Patient reported outcomes for phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG): listening to what matters for the patients and health professionals.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most common CDG is phosphomannomutase 2 (PMM2)-CDG which often has a severe clinical presentation and life-limiting consequences. There are no approved therapies for this condition. Also, there are no validated disease-specific quality of life (QoL) scales to assess the heterogeneous clinical burden of PMM2-CDG which presents a challenge for the assessment of the disease severity and the impact of a certain treatment on the course of the disease. AIM AND METHODS: This study aimed to identify the most impactful clinical signs and symptoms of PMM2-CDG, and specific patient and observer reported outcome measures (PROMs and ObsROMs, respectively) that can adequately measure such impact on patients' QoL. The most burdensome signs and symptoms were identified through input from the CDG community using a survey targeting PMM2-CDG families and experts, followed by family interviews to understand the real burden of these symptoms in daily life. The list of signs and symptoms was then verified and refined by patient representatives and medical experts in the field. Finally, a literature search for PROMs and ObsROMs used in other rare or common diseases with similar signs and symptoms to those of PMM2-CDG was performed. RESULTS: Twenty-four signs/symptoms were identified as the most impactful throughout PMM2-CDG patients' lifetime. We found 239 articles that included tools to measure those community-selected PMM2-CDG symptoms. Among them, we identified 80 QoL scales that address those signs and symptoms and, subsequently, their psychometric quality was analysed. These scales could be applied directly to the PMM2-CDG population or adapted to create the first PMM2-CDG-specific QoL questionnaire. CONCLUSION: Identifying the impactful clinical manifestations of PMM2-CDG, along with the collection of PROMs/ObsROMs assessing QoL using a creative and community-centric methodology are the first step towards the development of a new, tailored, and specific PMM2-CDG QoL questionnaire. These findings can be used to fill a gap in PMM2-CDG clinical development. Importantly, this methodology is transferable to other CDG and rare diseases with multiple signs and symptoms.

Special report on the 2007 adult and pediatric Position Development Conferences of the International Society for Clinical Densitometry.

The International Society for Clinical Densitometry (ISCD) conducts Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines in the field of bone densitometry. Topics for consideration are selected according to clinical relevance, a perceived need for standardization, and the likelihood of achieving agreement. Questions regarding nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests for each topic area are assigned to task forces for a comprehensive review of the scientific literature. The findings of the review and recommendations are then presented to an international panel of experts at the PDC. The expert panel votes on potential Official Positions for appropriateness, necessity, quality of the evidence, strength of the recommendation, and applicability (worldwide or variable according to local requirements). Recommendations that are approved by the ISCD Board of Directors become Official Positions. The first Pediatric PDC was 20-21 June 2007 in Montreal, QC, Canada. The most recent Adult PDC was held 20-22 July 2007, in Lansdowne, VA, USA. This Special Report summarizes the methodology of the ISCD PDCs and presents selected Official Positions of general interest.

Osteoporosis in children with neuromuscular diseases and inborn errors of metabolism.

The effects on bone of cerebral palsy (CP), Duchenne's muscular dystrophy and different metabolic diseases are reviewed from the literature. Children affected with neuromuscular diseases and inborn errors of metabolism may develope osteoporosis. Mechanical stimulation is paramount for bone strengthening, and immobilization is a well-known cause of osteoporosis. CP is the most common cause of disability in pediatrics. The main cause of low bone density in children and adolescents with CP and muscular dystrophy is lack of activity, but nutritional issues and pharmacological treatments can contribute to the clinical picture. Programs to exert mechanical stimulation of their bones are warranted, as much as nutritional programs. Treatment with bisphosphonates shows promising results in this population. The term ''inborn errors of metabolism'' comprise a large list of defects in the metabolism of amino acid transport and metabolism of peptides, carbohydrates, vitamins, minerals, and fatty acids. Other disorders included are errors in mitochondrial energy metabolism, problems with biosynthesis and breakdown of complex molecules, and neurotransmitter defects. Low bone density and fractures in these patients may be consequence of immobilization and muscle weakness, but also of treatments (e.g. steroids, dietary restrictions), and the primary disease. Adequate control of the primary disease is paramount to prevent bone problems.

