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Stent migration due to haemodynamic drag remains the primary cause of type I endoleak, potentially leading to aneurysm rupture. The prevalence of migration and endoleak can be partially attributed to deficiencies in stent-graft radial spring design and a lack in understanding of the mechanical properties of endovascular stents. A converged finite element model of a custom radial extensometer was developed, fit, and validated using experimental results for bare stent wire (”uncovered”) with outer diameter of 12 mm stent. During stent constriction to 50 % of the original cross- sectional area, a comparison of experimental and modeled results produced an r2 value of 0.946, a standard error of 0.099 N, and a mean percent error of 1.69 %. This validated finite element model can be used to analyze the mechanisms responsible for radial force generation in 316L stainless steel self-expanding endovascular stents, as well as to evaluate new stent designs.

Stents were manufactured to investigate the impact of altering stent design characteristics (leg length, bend angle, bend radius, and wire diameter) on radial force generation. Results from this design parameter study showed that leg length, bend angle, and wire diameter have a statistically significant impact on radial force generation, while lesser changes in bend radius did not (1.00 mm versus the original 0.794 mm). However, a larger variation of this parameter (1.588 mm) was statistically significant. Results gathered for all parameters were used in the creation of a prototypal software. Using input values of patient-specific arterial diameter and compliance, as well as stent design characteristic dimensions, this program has been developed to predict stent radial force at varying levels of expansion.

Stent migration and endoleak are common failure mechanisms for endovascular repair. Both can be partially attributed to a lack in understanding of the mechanical properties of endovascular stents. ...

Managed realignment often involves the construction of new sea walls at a location behind existing sea walls to create parcels of land that can be flooded to create new inter-tidal environments. It is employed in the UK to improve flood risk management within the context of flood risk management strategies, but so far most emphasis has focused upon creation of new wildlife habitat because this has been where the opportunities and funding have been found. Initial projects were relatively small in scale, but recent projects have been much larger. Scaling up the size of realignments introduces a variety of additional engineering and social challenges and the realignment of Wallasea Island in 2006 is one of the largest. There were a variety of issues encountered during the development of the Wallasea Island realignment that make it a good platform for exploring the issues and some of the solutions that have been found to date. This account describes the project and some of the measures taken to give it as high a level of social acceptability as possible. Such measures include design features for fish nurseries, provision of public access and careful liaison with affected communities.

The Fabry Registry is a global observational research platform established to define outcome data on the natural and treated course of this rare disorder. Participating physicians submit structured longitudinal data to a centralized, confidential database. This report describes the baseline demographic and clinical characteristics of the first 1765 patients (54% males (16% aged < 20 years) and 46% females (13% < 20 years)) enrolled in the Fabry Registry. The median ages at symptom onset and diagnosis were 9 and 23 years (males) and 13 and 32 years (females), respectively, indicating diagnostic delays in both sexes. Frequent presenting symptoms in males included neurological pain (62%), skin signs (31%), gastroenterological symptoms (19%), renal signs (unspecified) (17%), and ophthalmological signs (11%). First symptoms in females included neurological pain (41%), gastroenterological symptoms (13%), ophthalmological (12%), and skin signs (12%). For those patients reporting renal progression, the median age at occurrence was 38 years for both sexes, but onset of cerebrovascular and cardiovascular events was later in females (median 43 and 47 years, respectively) than in males (38 and 41 years, respectively). This paper demonstrates that in spite of the considerable burden of disease in both sexes that begins to manifest in childhood or adolescence, the recognition of the underlying diagnosis is delayed by 14 years in males and 19 years in females. The Fabry Registry provides data that can increase awareness of common symptoms in all age groups, as well as insight into treated and untreated disease course, leading to improved recognition and earlier treatment, and possibly to improved outcomes for affected individuals.

