Insights into particle dispersion and damage mechanisms in functionally graded metal matrix composites with random microstructure-based finite element model.

This study investigates the impact of Al 2 O 3 particle volume fraction and distribution on the deformation and damage of particle-reinforced metal matrix composites, particularly in the context of functionally graded metal matrix composites. In this study, a two-dimensional nonlinear random microstructure-based finite element modeling approach implemented in ABAQUS/Explicit with a Python-generated script to analyze the deformation and damage mechanisms in AA 6061 - T 6 / Al 2 O 3 composites. The plastic deformation and ductile cracking of the matrix are captured using the Gurson-Tvergaard-Needleman model, whereas particle fracture is modelled using the Johnson-Holmquist II model. Matrix-particle interface decohesion is simulated using the surface-based cohesive zone method. The findings reveal that functionally graded metal matrix composites exhibit higher hardness values ( HRB ) than traditional metal matrix composites. The results highlight the importance of functionally graded metal matrix composites. Functionally graded metal matrix composites with a Gaussian distribution and a particle volume fraction of 10% achieve HRB values comparable to particle-reinforced metal matrix composites with a particle volume fraction of 20%, with only a 2% difference in HRB . Thus, HRB can be improved significantly by employing a low particle volume fraction and incorporating a Gaussian distribution across the material thickness. Furthermore, functionally graded metal matrix composites with a Gaussian distribution exhibit higher HRB values and better agreement with experimental distribution functions when compared to those with a power-law distribution.

Base Deficit, Serum Albumin Level And Blood Haemoglobin Concentration Can Be Used As Predictor Factors For Mortality In Major Burn Patients.

Hypoalbuminemia as seen in major burn injury results in widespread endothelial dysfunction. Base deficit provides the best estimate for degree of tissue anoxia. Acute blood loss describes anemia present in burn patients. Controversy focuses on the administration of protein-based colloids: whether to provide them, which solutions to use, and when to begin? The aim of this study was to determine whether alteration of gas exchange, excess base deficit, hypoalbuminemia and anemia could predict mortality in major burn patients, whether to provide protein-based colloids, and when to begin fluid resuscitation. The prospective study included 42 major burn patients. All the patients were admitted to the burn intensive care unit at Menoufia University Hospital. Serum albumin level, hemoglobin concentration, arterial blood gases and base deficit were measured at admission, third day and after one week. Average serum albumin on admission was 3.33 ± 0.44, after 3 days 2.85 ± 0.54 and after 1 week 2.46 ± 0.67 gm./dL, while hemoglobin concentration was 14.79 ± 2.13, 12.25 ± 1.99, and 10.24 ± 2.47 gm./dl respectively. However, base deficit was 5.75 ± 2.40, 5.24 ± 2.05 and 5.45 ± 2.76 respectively, with significant statistical difference (p<0.001) between the death and survivor groups. Binary logistic regression analysis for independent predictors of mortality declared that base deficit, albumin and hemoglobin serum levels were independent predictors for mortality with an odds ratio of 2.23, 95% CI, 1.66-16.75 for base deficit, 3.56, 95% CI, 1.88-12.59 for albumin and 2.21, 95% CI, 1.56-13.54 for hemoglobin. Hypoalbuminemia, anemia and excess base deficit can be used as prognostic factors for mortality in major burn patients.

L'hypoalbuminémie du brûlé est la conséquence d'un dysfonctionnement endothélial généralisé. Les pertes sanguines occasionnent une anémie. Il persiste une controverse quant à l'utilisation des colloïdes naturels chez ces patients : faut il les utiliser et, si oui, lesquels et quand ? Les buts de ce travail étaient d'étudier si les altérations des échanges gazeux, le déficit de base, l'hypoalbuminémie et l'anémie étaient corrélés à la mortalité, s'il fallait utiliser des colloïdes naturels et quand. Il s'agit d'une étude prospective réalisée sur 42 patients admis en réanimation du CTB du CHU de Menoufia. L'albuminémie, le taux d'hémoglobine, la gazométrie et le déficit de base étaient mesurés à l'entrée, J3 et J7. L'albuminémie moyenne était de 33,3 ± 4,4 g/L à l'entrée, 28,5 ± 5,4 g/L à J3 et 24,6 ± 6,7 à J7. L'hémoglobine était à 14,79 ± 2,13 g/dL à l'entrée ; 12,25 ± 1,99 à J3 et 12,04 ± 2,47 à J7. Le déficit de base était respectivement de 5,75 ± 2,4 ; 5,24 ± 2,05 et 5,45 ± 2,76, avec une différence significative (p<0,001) entre vivants et décédés. En régression logistique binaire, le déficit de base (OR 2,23 ; IC 95 1,66-16,75) ; l'albuminémie (OR 3,56 ; IC 95 1,88-12,59) et l'anémie (OR 2,21 ; IC 95 1,56-13,54) apparaissent comme des variables indépendantes de mortalité. Ces 3 paramètres peuvent donc être utilisés pour prédire la mortalité d'un brûlé grave.