Performance modeling of an airborne Raman water-vapor lidar.

We have developed a sophisticated Raman lidar numerical model to simulate the performance of two ground-based Raman water-vapor lidar systems. After verifying the model using these ground-based measurements, we then used the model to simulate the water-vapor measurement capability of an airborne Raman lidar under both daytime and nighttime conditions for a wide range of water-vapor conditions. The results indicate that, under many circumstances, the daytime measurements possess comparable quality to an existing airborne differential absorption water-vapor lidar whereas the nighttime measurements have improved spatial and temporal resolution. In addition, an airborne Raman lidar can offer measurements that are difficult or impossible with the differential absorption lidar technique.

Reliability of the gross motor function measure for children with osteogenesis imperfecta.

PURPOSE: The Gross Motor Function Measure (GMFM) is a criterion-referenced evaluative measure designed to detect change over time for children diagnosed with cerebral palsy (CP). Reliability of this measure has not been tested for children with osteogenesis imperfecta (OI). The purpose of this study was to determine the intra- and interrater reliabilities of the GMFM for use with children diagnosed with OI. METHOD: One physical therapist administered and scored the GMFM for 19 children with OI who were followed at the Shriners Hospital for Children. The assessments were videotaped, then viewed and scored by five physical therapists, including the author, at least six weeks later. Intra- and interrater reliabilities were assessed using intraclass correlation coefficients (ICCs). Kappa statistics were calculated for items demonstrating more disagreement than the majority. RESULTS: The ICCs for intrarater reliability of the five dimensions and total score were 0.99. The ICCs for interrater reliability were 0.98 for the lying and rolling dimension and 0.99 for the other dimensions and total score. Kappa statistics for items demonstrating more disagreement than the majority ranged from 0.552 to 1.00. CONCLUSIONS: This study provides evidence of the reliability of the GMFM for children with OI when scored by pediatric physical therapists familiar with the measure. The videotape provided a consistent situation because each therapist did not directly interact with each child, but rather rated a videotaped session of the child's performance.

The fall, recovery, orbit, and composition of the Tagish Lake meteorite: a new type of carbonaceous chondrite.

The preatmospheric mass of the Tagish Lake meteoroid was about 200,000 kilograms. Its calculated orbit indicates affinity to the Apollo asteroids with a semimajor axis in the middle of the asteroid belt, consistent with a linkage to low-albedo C, D, and P type asteroids. The mineralogy, oxygen isotope, and bulk chemical composition of recovered samples of the Tagish Lake meteorite are intermediate between CM and CI meteorites. These data suggest that the Tagish Lake meteorite may be one of the most primitive solar system materials yet studied.

Type V osteogenesis imperfecta: a new form of brittle bone disease.

Osteogenesis imperfecta (OI) is commonly subdivided into four clinical types. Among these, OI type IV clearly represents a heterogeneous group of disorders. Here we describe 7 OI patients (3 girls), who would typically be classified as having OI type IV but who can be distinguished from other type IV patients. We propose to call this disease entity OI type V. These children had a history of moderate to severe increased fragility of long bones and vertebral bodies. Four patients had experienced at least one episode of hyperplastic callus formation. The family history was positive for OI in 3 patients, with an autosomal dominant pattern of inheritance. All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. A radiodense metaphyseal band immediately adjacent to the growth plate was a constant feature in growing patients. Lumbar spine bone mineral density was low and similar to age-matched patients with OI type IV. None of the type V patients presented blue sclerae or dentinogenesis imperfecta, but ligamentous laxity was similar to that in patients with OI type IV. Levels of biochemical markers of bone metabolism generally were within the reference range, but serum alkaline phosphatase and urinary collagen type I N-telopeptide excretion increased markedly during periods of active hyperplastic callus formation. Qualitative histology of iliac biopsy specimens showed that lamellae were arranged in an irregular fashion or had a meshlike appearance. Quantitative histomorphometry revealed decreased amounts of cortical and cancellous bone, like in OI type IV. However, in contrast to OI type IV, parameters that reflect remodeling activation on cancellous bone were mostly normal in OI type V, while parameters reflecting bone formation processes in individual remodeling sites were clearly decreased. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations affecting glycine codons or splice sites. In conclusion, OI type V is a new form of autosomal dominant OI, which does not appear to be associated with collagen type I mutations. The genetic defect underlying this disease remains to be elucidated.

Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age.

Severe osteogenesis imperfecta (OI) is a hereditary disorder characterized by increased bone fragility and progressive bone deformity. Cyclical pamidronate infusions improve clinical outcome in children older than 3 yr of age with severe OI. Because earlier treatment may have potential to prevent deformities and improve functional prognosis in young children, we studied nine severely affected OI patients under 2 yr of age (2.3-20.7 months at entry) for a period of 12 months. Pamidronate was administered i.v. in cycles of 3 consecutive days. Patients received four to eight cycles during the treatment period, with cumulative doses averaging 12.4 mg/kg. Clinical changes were evaluated regularly during treatment, and radiological changes were assessed after 6-12 months of treatment. The control group consisted of six age-matched, severely affected OI patients, who had not received pamidronate treatment. During treatment bone mineral density (BMD) increased between 86-227%. The deviation from normal, as indicated by the z-score, diminished from -6.5 +/- 2.1 to -3.0 +/- 2.1 (P < 0.001). In the control group the BMD z-score worsened significantly. Vertebral coronal area increased in all treated patients (11.4 +/- 3.4 to 14.9 +/- 1.8 cm2; P < 0.001), but decreased in the untreated group (P < 0.05). In the treated patients, fracture rate was lower than in control patients (2.6 +/- 2.5 vs. 6.3 +/- 1.6 fractures/year; P < 0.01). No adverse side-effects were noted, apart from the well known acute phase reaction during the first infusion cycle. Pamidronate treatment in severely affected OI patients under 3 yr of age is safe, increases BMD, and decreases fracture rate.

Remote detection of Raman scattering by use of a holographic optical element as a dispersive telescope.

We describe the retrieval of nighttime lidar profiles by use of a large holographic optical element to simultaneously collect and spectrally disperse Raman-shifted return signals. Results obtained with a 20-Hz, 6-mJ/pulse , frequency-tripled Nd:YAG source demonstrate profiles for atmospheric nitrogen with a range greater than 1 km for a time average of 26 s.

Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.

BACKGROUND: Severe osteogenesis imperfecta is a disorder characterized by osteopenia, frequent fractures, progressive deformity, loss of mobility, and chronic bone pain. There is no effective therapy for the disorder. We assessed the effects of treatment with a bisphosphonate on bone resorption. METHODS: In an uncontrolled observational study involving 30 children who were 3 to 16 years old and had severe osteogenesis imperfecta, we administered pamidronate intravenously (mean [+/-SD] dose, 6.8+/-1.1 mg per kilogram of body weight per year) at 4-to-6-month intervals for 1.3 to 5.0 years. Clinical status, biochemical characteristics reflecting bone turnover, the bone mineral density of the lumbar spine, and radiologic changes were assessed regularly during treatment. RESULTS: Administration of pamidronate resulted in sustained reductions in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. There was a mean annualized increase of 41.9+/-29.0 percent in bone mineral density, and the deviation of bone mineral density from normal, as indicated by the z score, improved from -5.3+/-1.2 to -3.4+/-1.5. The cortical width of the metacarpals increased by 27+/-20.2 percent per year. The increases in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (P<0.001). Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of the growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. All the children reported substantial relief of chronic pain and fatigue. CONCLUSIONS: In children with severe osteogenesis imperfecta, cyclic administration of intravenous pamidronate improved clinical outcomes, reduced bone resorption, and increased bone density.

The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3.

