Dental anomalies as a possible clue of 1p36 deletion syndrome due to germline mosaicism: a case report.

BACKGROUND: Monosomy 1p36 is the most common terminal deletion syndrome with an autosomal dominant pattern of inheritance. This syndrome is defined by an extremely wide spectrum of characteristics; however, developmental delay and intellectual disability of various degree are present in all patients and about the 90% of patients have a severe intellectual disability. Dental agenesis or other dental anomalies have not been described in previous reports. CASE PRESENTATION: We report the case of two little sisters born from healthy and non-consanguineous parents, presenting with dental anomalies and one of them with epilepsy, dilated cardiomyopathy with left-ventricular non-compaction, strabismus, history of poor growth, hypotonia and mild language delay. Patients were evaluated in several departments (genetic, child neuropsychiatric, cardiology, odontostomatology, ophthalmology, otorhinolaryngology) of Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. They underwent investigations such as electrocardiogram, echocardiogram, dental orthopantomography X-Ray and Computed Tomography, electroencephalograms, abdomen ultrasound, blood tests, IQ tests, genetic analysis. They both have an Intelligence Quotient greater than 70 and a negative neurologic exam. Each sister carries the same 1p36 deletion of about 2.3 Mb. Genetic analysis of the parents' blood samples (Single Nucleotide Polymorphism- array, karyotype and Fluorescent In Situ Hybridization) did not reveal any deletion, translocation or inversion and confirmed the paternity. A third sib of the probands does not carry the 1p36 deletion or other quantitative alterations. CONCLUSION: This report describes a new trait linked to monosomy 1p36, namely a mild intellectual outcome associated with significant dental anomalies. Our finding suggests that 1p36 deletion syndrome may present with a mild cognitive impairment or even with a normal intellectual development: this is very important for the genetic counselling, especially in a prenatal setting. Moreover, we report the third study with recurrent 1p36 deletion syndrome in two siblings, likely due to germline mosaicism. Finally, we believe that the dental anomalies should be investigated in 1p36 deletion syndrome and that the spectrum of the condition could be broader than we assume.

Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease.

PURPOSE: This study was designed to assess the effect of calcium on the efficacy of DEB during revascularization of steno-obstructive SFA lesions. METHODS: Sixty patients with de novo lesions of the superficial femoral artery underwent endovascular treatment with drug eluting balloons (DEB). DEB was selected according to vessel reference diameter (1:1). In case of residual stenosis > 50 % or flow-limiting dissection, postdilatation with conventional balloon or provisional stenting was done. Patients were classified into eight groups according to circumferential distribution of calcium on CT-angiography axial images (from 0° to 360°) and to its length (length < or > 3 cm) evaluated with digital-subtraction-angiography. Ankle-brachial index (ABI), late lumen loss (LLL), target lesion revascularization (TLR), primary (PP) and secondary (SP) patency, major adverse events (MAE), and Rutherford shift were evaluated at 1-year follow-up and correlated with the amount of calcium. RESULTS: Revascularization was successful in all cases. Flow-limiting dissection occurred in five cases (8.3 %) with a higher circumferential degree of calcium and solved in three cases with postdilatation and in the other two with provisional stenting. DEB effect was lower in patients with higher degree of calcium (>270° vs. <90°): ABI 0.71 ± 0.07 versus 0.92 ± 0.07; LLL 0.75 ± 0.21 versus 0.45 ± 0.1; PP 50 versus 100 %; SP 50 versus 100 %; TLR 25 versus 0 %; MAE 25 versus 0 %. CONCLUSIONS: Calcium represents a barrier to optimal drug absorption. Circumferential distribution seems to be the most influencing factor with the worst effect noticed in 360° calcium presence.

Cystinuria type I: identification of eight new mutations in SLC3A1.

