Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology.

Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers. A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation. Using antibodies specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in A beta 42, but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A beta 42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyloid precursor protein at the C-terminus of A beta to favor deposition of A beta 42.

[Improvements in lung preservation: 3 years' experience with a low-potassium dextran solution]. / Mejoras en la preservación pulmonar. Tres años de experiencia con una solución de dextrano bajo en potasio.

OBJECTIVE: Lung preservation quality is a crucial factor in the success of a lung transplant. In October 2000 we stopped using Euro-Collins (EC) lung preservation solution and began using a low potassium dextran solution (Perfadex [PER]). The objective of the present study was to assess outcome with the 2 solutions. MATERIAL AND METHODS: We analyzed the results of 68 lung transplants in which PER was used and compared the results with those of a historical control group consisting of the same number of transplants in which EC was used. RESULTS: There were no significant differences in the ages and diagnoses of the recipients in the 2 groups. Waiting list time was longer in the PER group. The most frequent cause of donor death in the EC group was craniocerebral trauma (62%), whereas in the PER group it was cerebral hemorrhage (54%). In the PER group more double lung transplants were performed than in the EC group (78% and 53% respectively; P=.002). There were no differences in the use of extracorporal circulation or ischemia time between the 2 groups. Early graft function, based on the patient's oxygenation index (ratio of PaO2 to inspired oxygen fraction [FiO2]) on arrival at the intensive care unit, was similar in the 2 groups. The incidence of severe graft failure (PaO2/FiO2<150 mm Hg) was significantly lower in the PER group than in the EC group (16% and 37% respectively; P=.01). No significant differences in hours of mechanical ventilation or postoperative mortality between the 2 patient series were found. CONCLUSIONS: Use of the newer lung preservation solution --PER-- led to a 50% lower incidence of severe ischemia-reperfusion graft injury during the early recovery from lung transplantation.

Estimación en la Intención de Agarres: Cilíndrico, Esférico y Gancho Utilizando Redes Neuronales Profundas / Estimation of Hand-Grip Intention: Cylindrical, Spherical and Hook Using Deep Neural Networks

Resumen Las amputaciones de extremidades superiores pueden producir diversos grados de incapacidad en la persona afectada, esto es exacerbado aún más, si se presenta durante un periodo de su vida laboral activa, por esta razón es de importancia social el estudio de las prótesis y algoritmos que ayuden a un mejor control de estas por parte del usuario. En esta investigación, se propone una arquitectura basada en redes neuronales recurrentes del tipo Long Short-Term Memory y redes convolucionales para la clasificación de señales electromiográficas, con aplicaciones para control de prótesis de mano. La red propuesta clasifica tres tipos de agarres realizados con la mano: cilíndrico, esférico y de gancho. El modelo propuesto al ser evaluado mostró una eficiencia (accuracy) del 89 %, en contraste con una red neuronal artificial basada en capas completamente conectadas que solo obtuvo una eficiencia del 80% en la predicción de los agarres. El presente trabajo se limita solamente a evaluar la red ante una entrada de electromiograma y no se implementó un sistema de control para la prótesis de la mano. Así, una arquitectura de redes convolucionales para el control de prótesis de mano que pueden ser entrenadas con las señales del sujeto.

Abstract Upper extremities amputations can produce different disability degrees in the amputated person, this is acerbated even more, when it happens during active working life. So, for this reason, it is of social importance the study of prostheses and algorithms that help a better control of these by the user. In this research, we propose an architecture based on recurrent neural networks, called Long Short-Term Memory, and convolutional neural networks for classification of electromyographic signals, with applications for hand prosthesis control. The proposed network classifies three types of movements made by the hand: cylindrical, spherical and hook grips. The proposed model showed an efficiency (accuracy) of 89%, in contrast to an artificial neural network based on completely connected layers that only obtained an efficiency of 80% in the prediction of the hand movements. The present work is limited to evaluate the network with an electromyogram input, the control system for hand prosthesis was not implemented. Thus, an architecture of convolutional networks for the control of hand prostheses that can be trained with the signals of the subject.

Presenilin-1-associated abnormalities in regional cerebral perfusion.