Hypocalcemia and hyperphosphatemia caused by parathyroid hormone (PTH)-resistance are the only discernible abnormalities in pseudohypoparathyroidism type Ib (PHP-Ib). Because mutations in the PTH/PTH-related peptide receptor, a plausible candidate gene, had been excluded previously, we conducted a genome-wide search with four PHP-Ib kindreds and established linkage to a small telomeric region on chromosome 20q, which contains the stimulatory G protein gene. We, furthermore, showed that the genetic defect is imprinted paternally and thus is inherited in the same mode as the PTH-resistant hypocalcemia in kindreds with PHP-Ia and/or pseudo-pseudohypoparathyroidism, two related disorders caused by different stimulatory G protein mutations.

Dissociation of bone formation from resorption during 2-week treatment with human parathyroid hormone-related peptide-(1-36) in humans: potential as an anabolic therapy for osteoporosis.

PTH administration increases bone mass in rodents and in humans. PTH-related protein (PTHrP) binds to and signals via the skeletal PTH receptor. Administration of PTHrP on a once daily basis increases bone mineral content in rats. In humans, PTHrP-(1-36) is equipotent to PTH-(1-34) and is active when administered s.c. These findings suggest that PTHrP might have therapeutic benefit in the treatment of osteoporosis. In this study, 13 postmenopausal estrogen-deficient women received a single daily s.c. dose of PTHrP-(1-36) for a 14-day period to determine whether PTHrP-(1-36) 1) could be given in doses that do not alter systemic mineral homeostasis, but increase markers of bone turnover; and 2) is tolerated without adverse effects. Daily s.c. PTHrP-(1-36) administration caused no significant changes in serum calcium or phosphorus concentrations, fractional calcium excretion, the tubular maximum for phosphorus, fractional calcium excretion, or plasma 1,25-dihydroxyvitamin D concentrations. Nephrogenous cAMP and endogenous PTH-(1-84) declined. Importantly, markers of bone formation trended upward, as reported in subjects treated with PTH. In marked contrast to findings in PTH-treated subjects, in PTHrP-treated subjects, markers of bone resorption declined in a highly significant fashion. These observations indicate that PTHrP-(1-36) treatment uncouples bone formation from resorption, in favor of formation. This uncoupling, if it were to continue over the longer term, would predict that PTHrP-(1-36) might be a potent anabolic therapeutic agent for osteoporosis.

Gender-related differences in the relationship between densitometric values of whole-body bone mineral content and lean body mass in humans between 2 and 87 years of age.

The mineral, lean, and fat contents of the human body may be not only allometrically but also functionally associated. This report evaluates the influence of muscle mass on bone mass and its age-related changes by investigating these and other variables in both genders in the different stages of reproductive life. We have analyzed the dual-energy X-ray absorptiometry (DEXA)-determined whole-body mineral content (TBMC), lean body mass (LBM), and fat body mass data (FBM) of 778 children and adolescents of both genders, aged 2-20 years [previously reported in Bone 16(Suppl.): 393S-399S; 1995], and of 672 age-matched men and women, aged 20-87 years. Bone mass (as assessed by TBMC) was found to be closely and linearly associated with muscle mass (as reflected by LBM) throughout life. This relationship was similar in slope and intercept in prepubertal boys and girls. However, while keeping the same slope of that relationship (50-54 g increase in TBMC per kilogram LBM): (1) both men and women stored more mineral per unit of LBM within the reproductive period than before puberty (13%-29% and 33%-58%, respectively); (2) women stored more mineral than age-matched men with comparable LBM (17%-29%) until menopause; and (3) postmenopausal women had lower values of bone mineral than premenopausal women, similar to those of men with comparable LBM. Men showed no age effect on the TBMC/LBM relationship after puberty. Multiple regression analyses showed that not only the LBM, but also the FBM and body height (but not body weight), influenced the TBMC, in that decreasing order of determining power. However, neither the FBM nor body height could explain the pre/postpubertal and the gender-related differences in the TBMC/LBM relationship. Accordingly: (1) calculated TBMC/LBM and FBM-adjusted TBMC/LBM ratios were lower in girls and boys from 2-4 years of age until puberty; (2) thereafter, females rapidly reached significantly higher ratios than age-matched men until menopause; and (3) then, ratios for women and age-matched men tended to equalize. A biomechanical explanation of those differences is suggested. Sex hormones or related factors could affect the threshold of the feedback system that controls bone remodeling to adapt bone structure to the strains derived from customary mechanical usage in each region of the skeleton (bone "mechanostat"). Questions concerning whether the mineral accumulation in women during the reproductive period is related or not to an eventual role in pregnancy or lactation, or whether the new bone is stored in mechanically optimal or less optimal regions of the skeleton, are open to discussion.

