pathophysiology of irreversible airflow obstruction in asthma.     

A closer look at Neanderthal postcanine dental morphology: the mandibular dentition

Neanderthals are known to exhibit unique incisor morphology as well as enlarged pulp chambers in postcanine teeth (taurodontism). Recent studies suggest that their overall dental pattern (i.e., in morphologic trait frequencies) is also unique. However, what this means in a phylogenetic sense is not known. Although exploring the polarity of dental morphologic characters is essential to understanding the phylogenetic implications of unique patterns of variation, few have undertaken this task. This study moves beyond standard scoring methods, which are based on modern humans, to include several postcanine traits that have not been considered previously. In addition, Homo erectus is used as an outgroup to Neanderthals and modern humans to explore the polarity of these traits. The findings of this study suggest that Neanderthals are not only unique in their pattern of dental trait frequencies (as found in previous studies) but that they present several dental autapomorphies, as well. These include a high frequency of the mid-trigonid crest in lower molars and unique morphology of the lower premolars. Interestingly, these characters are not observed in the Mauer mandible, which some have claimed to be a member of a chronospecies that is a unique ancestor to Neanderthals.