A 7-day intravenous toxicity study and neurotoxicity assessment of pyridorin in Sprague-Dawley rats.

Pyridorin®, a naturally occurring metabolite of vitamin B6 that inhibits and scavenges reactive oxygen species, is being developed as a potential therapeutic for acute kidney injury. An investigational new drug application (IND) was opened for Pyridorin in support of its ongoing oral drug clinical development program. Currently, a Pyridorin intravenous (IV) formulation is being developed for use in surgical patients. To support the IND for Pyridorin, a full battery of nonclinical Good Laboratory Practice compliant studies was performed with no neurological or behavioral signs of toxicity seen following oral or IV administration of pyridoxine dihydrochloride (the active ingredient in Pyridorin). However, excessive ingestion of vitamin B6 has been reported to cause neurotoxic syndrome in humans. Therefore, under Food and Drug Administration recommendation, a 7-day IV study in rats was conducted to further evaluate the drug's potential to cause neurotoxicity. Blood plasma samples indicated that exposure to pyridoxamine dihydrochloride and its metabolites, pyridoxal, pyridoxine, and 4-pyridoxic acid was linearly dose proportional and independent of gender. At doses of up to 200 mg/kg/day pyridoxine dihydrochloride, no treatment-related effects were seen in rats, providing further evidence for the absence of pyridoxine dihydrochloride-related changes in the nervous system. A no observed adverse effect level of 200 mg/kg/day was identified for this study.

Clonidine as an adjuvant in the management of acute poisoning by anticholinesterase pesticides.

INTRODUCTION: Anticholinesterase pesticides are widely used in agriculture and domestic settings throughout the world, and they are responsible for great morbidity and mortality. In Egypt and other developing countries, there is a pressing need for new affordable antidotes to treat anticholinesterase pesticide poisoning. Hence, this study was conducted to evaluate the safety and effectiveness of moderate doses of clonidine in the management of adult patients with acute anticholinesterase pesticide poisoning. METHODOLOGY: This study was an open-label, phase II pilot clinical trial. Sixty patients with acute anticholinesterase pesticide poisoning gave consent to participate in the study. They were divided into 2 equal groups, with 30 patients in each group. Group I received clonidine plus the routine treatment, while group II received only the routine treatment. Patients were subjected to full history taking, and their vital and clinical data were recorded. Serum cholinesterase levels and routine laboratory investigations were measured. The different outcomes of the patients were assessed. RESULTS: The baseline characteristics of both groups were similar. Thirteen (43.3%) patients developed significant hypotension during clonidine treatment. The clinical outcomes (including mortality, need for assisted ventilation, length of hospital stay, and total doses of atropine) showed no significant differences between the two groups. CONCLUSION: The use of clonidine in acute anticholinesterase pesticide poisoning may be associated with a high incidence of hypotension requiring intervention. The clinical outcomes may not significantly improve in clonidine-treated patients.

Mutations of the von Hippel-Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma.

The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-α results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cell-mediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1α and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNγ secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-I-specific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNα, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNα resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with anti-angiogenic drugs may be beneficial for patients with mutated VHL.

Adipsic hypernatremia and bilateral renal stones in a child with ectrodactyly-ectodermal dysplasia-cleft lip-palate (EEC) syndrome.

EEC syndrome an autosomal dominant disorder with variable expression and cardinal signs of ectrodactyly, ectodermal dysplasia, and orofacial clefts. In this report, we describe a patient with EEC syndrome, adipsic hypernatremia without brain anomalies, and bilateral renal stones, two manifestations that were not reported before.

The role of different inoculum levels of Meloidogyne javanica juveniles on nematode reproduction and host response of peanut plant.