BACKGROUND: Cystinuria is a heritable disorder of amino acid transport characterized by the defective transport of cystine and the dibasic amino acids through the brush border epithelial cells of the renal tubule and intestine tract. Three types of cystinuria (I, II, and III) have been described based on the urinary excretion of cystine and dibasic amino acids in obligate heterozygotes. The SLC3A1 gene coding for an amino acid transporter named rBAT is responsible for type I cystinuria, whereas the SLC7A9 gene coding for a subunit (b0,+AT) of rBAT is involved in determining non-type I (types II and III) cystinuria. METHODS: The SLC3A1 gene sequence was investigated in a sample of seven type I/type I, three type I/non-type I, six type I/untyped, and four untyped unrelated cystinuric patients by RNA single-strand conformation polymorphism (RNA-SSCP). RESULTS: Eight new point mutations (S168X, 765+1G>T, 766-2A>G, R452Q, Y461X, S547W, L564F, and C673W) and seven previously reported mutations were detected. These new mutations increase the number of mutated alleles so far characterized in SLC3A1 to 62. CONCLUSIONS: We have found SLC3A1 mutations in 0.739 of the type I chromosomes studied. The relatively high proportion of uncharacterized type I chromosomes suggests either that there may be mutations not yet found in SLC3A1 or that many of the assigned type I chromosomes in mixed type I/non-type I patients may have mutations in SLC7A9. If the hypothesis is excluded in the future, we believe that a third gene may be involved in cystinuria.

Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria.

Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine. Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (b(o,+)AT), cause non-Type I cystinuria. Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients. These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found. Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids. Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity. In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b(o,+)AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in non-conserved residues give rise to a mild phenotype. These data provide the first genotype-phenotype correlation in non-Type I cystinuria, and show that a mild urinary phenotype in heterozygotes may associate with mutations with significant residual transport activity.

Ethnicity and analgesic practice.

STUDY OBJECTIVE: We previously reported that Hispanic ethnicity was an independent risk factor for inadequate analgesic administration among patients presenting to a single emergency department. We then attempted to generalize these findings to other ethnic groups and EDs. Our current study objective is to determine whether black patients with extremity fractures are less likely to receive ED analgesics than similarly injured white patients. METHODS: We conducted the following retrospective cohort study at an urban ED in Atlanta, GA. All black and white patients presenting with new, isolated long-bone fractures over a 40-month period were studied. After abstracting demographic information from the medical record and subsequently removing ethnic identifiers, we submitted the medical record to a physician who recorded characteristics of the patients' injury and treatment. We then submitted the records to a nurse, again blinded to ethnicity, who recorded analgesic administration. We used multiple logistic regression to determine the independent effect of ethnicity on analgesic use while controlling for multiple potential confounders. Our main outcome measure was the proportion of black versus white patients receiving ED analgesics. RESULTS: The study group consisted of 217 patients, of whom 127 were black and 90 were white. White patients were significantly more likely than black patients to receive ED analgesics (74% versus 57%, P =.01) despite similar records of pain complaints in the medical record. The risk of receiving no analgesic while in the ED was 66% greater for black patients than for white patients (relative risk 1.66, 95% confidence interval, 1.11 to 2.50). This effect persisted after controlling for multiple potential confounders. CONCLUSION: Black patients with isolated long-bone fractures were less likely than white patients to receive analgesics in this ED. No covariate measured in this study could account for this effect. Our findings have implications for efforts to improve analgesic practices for all patients.

Three-dimensional volumetric ultrasound imaging of arterial pathology from two-dimensional intravascular ultrasound: an in vitro study.

The objectives of this study were to evaluate: (1) the feasibility of generating three-dimensional (3-D) ultrasound (US) volumetric images of arterial segments from intravascular (IV) US images by retaining full range of gray levels; (2) the feasibility of volumetric quantitation of various arterial wall pathology from the 3-D volume US images of arterial segments. IVUS provides morphologic details of arterial wall diseases. This is seen as variation in gray levels. However, when a 3-D US image is generated currently, the full range of gray levels is not utilized. This limits optimal assessment of arterial wall pathology. Sequential cross-sectional IVUS images from 11 arterial segments consisting of various pathology were obtained in vitro by calibrated withdrawal of an IVUS catheter. These images were digitized by an 8 bit digitizer to retain full 256 gray levels of brightness. 3-D volume generation was carried out using "ANALYZE" software. After the IVUS imaging, arterial segments were sectioned transversely in a 0.3-0.4 mm cross section and stained with hematoxylin, eosin and elastin. Geometrical measurements and gross morphological changes of the arterial segments were noted and correlated with the corresponding section of the image from the three-dimensional volume. Arterial wall pathology, its extent and its effect on lumen geometry were easily appreciated in multiple tomographic sections of a 3-D volume image. Similarly, arterial wall pathology was easily quantitated from 3-D volume. The above assessments were only feasible by retaining full range of gray levels in the 3-D volume image. This study indicates that (1) it is feasible to generate a 3-D US volume image by retaining full range of gray levels from IVUS images, (2) retaining full range of gray levels allows optimal assessment of arterial wall pathology and its extent in 3-D volume, and (3) IVUS allows quantitation of arterial wall pathology, and thereby one can assess the effect of intervention.