OBJECTIVE: To investigate the influence of the presenilin-1 gene (PS-1) mutation on regional cerebral perfusion, SPECT was evaluated in 57 individuals. The subjects were members of a large pedigree from Colombia, South America, many of whom carry a PS-1 mutation for early-onset AD. METHODS: Members of this large kindred who were cognitively normal and did not carry the PS-1 mutation (n = 23) were compared with subjects who were carriers of the mutation but were asymptomatic (n = 18) and with individuals with the mutation and a clinical diagnosis of AD (n = 16). Cerebral perfusion was measured in each subject using hexamethylpropyleneamine oxime SPECT. The data were analyzed in two ways: 1) Mean cerebral perfusion in each of 4320 voxels in the brain was compared among the groups using t-tests (t-maps); and 2) each individual received a weighted score on 20 vectors (factors), based on a large normative sample (n = 200), using a method known as singular value decomposition (SVD). RESULTS: Based on t-maps, subjects with the PS-1 mutation who were asymptomatic demonstrated reduced perfusion in comparison with the normal control subjects in the hippocampal complex, anterior and posterior cingulate, posterior parietal lobe, and anterior frontal lobe. The AD patients demonstrated decreased perfusion in the posterior parietal and superior frontal cortex in comparison with the normal control subjects. Discriminant function analysis of the vector scores derived from SVD (adjusted for age and gender) accurately discriminated 86% of the subjects in the three groups (p < 0.0005). CONCLUSION: Regional cerebral perfusion abnormalities based on SPECT are detectable before development of the clinical symptoms of AD in carriers of the PS-1 mutation.

Flow cytometric analysis of surface major histocompatibility complex class II expression on human epithelial cells prepared from small intestinal biopsies.

A technique for preparing viable, single cell suspensions of the epithelial layer of small intestinal tissue obtained endoscopically is described. Constant agitation of four biopsies for 60 min in the presence of chelating and reducing agents gave yields of 1.2-6.7 x 10(6) cells, of which 11-30% were intraepithelial lymphocytes (IEL). Passage through a nylon wool column removed dead cells. This preparation was suitable for flow cytometric analysis. Using this technique, surface MHC class II molecule expression was studied in 14 patients with normal small intestinal mucosa. Fluorescence labelling of these cells showed strong HLA-DR expression by epithelial cells (EC), DP was expressed less strongly, while little DQ expression could be detected. This technique demonstrates that small intestinal biopsies taken during routine endoscopy can yield adequate numbers of viable epithelial cells to perform flow cytometric analysis.

Evaluation of the thromboxane A2 synthetase inhibitor OKY-046 in a warm ischemia-reperfusion rat model.

The pathophysiology of ischemia-reperfusion renal injury is mediated, in part, by the generation of the vasoconstricting prostanoid thromboxane A2 (TXA2). This study was undertaken to evaluate the renoprotective effects, as well as the optimal timing and dosage, of a selective thromboxane synthetase inhibitor, OKY-046, in a unilateral nephrectomized, 60 min ischemia, 72 hr reperfusion, rodent model. Forty-one rats were subjected to right nephrectomy only (group A), or right nephrectomy with 60 min of left renal ischemia and treatment with inactive vehicle only (group B), or 2 mg/kg or 4 mg/kg of OKY-046 administered intravenously before (groups C and D) or after (groups E and F) pedicle clamping. Outcome variables included animal survival; change in kidney weight; 0, 24, and 72 hr plasma creatinine (CR); urea nitrogen (BUN); thromboxane B2 (TXB2) and 6-keto prostaglandin F(1alpha) (6 kPGF(2alpha)) levels; creatinine clearance (CRCL); and histologic evidence of renal injury. Animal survival and postperfusion kidney weight were not significantly different among the groups. However, renal functional parameters were significantly improved with the 2 mg/kg dose of OKY-046 administered after renal ischemia. (group B 72 hr Cr= 8.01 +/- 1.1 mg% vs. group E=3.99 +/- 1.5 mg%, and group B 72 hr BUN=241.3 +/- 32.8 mg% vs. group E=52.6 +/- 22.5 mg%). The CRCL was also improved in group E vs. group B, although these results did not reach statistical significance (group B=0.069 ml/min vs. group E=0.194 ml/ min). The 24 hr TXB2 levels were significantly increased in group B (0 hr=754.1 +/- 219.4 pg/ml vs. 24 hr=2055.9 +/- 550.0 pg/ml), and pre- or posttreatment with OKY-046 abrogated this increase (group C 0 hr=517.1 +/- 80.9 pg/ml vs. 24 hr=384.7 +/- 251.5 pg/ml, and group E 0 hr=781.6 +/- 390.4 pg/ml vs. 24 hr=183.0 +/- 81.4 pg/ml). The 24 hr 6 kPGF(1alpha) levels decreased in all groups, whereas 72 hr 6 kPGF(1alpha) levels increased above baseline in groups A, C, and E, but not in group B. These data demonstrate the beneficial effects of thromboxane A2 synthesis inhibition in the setting of ischemia-reperfusion injury and suggest that this renoprotection correlates with late vasodilatory prostanoid synthesis.