A pot experiment was conducted to determine the influence of three of inoculum levels (1000, 2000 and 3000 J2 pot(-1)) of Meloidogyne javanica on nematode reproduction and host response of peanut plant cv. Giza 4 under greenhouse conditions at 30 +/- 5 degrees C. In general, nematode reproduction and host damage were both affected by the initial inoculum levels. The greater reduction percentage of plant fresh (57.7%), shoot dry (38.82) and pods weights (52.59%) and nodules numbers (73.33%) were recorded at inoculum level 2000 J2/peanut plant, when rate of nematode build-up reached the maximum value of 1.64. Regression analysis of Pi vs. rate of nematode build-up on peanut plants gave value of R2 amounted to 0.3193. On the other hand, when the initial inoculum level added increased up to 3000 J2/peanut plant, the percentage reduction of whole plant fresh weight (47.07%) and other growth parameters as well as nematode build-up (0.8) also obviously decreased.

Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma.

BHD, TP53, and HNF1beta on chromosome 17 were studied in 92 cases of renal cell carcinoma (46 chromophobe, 19 clear cell, 18 oncocytoma, and nine papillary). Six, thirteen, and zero cases had, respectively BHD, TP53, and HNF1beta mutations, (84% mutations involved chromophobe), suggesting a role for BHD and TP53 in chromophobe subtype.

A functional observational battery for use in canine toxicity studies: development and validation.

The most commonly used nonrodent species in regulatory toxicity and safety assessment studies has been and remains the dog, with the beagle being the standard breed employed. Although a standard functional observational battery (FOB) or neurobehavioral screen for use in rodents (primarily rats) has been incorporated into rodent studies since the late 1980s, this is not the case in nonrodents. In the pharmaceutical area (where repeat exposure nonrodent studies are generally required to develop a drug for humans), some work has been previously conducted towards developing a similar screen in the dog but progress has been limited. Given both the differential metabolism and sensitivity of the dog compared to rodents and the extreme desirability of having as complete a set of toxicity and/or functionality measures in the same species (to simplify and improve the accuracy of dose/response metrics) as possible, the need for such a standardized and validated methodology is clear. Study data from prior work establish the susceptibility of dogs to a wide variety of neurotoxic agents, including 6-aminonicotinamide (ANA), methanol, lasalocid, metronidazole, acrylamide, clinoquinol, organo tins, and mercury. Additionally, the dog is likewise well established as a sensitive model for a wide range of peripheral and central nervous system-active pharmacologic agents, as required by recent regulatory requirements for safety pharmacology evaluations. Here we report on a robust and yet sensitive noninvasive screening methodology for detecting and providing initial quantitation and characterization of such direct and indirect neurotoxic and neuropharmacologic effects that has been developed. Additionally, an analysis and interpretation component that allows differentiation of neurotoxic from neuropharmacologic activities has also been adapted from prior work by one of the authors. Comparative species difference in sensitivity to neuroactive agents are also discussed, as well as means for integrating this evaluation screen into existing standard design. Particularly, with the recent promulgation of safety pharmacology testing requirements (the in vivo cardiovascular component of which is performed in the dog), the availability of such an evaluation paradigm presents a valuable potential addition to existing study designs without increasing animal usage.

Color bar coding the BRCA1 gene on combed DNA: a useful strategy for detecting large gene rearrangements.

Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast and ovarian cancers. BRCA1 germline mutations, however, are found less frequently than expected. Mutation detection strategies, which are generally based on the polymerase chain reaction, therefore focus on point and small gene alterations. These approaches do not allow for the detection of large gene rearrangements, which also can be involved in BRCA1 alterations. Indeed, a few of them, spread over the entire BRCA1 gene, have been detected recently by Southern blotting or transcript analysis. We have developed an alternative strategy allowing a panoramic view of the BRCA1 gene, based on dynamic molecular combing and the design of a full four-color bar code of the BRCA1 region. The strategy was tested with the study of four large BRCA1 rearrangements previously reported. In addition, when screening a series of 10 breast and ovarian cancer families negatively tested for point mutation in BRCA1/2, we found an unreported 17-kb BRCA1 duplication encompassing exons 3 to 8. The detection of rearrangements as small as 2 to 6 kb with respect to the normal size of the studied fragment is achieved when the BRCA1 region is divided into 10 fragments. In addition, as the BRCA1 bar code is a morphologic approach, the direct observation of complex and likely underreported rearrangements, such as inversions and insertions, becomes possible.

Statistical approaches to the design of toxicology studies.

Application of statistics to toxicological studies involves hypothesis testing, model fitting, and reduction of dimensionality. This unit reviews statistical approaches to data (i.e., descriptive statistics, experimental design, outliers and rounding of numbers, and specific applications) and includes a set of decision trees to assist in choosing the appropriate methods.

Genetic testing for breast cancer predisposition.