Echo particle image velocimetry (Echo PIV) presents itself as an attractive in vivo flow quantification technique to traditional approaches. Promising results have been acquired; however, limited quantification and validation is available for post-stenotic flows. We focus here on the comprehensive evaluation of in vitro downstream stenotic flow quantified by Echo PIV and validated in relation to digital particle image velocimetry (DPIV). A Newtonian blood analog was circulated through a closed flow loop and quantified immediately downstream of a 50 % axisymmetric blockage at two Reynolds numbers (Re) using time-averaged Echo PIV and DPIV. Centerline velocities were in good agreement at all Re; however, Echo PIV measurements presented with elevated standard deviation (SD) at all measurements points. SD was improved using increased line density (LD); however, frame rate or field of view (FOV) is compromised. Radial velocity profiles showed close agreement with DPIV with the largest disparity in the shear layer and near-wall recirculation. Downstream recirculation zones were resolved by Echo PIV at both Re; however, magnitude and spatial coverage was reduced compared to DPIV that coincided with reduced contrast agent penetration beyond the shear layer. Our findings support the use of increased LD at a cost to FOV and highlight reduced microbubble penetration beyond the shear layer. High local SD at near-wall measurements suggests that further refinement is required before proceeding to in vivo quantification studies of wall shear stress in complex flow environments.

SYNOPSIS Empirical studies and other evidence indicate that tree farming has had a marked impact on biodiversity in some areas of South Africa, Plant and animal species have been made extinct or are threatened by afforestation, and afforestation is largely responsible for the endangered status of one Veld Type, in KwaZulu-Natal. This information does not support the contention by Pott (1997) that “…much of the criticism of plantation forestry as a form of land use is based on emotional bias rather than on hard evidence.” The call by Pott (1997) for research and monitoring in the context of the impacts that various land uses, including timber farming, have on biodiversity, and for the management of components of biodiversity on timber farms is strongly supported.

Objective To investigate whether, in the absence of galactosemia, relatively high intestinal lactase activity or low activity of an enzyme involved in galactose catabolism reduces fertility, as it does in the presence of galactosemia. Design Retrospective cohort study. Setting Healthy women selected from the community. Patients Fifty-three married women. Intervention Urinary galactose after an oral lactose challenge (a measure of intestinal lactase activity), erythrocyte galactose-1-phosphate uridyltransferase (transferase) activity, and transferase polymorphisms by isoelectric focusing. Main Outcome Measure Pregnancy rate (number of pregnancies divided by number of months at risk) in the 12months after stopping use of birth control to become pregnant. Results Relatively high urinary galactose was not related to a decreased rate of pregnancy during the first 12months (≥24.6 compared with ≤14.3mg: relative risk [RR] = 1.9; 95% confidence interval [CI] = 0.86 to 4.0). Relatively high transferase activity was not related to an increased rate of pregnancy (≥19.5 compared with ≤17.2 μ mol/h per g hemoglobin: RR=1.1; 95% CI=0.56 to 2.4). Low-activity transferase polymorphisms were not related to a decreased rate (RR = 1.2; 95% CI=0.58 to 2.5). Conclusion Our study does not support the hypothesis that the biologic variation in galactose metabolism that exists in the general population influences infertility.