Renoprotective effects of the 21-aminosteroid U74389G in ischemia-reperfusion injury and cold storage preservation.

Free radical mediated lipid peroxidation (LPO) has been implicated in the pathogenesis of ischemic-reperfusion injury (IRI). To address the renoprotective effect(s) of LPO inhibition, the efficacy of the 21 aminosteroid U74389G was evaluated in three IRI models. In Model 1 51 unilateral nephrectomized rats that underwent 60 min of warm ischemia followed by a 72-hr reperfusion interval were treated with the test vehicle only, or 3, 6, or 12 mg/kg of U74389G intravenously, 5 min pre- or postischemia. In Model 2 Sprague-Dawley rats underwent sham operation (n=9), or 45 min of warm ischemia and 10 min of reperfusion with U74389G (6 mg/kg; n=10) or test vehicle only (n=10) administered intravenously over 10 min beginning 5 min prior to clamp release. After reperfusion, LPO was determined by assay of snap frozen tissue for thiobarbituric acid (TBA) concentrations (nmol/g tissue weight). In Model 3 domestic lean maid pigs (14-18 kg) underwent left nephrectomy with 30 min of warm ischemia, Collins C-4 flush, and 24 hr of cold storage preservation. Heterotopic autotransplantation and immediate contralateral nephrectomy was then performed in Group A-nonischemic controls (n=4), Group B-ischemic controls (n=5), and Group C-U74389G (6 mg/kg) administered preischemia and at autotransplantation (n=5). In Model 1 maximal renoprotection was demonstrated with the 6 mg/kg dose of U74389G administered after ischemia (ischemic control 72-hr serum creatinine (Cr) = 8.01+/-1.1 mg% vs. 3.32+/-0.96 mg%; ischemic control creatinine clearance = 0.069+/-0.03 ml/min vs. 0.206+/-0.04 ml/min; P<0.05). In Model 2 TBA levels were significantly lower in U74389G treated animals (88.5+/-10.0 vs. ischemic controls = 296.8+/-81.4; P=0.02). In Model 3 graft survivals were 100%, 0%, and 60% respectively. Peak Cr and BUN (mg%) were significantly greater in Group C vs. Group A, (Group A Cr = 8.59+/-0.63 vs. Group C = 12.8+/-1.01; Group A BUN = 64.1+/-2.73 vs. Group C = 104.9+/-12.21)--however, by day 10, thee were no significant differences in renal function: (Group A Cr = 2.15+/-0.3 vs. Group C = 2.10+/-0.06; Group A BUN = 27.0+/-6.0 vs. Group C = 31.1+/-6.4). These results support the beneficial effects of LPO inhibitors in models of ischemia-reperfusion, as well as preservation/transplantation, and suggest that this renoprotection correlates with decreased membrane lipid peroxidation.

Percutaneous renal biopsy in the 1990s: safety, value, and implications for early hospital discharge.

To determine the parameters associated with significant bleeding and to examine the value of performing a renal biopsy, we studied 83 consecutive patients, including 24 renal allograft recipients, who had undergone percutaneous renal biopsy. The patients were stratified into four groups according to the percentage of decline in their hematocrit (Hct) at 24 hours postbiopsy, as follows: 10% or greater (n = 21; 25%) and less than 10% decline (n = 62; 75%). The latter group was further subgrouped into 5% to 10% (n = 22) and less than 5% decline (n = 40). There was a significant decline in Hct postbiopsy, with a linear correlation between the decrease in Hct at 6 and 24 hours (R2 = 0.47; P < 0.0001), suggesting that the former was a predictor of the latter. There was a linear correlation between the number of passes and number of cores obtained for the first four passes, but an inverse correlation when five passes or greater were required. Interestingly, there was no correlation between bleeding (>10% decline in Hct) and the number of passes or cores obtained. Gross hematuria and blood transfusion requirement were each encountered in three patients (3.6%). Importantly, the prebiopsy clinical diagnosis was altered in 18 of 59 native kidney biopsies (33%) and 10 of 24 transplant biopsies (41%). We conclude that percutaneous renal biopsy using an automated spring-loaded gun device coupled with ultrasound guidance is a safe technique and provides essential clinical information. Importantly, patients with a stable Hct at 6 hours were at low risk for bleeding at 24 hours while hospitalized. It remains to be determined if these findings could be extrapolated to early discharge from hospital.