The recent identification of the BRCA1 and BRCA2 genes has improved our understanding of the association between breast and ovarian cancers in certain families. Carriers of predisposing germline mutations must decide on different options for management, including close follow-up or prophylactic surgery. Further studies are needed to elucidate the optimal management of these patients and to identify the factors that modify their risk for developing breast cancer. Finally, we must work to prevent any form of discrimination against those who, following genetic testing, are found to be at increased risk for breast cancer.

No evidence for germline PTEN mutations in families with breast and brain tumours.

Germline mutations of the PTEN gene are involved in Cowden disease, a genetic condition associated with an increased risk of breast cancer. Further somatic PTEN mutations have been found in glioblastomas and to a lesser extent in meningiomas. Therefore, PTEN germline mutations were searched for in a series of 20 unrelated women with breast cancer who also had a personal or familial breast-brain tumour history. Inclusion criteria were 1. family history of breast cancer; 2. absence of germline BRCA1 and p53 mutation; and 3. at least one case of brain tumour (glioblastoma, meningioma, or medulloblastoma) in either the index case or one of their first or second degree relatives. Any stigmata of Cowden disease was an exclusion criteria. Screening of the PTEN gene for point mutations or small rearrangements were performed using the denaturing gradient gel electrophoresis method on the 9 coding exons. No disease-associated mutation of the PTEN gene has been detected in our series. It is, thus, unlikely that PTEN is a significant BRCA predisposing locus. However, one might ask whether breast cancer cases resulting from germline PTEN mutation could occur without any mammary histological feature of Cowden disease.

IRAG working group 1. Organotypic models for the assessment/prediction of ocular irritation. Interagency Regulatory Alternatives Group.

The brief of the Organotypic Models Working Group was to review data submitted to the Interagency Regulatory Alternatives Group on the use of isolated eyes and components of the eye used to predict eye irritation potential. Data submissions were received on four test systems: the isolated rabbit eye (one submission), the isolated chicken eye (one submission), the bovine cornea (eight submissions) and the cultured bovine lens (one submission). On the basis of the data submitted on each test it was concluded that the isolated rabbit eye test as performed was capable of screening for severe eye irritants, but overall was of no practical value for determining irritation potential across the full range; that the isolated chicken eye test as performed showed promise as a method of predicting eye irritation potential, but the database was too small and needed expanding; that the bovine corneal opacity test had an extensive database and overall performed reasonably at screening out severe irritants and performed well for assigning relative potencies; and that the bovine lens test should be researched further to demonstrate its utility. The overall conclusion drawn was that the isolated eye tests and the bovine corneal opacity test can be used now to screen for severely irritating materials. However, it would be unwise to rely solely on these organotypic methods to provide evidence of lack of eye irritation hazard.

The mouse ear swelling test (MEST) in the 1990s.

The mouse ear swelling test (MEST) was developed in the early 1980s to provide a lower cost, shorter and objectively graded alternative to the existing guinea pig based tests for delayed contact hypersensitivity. In the ensuing time, the test design has been modified and its use has been extended to additional applications (phototoxicity and photosensitisation screening and as a mechanistic tool in studying tumor promoting agents) and to evaluating a broader range of test materials (treated fabrics, medical devices, environmental pollutants, specialty chemicals, drugs, etc.) in the hands of new investigators. Likewise, other murine based tests have been developed. The MEST and one other murine test (the local lymph node assay, or LLNA) have also now been included in the lists of regulatorily accepted sensitization test systems. The current version of the MEST protocol is presented here, along with the rationale for changes, a review of evaluations and interlaboratory trials and an overview of the range of uses to which it has been applied.

Identification of an inversion 16 coexisting with an isochromosome 22q by in situ hybridization in a case of childhood AML M4e.

Rearrangements involving chromosome 16, including inv(16) (p13q22), del(16)(q22), and t(16;16)(p13;q22), are frequent findings in acute myeloblastic leukemia (AML). Each of these rearrangements can occur as the sole karyotypic change or in association with additional chromosomal abnormalities, including in decreasing order of frequency: trisomy 22, trisomy 8, and deletion of the long arm of chromosome 7. We report a pediatric case of de novo AML, M4e subtype, with a unique combination of inv(16) (p13q22) and i(22q) occurring within the same leukemic clone. The inv(16) was detected by fluorescence in situ hybridization (FISH) analysis with two cosmid probes specific for sequences flanking the inv(16) breakpoint on the long arm of chromosome 16. Use of a chromosome-22-specific painting probe unequivocally identified a small metacentric chromosome as an i(22q). This case illustrates a variation in the association of trisomy 22 with inv(16) and suggests that duplication of the long arm of chromosome 22 may contain critical gene(s) involved in the multistep process of evolution of leukemia with 16q22 abnormalities.