The fragile-X syndrome of mental retardation is associated with an expansion in the number of CGG repeats present in the FMR1 gene. The repeat region is within sequences characteristic of a CpG island. Methylation of CpG dinucleotides that are 5' to the CGG repeat has been shown to occur on the inactive X chromosome of normal females and on the X chromosome of affected fragile-X males, and is correlated with silencing of the FMR1 gene. The methylation status of CpG sites 3' to the repeat and within the repeat itself has not previously been reported. We have used two methylation-sensitive restriction enzymes, AciI and Fnu4HI, to further characterize the methylation pattern of the FMR1 CpG island in normal individuals and in those carrying fragile-X mutations. Our results indicate that: (i) CpG dinucleotides on the 3' side of the CGG repeat are part of the CpG island that is methylated during inactivation of a normal X chromosome in females; (ii) the CGG repeats are also part of the CpG island and are extensively methylated as a result of normal X-chromosome inactivation; (iii) similar to normal males, unaffected fragile-X males with small CGG expansions are unmethylated in the CpG island; for affected males, the patterns of methylation are similar to those of a normal, inactive X chromosome; (iv) in contrast to the partial methylation observed for certain sites in lymphocyte DNA, complete methylation was observed in DNA from cell lines containing either a normal inactive X chromosome or a fragile-X chromosome from an affected male.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: Acid alpha-glucosidase is present in various tissues, including blood cells. Historically, enzyme measurement in cultured fibroblasts, or muscle, has been the gold standard to confirm a diagnosis of Pompe disease, due to the possibility of alternate isoenzyme activity masking disease in white cell assays. Enzyme measurement in an isolated lymphocyte population with acarbose, an inhibitor of neutral alpha-glucosidase, has greatly improved the sensitivity and specificity of the test in blood cells allowing for more rapid laboratory testing for Pompe disease. Methods: An assay for acid alpha-glucosidase was performed with and without inhibitor in lymphocytes from 14 patients with a clinical suspicion of infantile Pompe disease. Concurrent testing was performed in fibroblasts in an independent laboratory. Results: Thirteen of 14 patients demonstrated a clear deficiency in lymphocytes with acarbose inhibition. One patient was indeterminate, although below normal activity, suggesting the need for confirmatory testing. Tissue enzyme activity in all was consistent with infantile Pompe disease, and corroborated enzyme activity seen in lymphocytes. There were no false positives for disease, making the positive predictive value of lymphocyte enzyme testing 100%. Conclusion: Enzyme assay using acarbose as an inhibitor, can be performed in isolated lymphocytes for rapid diagnosis of infantile Pompe disease.

The Hurd Volcaniclastic Deposit lies within the Kinojevis Assemblage, a group of submarine volcanic rocks dominated by Mg-and Fe-rich metamorphosed pillow-basalt. The volcaniclastic deposit can be subdivided into two facies, a lower unorganized massive facies and an upper imbricated facies. The lower facies is composed of cm-to-m-scale flow-banded dacite blocks interspersed with angular to curved-to-blocky and equant mm-to-cm-scale fragments of altered glass; it has a sharp but undulatory basal contact with underlying massive to lobate dacitic lavas. Some blocks are partly composed of in-situ breccia, and agglomerations or curvilinear arrays of spherulites. This lithofacies contains well-developed columnar joints that terminate at the sharp contact with the ∼2m thick upper imbricated facies. With the exception of numerous large imbricated tabular clasts, the imbricated facies is dominated by blocky to angular mm-to-cm-scale fragments. The presence of pillows, chert, jig-saw fit breccias, and microscopic quench textures are evidence of a subaqueous environment of deposition. Similarly, the presence of columnar joints, plastically deformed clasts, quench breccias, and possible gas escape structures indicate hot emplacement, perhaps by a gas-supported pyroclastic flow. Together, the massive and imbricated facies represent one flow unit that was quickly emplaced. The lower facies was deposited by a high-density flow isolated from the aqueous environment by the development of a steam carapace, whereas the overlying facies was emplaced by a turbulent, aqueous flow. The onset of magmatic fragmentation may have been the result of sudden decompression possibly triggered by the gravitational collapse of a submarine dacite dome.

Severe infantile Gaucher disease associated with ichthyosis and neonatal death is a rare subgroup of Type II Gaucher disease. This group of infants has little, if any, detectable beta-glucocerebrosidase activity, and prior genetic analyses have been limited in detecting the mutations responsible for this phenotype. We document an Hispanic infant succumbing with arthrogryposis and collodion membrane covering the skin who had no detectable beta-glucocerebrosidase activity in tissue samples and who was homozygous for a rare recombinant allele, RecNciI. Microscopic evaluation demonstrated accumulation of Gaucher cells in visceral organs and extensive loss of neurons in the anterior horns, brainstem, and cortex of the nervous system. The apoptosis of neuronal cells from the anterior horns and brainstem are a reasonable explanation for the arthrogryposis and neonatal death, respectively.