High precision quantitative angiography.

Statistical considerations on the precision in the determination of blood vessel dimensions from digitized cine angiographic images are described. The resolution requirements related to "point measurements" and segmental diameter curve evaluations are discussed. The error associated with inaccurate determination of the vessel's centerline is analyzed. The concepts have been implemented on a high-speed image analyzing system, which measures blood vessel diameters with advanced automation. The performance of the system was evaluated with blood vessel phantoms, ranging in diameter from 0.88 to 6.26 mm. For these phantoms the minimum measurable change in vessel dimension over 20-pixel (-1.1 mm) long segments ranged from 3.4 to 0.2 percent, respectively.

Reproductive technologies: the two sides of the glass jar.

From our knowledge of fertilization and implantation, new methods of reproduction have been developed. These new reproductive technologies make possible new parenting arrangements, resetting the biological clock for women, selecting the timing of birth, sex and number of children, pre-implantation diagnosis and gene replacement. The new ways of making babies present us with a myriad of ethical, legal, social and psychological concerns.

Simultaneous assay of hydrocodone bitartrate and acetaminophen in a tablet formulation.

A reversed-phase pressurized liquid chromatographic procedure is presented for the simultaneous quantitation of hydrocodone bitartrate and acetaminophen in a tablet formulation. The separation method was based on an octadecylsilane column with a buffered (pH 4.5) methanol-water mobile phase. Measurement was with a UV spectrophotometer set at 283 nm, compared to external standards. Assays for the active ingredients in tablet samples averaged 99.7% of the label claim for hydrocodone bitartrate and 100.3% for acetaminophen. The respective relative standard deviations of the retention time and precision were 2.2 and 1.75% for hydrocodone and 3.3 and 0.95% for acetaminophen. The range of interest studied was 0.035 to 0.065 mg/ml for hydrocodone bitartrate and 3.50 to 6.50 mg/ml for acetaminophen. The assay method was also compared to colorimetric and USP procedures for the active ingredients. The method was suitable for control, content uniformity, and stability-indicating use.

Giant cell tumor in Paget's disease of bone: familial and geographic clustering.

Four patients with benign giant cell tumor and one patient with probable benign giant cell tumor associated with Paget's disease of bone are reported. The familial and geographic clustering of these cases is unique in that three patients were related and all patients traced ancestral roots to the same area of southern Italy. Tumors arose from the cranial or facial bones in three patients and from vertebral bodies in two patients. All caused symptoms by local compression, and treatment by curettage or radiotherapy was successful in all patients. Three separate tumors in one patient shrank dramatically in response to treatment with high doses of dexamethasone, and one patient whose tumor caused spinal cord compression showed marked improvement in neurologic function on therapy with dexamathasone.

Response of 1alpha,25-dihydroxyvitamin D3 to hypocalcemia in human subjects.

We determined the response of 1alpha,25-dihydroxyvitamin D3 after mithramycin-induced hypocalcemia in eight subjects with polyostotic Paget's disease of bone. Thirty-six hours after infusion of mithramycin (25 microgram per kilogram), the average calcium declined from 9.9 +/- 0.14 (S.E.M.) to 8.0 +/- 0.19 mg per deciliter (P less than 0.005). Serum parathyroid hormone increased from 122 +/- 6 to 226 +/- 36 microliter eq per milliliter (P less than 0.05), serum phosphate decreased from 3.8 +/- 0.11 to 2.9 +/- 0.14 mg per deciliter (P less than 0.005), and urinary cyclic 3,5'-adenosine monophosphate increased from 4.6 +/- 0.35 to 7.5 +/- 0.80 mumol per gram of creatinine (P less than 0.005). Serum 1alpha25-dihydroxyvitamin D3 rose from 98 +/- 12 to 332 +/- 61 pM (P less than 0.05), the increase following the changes in parathyroid hormone and phosphate by 12 to 24 hours. When this lag period was taken into account, there was a significant relation (P less than 0.01) between the increase in 1alpha,25-dihydroxyvitamin D3 and changes in parathyroid hormone (correlation coefficient, r = +0.91) and phosphate (r = -0.96). The relatively rapid response of 1alpha,25-dihydroxyvitamin D3 to hypocalcemia occurs with a time course consistent with regulation by parathyroid hormone and phosphate.