Myofibrillar degeneration and necrosis of the visceral smooth musculature: an ischemic visceral myopathy.

Pathologic studies of the visceral smooth musculature in humans are scant despite the relatively frequent occurrence of alterations in these muscles in autopsy material. We investigated the different types of lesions of this musculature observed in various conditions associated with ischemia--acute tubular necrosis, congenital heart disease (low output syndrome due to open heart surgery), and necrotizing enterocolitis in premature babies. Control cases included normal rat tissue undergoing autolysis and rigor mortis and bowel resected from patients with ulcerative colitis and Hirschsprung's disease. Four histologically distinct lesions were present on hematoxylin--eosin staining in the ischemic group: contraction bands, wavy fibers, thick waves, and coagulation necrosis. These lesions were absent in the control groups. We conclude that myofibrillar degeneration and necrosis of the visceral musculature are common in disorders associated with visceral ischemia. These changes are not artifacts produced by autolysis, rigor mortis, or technical handling, nor are they induced by nonischemic inflammatory conditions. Catecholamines may play a role in their genesis.

Myocardial toxoplasmosis complicating cardiac transplant.

The increase in numbers of immunocompromised patients has been reflected by an increasing frequency of opportunistic infections. Of these, Toxoplasma gondii has been reported as a significant human pathogen following cardiac transplantation. In this setting, quiescent toxoplasma myocardial cysts may become active after implantation into a therapeutically immunosuppressed host. The consequences of infection are significant and carry a high morbidity and mortality. We present the clinical and pathologic characteristics of a patient with toxoplasma infection complicating cardiac transplant and review previously reported cases of this entity.

Subglottic inflammatory pseudotumor in a 6-year-old child.

Inflammatory pseudotumors have been given diverse--no fewer than 19--names in the literature. The most frequent localization is in the lung, the gastrointestinal tract, and salivary glands. The case presented here at the subglottic level is exceptional. Although the intraoperative diagnosis is not easy, the prognosis is usually good. Malignant degenerations have not been described. In those cases that cannot be operated on or that extend into the mediastinum, radiotherapy is indicated.

Intrahousehold allocation of resources in larger and smaller Mexican households.

This paper focuses on aspects of intrahousehold allocation of resources. It suggests that there is a first step involved in understanding household decisions as to allocation or misallocation of food within the household, which is that of understanding intrahousehold allocation of income. In this study, carried out in northwestern Mexico, what has been reported in the literature as examples of unequal access to food, particularly in larger households, may better be considered examples of lack of access on the part of purchasers of household food to all of the income which comes into the household.

Surgical treatment of thoracic hydatidosis. A review of 100 cases.

Hydatid cystic disease continues to hold an important place in chest disease in our country. The authors review their experience from 1977 to 1987 of 100 patients who underwent surgery for pulmonary hydatidosis. Mean age was 36.21 years. Fifty-nine cases were ruptured cysts (RC) and 41 were unruptured cysts (UC). The diagnosis was based on epidemiological, radiological and mainly serological and endoscopic criteria. The indirect haemagglutination test was positive in 100% of RC and 80% of UC, while 70.2% of the patients who underwent fiberoptic bronchoscopy showed pathological changes. The most commonly used surgical procedure in UC was open subtotal cystopericystectomy (89.09%), while wedge resection (41.81%) was the most commonly used technique for the RC. There were no operative deaths and no recurrences were observed for a mean follow-up of 5.4 years. The indications for adjuvant chemotherapy with mebendazole are presented.

Lupus nephritis in an anti-nuclear antibody-negative young male. The simultaneous presence of class III and class V renal lesions.

We report about a 27-year-old white male, a known case of class III lupus nephritis with a very high anti-nuclear antibody (ANA) titer, who after 10 years of complete clinical and serological remission presented with sudden development of malar rash, proteinuria and an increase in the serum creatinine. Repeated serologic studies were all negative for ANA. A repeat kidney biopsy disclosed the presence of focal segmental glomerulosclerosis lupus nephritis (class IIIc) superimposed with a new membranous lupus nephritis (class V).

Renal biopsy diagnosis of acute lymphocytic leukemia.

Hyperuricemia, due to inborn errors of metabolism, dehydration, or tumor lysis, may cause renal insufficiency. Hyperuricemia from tumor lysis syndrome in malignancy is usually associated with electrolyte disturbances such as hyperkalemia, hyperphosphatemia or hyper or hypocalcemia. Tumor infiltration into the kidneys can occur, yet this accounts for renal insufficiency in only 1% of patients. This infiltration of tumor cells into the kidneys is usually associated with evidence of malignancy elsewhere as identified by physical exam, radiographic studies, and examination of the peripheral smear or bone marrow. We report an unusual presentation of a child with acute lymphocytic leukemia presenting with acute renal failure, nephromegaly and hyperuricemia without electrolyte disturbances or systemic evidence of tumor elsewhere. We stress the importance of kidney biopsy in order to identify the etiology of the renal failure and hyperuricemia.