The Orthofix ProCallus fixator was developed from the original Dynamic Axial Fixator to take account of recent developments in the understanding of the mechanism of fracture repair and the role of micromovement.

Two privately owned domestic rabbits (Oryctolagus cuniculus) in Maryland were found to be infected with the raccoon variant of the rabies virus in 1998. Both rabbits had an acute onset of anorexia and paralysis or paresis of the left forelimb; 1 also developed head tremors and a head tilt. One of the rabbits became ill 25 days after being attacked by a raccoon (Procyon lotor) and was euthanatized 3 days after onset of illness. The other rabbit, which was housed in an outdoor hutch, died 4 days after onset of clinical signs; the source of infection in that rabbit remains unknown. Currently, there is not a rabies vaccine approved for use in rabbits; thus, the only way to prevent the infection in rabbits is to prevent exposure. Veterinarians in rabies-enzootic areas should be familiar with the clinical signs of rabies in rabbits and should caution rabbit owners about the need to protect their pets from contact with wildlife.

Background Timely diagnosis and continued monitoring of patients with type I Gaucher disease is critical because skeletal involvement can permanently disable patients and visceral organ involvement can lead to abdominal pain and secondary hematologic and biochemical complications. Objective To seek clinical consensus for minimum recommendations for effective diagnosis and monitoring of patients with type I Gaucher disease. Participants, Evidence, and Consensus Process Contributing authors collaborated in quarterly meetings over a 2-year period to synthesize recommendations from peer-reviewed publications and their own medical experiences. These physicians care for most patients with Gaucher disease in the United States and serve as the US Regional Coordinators for the International Collaborative Gaucher Group Registry, the world's largest database for this disorder. Conclusions The definitive method of diagnosis is enzyme assay of β-glucocerebrosidase activity. Schedules differ for monitoring complications of type I Gaucher disease, depending on symptoms and whether enzyme replacement therapy is used. Hematologic and biochemical involvement should be assessed by complete blood cell count, including platelets, acid phosphatase, and liver enzymes, at baseline and every 12 months in untreated patients and every 3 months and at enzyme replacement therapy changes in treated patients. Visceral involvement should be assessed at diagnosis using magnetic resonance imaging or computed tomographic scans. Skeletal involvement should be assessed at diagnosis using T 1 - and T 2 -weighted magnetic resonance imaging of the entire femora and plain radiography of the femora, spine, and symptomatic sites. Follow-up skeletal and visceral assessments are recommended every 12 to 24 months in untreated patients, and every 12 months and at enzyme replacement therapy changes in treated patients.

We studied four variable number of tandem repeat (VNTR) loci (D4S139, D10S28, D17S74, and D17S79) in five ethnic populations from the Seattle metropolitan area. DNA samples purified from randomly chosen individuals were digested with Hae III or Hinf I and probed with pH30, for D4S139; TBQ7 for D10S28; pCMM86 for D17S74 and pAC256 for D17S79. The allele frequencies, expected Hardy-Weinberg values, observed heterozygosities and genetic distances among the populations were obtained for all these loci. D4S139 restriction fragment lengths (RFLs) varied in size from 1.4 to 22 kilobase pairs (kbp). The observed heterozygosities (H) varied from 84% in Native American populations to 94% among Blacks. D10S28 RFLs varied in size from 650 base pairs (bp) to 10.1 kbp. H varied from 90% in Native Americans to 96% in Caucasians and Hispanics. D17S74 RFLs varied in size from 782 bp to 9.3 kbp. H varied from 87% in Asians to 92% among Blacks. D17S79 RFLs varied in size from 400 bp to 3 kbp. H varied from 87% in Hispanics to 95% in the Black population. The frequencies of genotypes of the loci conformed to Hardy-Weinberg equilibrium with the exception of the D17S79 in Hispanics and Native Americans. The genetic distances between the populations were also determined.

To investigate whether, in the absence of galactosemia, relatively high intestinal lactase activity or low activity of an enzyme involved in galactose catabolism reduces fertility, as it does in the presence of galactosemia.Retrospective cohort study.Healthy women selected from the community.Fifty-three married women.Urinary galactose after an oral lactose challenge (a measure of intestinal lactase activity), erythrocyte galactose-1-phosphate uridyltransferase (transferase) activity, and transferase polymorphisms by isoelectric focusing.Pregnancy rate (number of pregnancies divided by number of months at risk) in the 12 months after stopping use of birth control to become pregnant.Relatively high urinary galactose was not related to a decreased rate of pregnancy during the first 12 months (or = 24.6 compared withor = 14.3 mg: relative risk [RR] = 1.9; 95% confidence interval [CI] = 0.86 to 4.0). Relatively high transferase activity was not related to an increased rate of pregnancy (or = 19.5 compared withor = 17.2 mumol/h per g hemoglobin: RR = 1.1; 95% CI = 0.56 to 2.4). Low-activity transferase polymorphisms were not related to a decreased rate (RR = 1.2; 95% CI = 0.58 to 2.5).Our study does not support the hypothesis that the biologic variation in galactose metabolism that exists in the general population influences infertility.

Outcome of and complications associated with bilateral adrenalectomy in 8 cats with pituitary-dependent hyperadrenocorticism and bilateral adrenocortical hyperplasia and outcome of and complications associated with unilateral adrenalectomy in 2 cats with adrenocortical tumor (adrenocortical adenoma, 1 cat; adrenocortical carcinoma, 1 cat) and unilateral adrenomegaly were determined. Glucocorticoids were administered to all cats at the time of surgery, and mineralocorticoids were administered to the 8 cats that underwent bilateral adrenalectomy. A ventral midline celiotomy was performed in all cats. Intraoperative complications did not develop in any cat. Postoperative complications developed in all cats and included abnormal serum electrolyte concentrations (n = 8), skin lacerations (n = 5), pancreatitis (n = 3), hypoglycemia (n = 2), pneumonia (n = 1), and venous thrombosis (n = 1). Three cats died within 5 weeks after surgery of complications associated with sepsis (n = 2) or thromboembolism (n = 1). Clinical signs and physical abnormalities caused by hyperadrenocorticism resolved in the remaining 7 cats 2 to 4 months after adrenalectomy. Insulin treatment was discontinued in 4 of 6 cats with diabetes mellitus. Median survival time for these 7 cats was 12 months (range, 3 to30 months). Two cats died of acute adrenocortical insufficiency 3 and 6 months after bilateral adrenalectomy, 2 cats were euthanatized because of chronic renal failure 3 and 12 months after bilateral (n = 1) or unilateral (n = 1) adrenalectomy, and 2 cats were alive 9 and 14 months after bilateral adrenalectomy. In the remaining cat, clinical signs recurred 10 months after the cat had undergone unilateral adrenalectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Seven cats with thyroid carcinomas that had previously undergone surgical removal of neoplastic tissue were treated with 30 mCi of radioactive iodine (131I). Six of the cats had clinical signs of hyperthyroidism; 1 did not. There were no complications associated with 131I treatment, and clinical signs resolved in all cats. Technetium scans of 4 cats made after treatment did not have evidence of isotope uptake. In the remaining 3 cats, small areas of isotope uptake, the intensity of which was equal to or less than the intensity of uptake in the salivary glands, were seen. All 7 cats became hypothyroid after treatment; 4 required L-thyroxine supplementation. One cat was alive 33 months after treatment. The other 6 cats were euthanatized because of unrelated diseases 10 to 41 months after treatment.