Twinning rates in admixed Costa Rican populations.

The frequency of twinning in two admixed Costa Rican groups of women from the Limón province was investigated. One group was self-classified as Black, and the other group was self-classified as White. The twinning rate for each group was computed as the number of twin maternities divided by the total number of confinements multiplied by 1,000. Both groups have virtually identical twinning rates, even though Black subjects were expected to have higher rates than White women. The twinning rate of both groups is higher than that in other New World admixed Black groups. This is particularly surprising for White females, whose European ancestral population is largely from Spain, the European country with the lowest twinning rate. The virtually identical twinning rate is probably a result of the highly frequent gene flow between Blacks and Whites in the population. © 1994 Wiley-Liss, Inc.

Neuropsychological profile of a large kindred with familial Alzheimer's disease caused by the E280A single presenilin-1 mutation.

It was hypothesized that subjective memory complaints represent the earliest sign of dementia in carriers of the presenilin-1 (PS1) mutation. A total of 122 subjects (44 males, 78 females) were included in this study. Forty of them were positive for the mutation in the PS1 gene (mutation positive, MP) whereas 82 showed negative results (mutation negative, MN). Subjects were active, functionally normal, even though some of them complained of memory difficulties. Two groups of neuropsychological instruments were administered: (a) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery (Morris et al., 1989), and (b) some additional neuropsychological tests (Raven Test, Wechsler Memory Scale, Rey-Osterrieth Complex Figure, Boston Naming Test, Naming of Categories, Boston Diagnostic Aphasia Examination, Memory of Three Phrases, Knopman Test, Digit Symbol, and Visual "A" Cancellation Test). Performance in both groups was quite similar. In a secondary analysis, the MP group was subdivided into two subgroups: without and with memory complaints. When comparing both subgroups, a better performance in the first subgroup was found throughout the different subtests. Statistically significant differences were observed in the following test scores: Mini-Mental State Examination, Naming Test (Low Frequency), Memory of Words Test, Recall of Drawings, Wechsler Memory Scale (Logical Memory, Associative Learning, and Total Score), Rey-Osterrieth Complex Figure (Immediate Recall Condition), Boston Diagnostic Aphasia Examination (Complex Ideational Material Subtest), Memory of Three Phrases Test, Serial Verbal Learning (maximum score and Delayed Recall), Knopman Test (First Trial, Second Trial, and Recall after 5 Minutes), Digit Symbol, and Visual "A" Cancellation Test (Additions). Results supported the hypothesis that memory complaints represent the earliest symptom of familial Alzheimer's disease. In addition to the memory difficulties, other minor cognitive impairments were also found, particularly, mild anomia, concentration difficulties and defects in the understanding of complex verbal material.

Nodular renal blastema and metanephric hamartomas in children with urinary tract malformations: a morphologic spectrum of abnormal metanephric differentiation.

In a retrospective review, we identified a variety of abnormal immature and differentiated metanephric tissues including nodular renal blastema and metanephric hamartomas in 12 children with urinary tract malformations with or without renal dysplasia. Four infants also had trisomy. Nodular renal blastema was characterized by small subcapsular clusters of primitive metanephric cells, in some cases with evidence of tubular, papillary, or trabecular differentiation. Metanephric hamartomas included papillary adenomas and tubular hamartomas. Undifferentiated renal blastema was multifocal, but more differentiated blastema usually occurred as isolated nodules. When accompanied by renal dysplasia, blastema tended to show differentiation. One child had a spectrum of lesions with both blastema and more differentiated metanephric hamartomas.

Pathology of renal transplantation.

Renal transplantation is the most appropriate form of treatment for end-stage renal disease in all age groups. We present the experience of two hospitals in the pathology of kidney allograft. Renal biopsy is the most adequate method for the follow-up of these patients, because it permits the differential diagnosis of acute and chronic rejection, transplant glomerulopathy, recurrent and "de novo" glomerulonephritis and immunosuppression nephrotoxicity, mainly by cyclosporine A. We present the pathology features of all these entities, and study the representativity of the biopsy for diagnosis of rejection. The actuarial survival of the graft is 82% and 71% at 1 and 5 years, respectively.