mtDNA sequence variation was examined in 60 Native Americans (Mixtecs from the Alta, Mixtecs from the Baja, Valley Zapotecs, and Highland Mixe) from southern Mexico by PCR amplification and high-resolution restriction endonuclease analysis. Four groups of mtDNA haplotypes (haplogroups A, B, C, and D) characterize Amerind populations, but only three (haplogroups A, B, and C) were observed in these Mexican populations. The comparison of their mtDNA variation with that observed in other populations from Mexico and Central America permits a clear distinction among the different Middle American tribes and raises questions about some of their linguistic affiliations. The males of these population samples were also analyzed for Y-chromosome RFLPs with the probes 49a, 49f, and 12f2. This analysis suggests that certain Y-chromosome haplotypes were brought from Asia during the colonization of the Americas, and a differential gene flow was introduced into Native American populations from European males and females.

The last chapter discussed soil models describing behaviour caused by one-dimensional changes in normal stress. In this chapter, we will consider a very simple soil model describing the behaviour of soil subjected to shear. Before examining this model, however, it will be useful to have a general understanding of the way in which real soils are found to behave.

A system of surface and body forces applied to a body will cause changes in the stresses and strains within it. The changes in strain will usually be partly elastic and immediately recoverable, but may also result in part from irrecoverable plastic yield. As the forces increase, a growing part of the body may reach the limit of its shear strength. Once this part is sufficiently extensive to form an unstable mechanism, unlimited yield will occur. This will continue as long as the forces can be maintained in the face of the changing geometry of the body. This unlimited yield is called collapse, and the system of forces which will produce it is called the collapse load.

The clay minerals are a group of complex alumino-silicates, mainly formed during the chemical weathering of primary minerals. Because of their small size and flat shape, they have very large specific surfaces. There is usually a negative electric charge on the crystal surfaces, and the electro-chemical forces on these surfaces are therefore predominant in determining their engineering properties. In order to understand why these materials behave as they do, it will be necessary to examine their crystal structure in some detail.

It was shown in Section 6.18 above that the classical Mohr-Coulomb soil model has two important implications. These are: (a) that the volume changes which commonly accompany shear strains have no effect on the shear strength, and (b) that the shear strength is independent of the intermediate principal stress component.

In Section 8.22, we showed that, for material stability, the lateral pressure in the soil may have any value between the maximum or passive pressure p p and the minimum or active pressure p a , the actual value depending on the lateral strains. The condition of zero lateral strain is of particular interest, since it closely approximates to the state of strata of large lateral extent, consolidating under a uniform increase of overburden. The coefficient of earth pressure at rest (K 0) is defined as the ratio σ′ x /σ′ z for this condition of no lateral strain.

Consider a point B in a mass of saturated uniform porous soil. Let B be at a height z above some arbitrary datum level (A-A in Fig. 4.1), and let the pore pressure at B be u. A column of water in equilibrium with the pore pressure at B would rise to a Open image in new window Fig. 4.1 Total head and hydraulic gradient. height u/γ w above B. The total head (h) at B is defined as the height of this column of water above the datum level. The total head (h) is equal to the sum of the position head and the pressure head: $$ h = z + u/\gamma _w $$

The purpose of a structural foundation is to transfer the structural loads safely to the ground below. Failure of a foundation may take one of two forms [11.9]: (a) Catastrophic collapse of the soil beneath the foundation, if the shear strength is inadequate to support the applied load. Failures of this type are not very common, but, where they do occur, they may lead to large movements and distortion of the superimposed structures, and they may take place very rapidly. (b) Excessive settlement of the structure, due in part to distortion of the soil mass as a result of the applied shear stresses, and in part to consolidation of the soil as a result of the increased normal stresses.

Most of the Earth’s land surface, and parts of the bed of the sea, are covered with a layer of granular sediments, mainly derived from the breakdown and decomposition of rocks. Where such sediments either remain entirely uncemented, or are so lightly cemented as not to change their essentially particulate nature, or where cemented materials have been broken up by excavation, they are described as soils. It is this particulate or granular nature which distinguishes soils, in the general engineering sense, from rocks.

The voids between the solid particles of soil are filled with fluid—either water or air or a combination of the two. Except perhaps within the adsorbed water layers, these fluids can offer no resistance to static shear forces. They can, however, support normal pressures, and these normal pressures form part of the total stress in the soil.

A thorough investigation of the site is an essential preliminary to the construction of any civil engineering works. The British Standard Code of Practice defines the objects of such an investigation to be as follows: (a) To assess the general suitability of the site for the proposed works. (b) To enable an adequate and economical design to be prepared. (c) To foresee and provide against difficulties that may arise during construction due to ground and other local conditions. (d) To investigate the occurrence or causes of all natural or created changes of conditions and the results arising therefrom [15.1].

Failure of a slope frequently takes the form of quite large translational or rotational movements of a body of soil having a lower boundary deep within the soil mass. The stability of the slope with respect to this type of failure may be analysed by any of the methods described in Chapter 8, but most of the methods in general use depend on considerations of limiting equilibrium (Section 8.27). Failure is assumed to occur as a result of sliding along a rupture surface at the lower boundary of the moving soil mass, and a systematic search is made for the rupture surface which yields the least factor of safety against this form of failure.

In solving a problem in soil mechanics, the first step is to build up a mathematical model of the material. This model consists of a set of statements describing, in mathematical terms, the behaviour of the material when subjected to changes in external forces, pore pressures, displacements, etc. The statements are usually given in the form of general expressions describing the behaviour of some general class of materials, but they contain parameters to which numerical values may be assigned after tests on a particular material.

Hawkinsinuria, a disorder of tyrosine metabolism has been documented in two families in the United States, in one of which there was clear evidence of autosomal dominant inheritance. Metabolic acidosis and failure to thrive appear to be confined to infancy. Tyrosyl metabolites and 5-oxoproline are also found only in infancy, while 4-hydroxycyclohexylacetic acid was present only with time. The disease may be detected by organic acid analysis or by staining an electropherogram for sulfur containing compounds.

Factor IXSeattle 1 is a 10-kb intragenic deletion identified in a family that has hemophilia B. By sequencing across the site of the deletion, we discovered at the deletion junction a 13-bp sequence (5' . . . TAGAA-GTTCACTT . . . 3') that was homologous to two 14-bp sequences 10 kb apart in introns D and F of the normal factor IX gene. The presence of these homologous sequences in two different regions of the normal gene allows us to propose that genetic recombination has occurred between the sequences, resulting in the gene deletion. The precise recombination site was able to be localized to one of 5 bp (5' . . . AGTTC . . . 3') in the middle of the homologous sequences. The exact length of the deletion is 10,000 bp.

Gaucher disease is the most common lysosomal storage disease and is caused by a deficiency of glucocerebrosidase. It is typically considered an adult disorder, manifest with hematologic changes and bone fractures. The five most common genotypes, consisting of 570 patients, were selected from the ICGG Registry (2000+ patients) and stratified according to clinical symptoms. Surprisingly, 50% of all patients in the registry were less than 10 years when diagnosed. The most common genotype was N370S/N370S (38%), followed by N370S/L444P (27%), N370S/84GG (20%), L444P/L444P (11%), and N370S/IVS2+1 (4%). The age at diagnosis was 27.8 years for N370S/N370S, 17.9 years for N370S/L444P, 9.4 years for N370S/84GG, 8.9 years for N370S/IVS2+1, and 2.5 years for L444P/L444P. All patients with the N370S allele were classified as type I and were free of neurologic symptoms. 78% of children with the L444P/L444P genotype had eventual neurologic symptoms and were classified as type III. Radiologic evidence of bone disease was present in 92% of N370S/N370S, but was rare in L444P/L444P patients at diagnosis. The largest spleen volumes were in L444P/L444P (40 × norm), followed by N370S/IVS2+1 (19.1 x), N370S/84GG (18.7 x), N370S/L444P (15.4 x), and N370S/N370S (12.1 x). Some rare alleles present with unique clinical signatures. Patients homozygous for D409H are severe with aortic valve calcification. Infants homozygous for a rare recombinant allele, RecNcil, are born with “collodian” skin and severe neurologic symptoms.

Galactosylceramide beta-galactosidase activity was assayed in cultured amniotic fluid cells from two pregnancies at risk for Krabbe's leucodystrophy. The elective termination of one pregnancy was carried out after demonstration of a severe deficiency of galactosylceramide beta-galactosidase activity. The diagnosis of Krabbe's leucodystrophy in the affected fetus was confirmed enzymatically by a deficiency of galactosylceramide beta-galactosidase inbrain, liver, kidney, and cultured skin fibroblasts, and histologically by the ultrastructural demonstration of the typical intracellular inclusions in cells of the spinal cord.

Purine-nucleoside phosphorylase (NP) deficiency is associated with severely defective thymus-derived (T)-cell and normally functioning bone marrow-derived (B)-cell immunity. In this study, two unrelated families with a total of three NP deficient members were investigated. High pressure liquid chromatography of the plasma of the three patients showed inosine levels greater than 66 muM. This nucleoside was absent from the plasma of their parents and control samples.NP was purified from normal human erythrocytes by affinity chromatography and an antiserum prepared in rabbits was used to study the NP variants in the two families. In family M the patient had no detectable erythrocyte NP activity and no detectable immunological-reacting material (irm) to the NP antibody. The parents, who are second cousins, had less than one-half of normal enzyme activity and approximately 14% irm attributable to a variant protein. Their electrophoretic patterns revealed a series of isozymes with slower than normal migration. In family B the patients had 0.5% residual enzyme activity and about one-half normal irm. Their electrophoretic pattern showed faintly staining bands which migrated faster than normal NP. The mother of the patients had one-half normal enzyme activity, 11% irm attributable to her variant protein, and a normal electrophoretic pattern. The father had less than one-half normal enzyme activity, equal amounts of normal and variant irm, and an electrophoretic pattern that showed increased activity of the more rapidly migrating isozyme bands.The combined use of immunological and electrophoretic techniques has shown the presence of three separate mutations; one in family M and two in family B associated with severely defective T-cell function.

Human pyrimidine nucleoside monophosphate kinase is a polymorphic enzyme having two allelic gene products, UMPK 1 and UMPK 2, in several populations. A procedure is described for the partial purification of this enzyme from human red blood cells resulting in a 1500-fold purification of the enzyme for UMPK 1 and 583-fold for UMPK 2. The purified enzyme preparation catalyzed the phosphorylation of UMP, CMP, and dCMP, and used ATP as the preferred phosphate donor. The heavy metals, mercury, and copper, were found to be strong inhibitors of pyrimidine nucleoside monophosphate kinase activity. EDTA was found to protect the enzyme from inactivation by the heavy metals, and 2-mercaptoethanol stabilized the enzyme during purification. UMPK 1 and UMPK 2 were found to have similar kinetic properties; however, UMPK 2 had a slower electrophoretic mobility and greater thermolability than UMPK 1.

To predict the stresses and displacements in soil beneath a flexible foundation it has been found that a better agreement with observed results is obtained by assuming that Young's modulus increases with depth. An outline is given of a finite element method which has been used to study the behaviour of a rigid circular plate on a half-space together with an extension of the method to allow for plate flexibility. In this note, the authors provide influence coefficients from which the contact stress and settlement may be computed. /TRRL/