[Extended use, up to 6 years, of an oral amino-bisphosphonate in patients with established osteoporosis]. / Uso prolongado, hasta 6 años, de un amino-bisfosfonato oral en pacientes con osteoporosis establecida.

In osteoporotic women (n:163), 63.8 (+/- 8.1) years old and 15.2 (+/- 8.3) years since menopause, oral (200 mg/day) pamidronate was administered during protracted periods, up to 6 years. During the first 4 years of therapy significant increases from basal in both, lumbar spine and femoral neck were reported (p < 0.01). Patients who underwent to 5-6 years of treatment also showed positive results in both skeletal sites. Whole body mineral content estimated a 23.8 g/year mean gain during a 4-year period. Biochemical bone markers of resorption and formation reflected a variable degree of bone turnover decrease. Such changes were more pronounced at the beginning, and remained steady after the first year of continuous therapy. Calcemia remained between normal range without any hypocalcemic episode being reported. Phosphatemia, within normal range, showed a smooth trend to increase. PTH remained within normal range and vitamin D tended to slightly increase. The total number of new bone fractures and total number of patients with new fractures were less frequent during the pamidronate treatment period than before (p < 0.01). Indeed, the relative risk (RR) of fracture was estimated comparing the treatment lapse, 495 patient/year, vs a pretreatment period of 1,814 patient/year. Overall RR resulted less than 1 (RR = 0.83; CI 95% = 0.53-1.26). In total, hip, forearm and "other" fractures, RR was also less than 1 and remained over 1 in vertebral fractures. The latter can be explained because our sample started its treatment probably in a period of increased spine crushing. Overall fracture results, in a sample of patients as own controls and in spite of differences in ages, suggested that during treatment, patients improved their skeletal biomechanical competence, mainly in sites where cortical bone plays a meaningful role, as in femoral neck. It is concluded that pamidronate is an effective tool to ameliorate the skeletal conditions of postmenopausal osteoporotic women.

Mineral density gain in vertebrae of osteoporotic women on oral pamidronate reverts a year after treatment discontinuance.

Long-term treatment with 200 mg dry weight/day of pamidronate (APD) by oral route has been proposed to increase bone mineral density (BMD) in postmenopausal osteoporotic women. However, there is widespread concern over the possibility of bone metabolism "freezing" by protracted use of medication liable to inhibit bone resorption. Accordingly, an open population of 39 osteoporotic women was studied in order to determine BMD variations in lumbar vertebrae and femoral neck and to confirm whether given APD doses increase bone mineralization. A parallel group of osteoporotic women was likewise evaluated to determine the potential reversibility of such effect on discontinuing treatment. Results were beneficial at both skeletal sites in subjects on APD therapy, disclosing at 18 months treatment 9.0% mean peak mineral gain versus basal status at lumbar spine. In the few responders completing 4 years of treatment, mean differences versus basal status were +4.9% in vertebrae and +6.2% at femoral neck. In lumbar vertebrae there was a rapid trend in mineral gain up to 18 months on treatment, which declined thereafter to a quarter of its early rate. Concurrently, in the group of 21 baseline-matched women, effects were evaluated after discontinuing daily APD administration one year (n = 11) or two years (n = 7) later. In both subgroups, there was a loss in lumbar (-7.1% and -9.8% respectively; p<0.01) and femoral neck BMD (-2.2% and -4.2% respectively; p: n.s.) on performing measurement one year after APD withdrawal. Furthermore, after three years treatment and subsequent discontinuance, three patients presented bone loss in lumbar vertebrae and minimal changes at femoral neck one year after APD withdrawal. Therefore, APD induces moderate BMD gain which proves reversible on discontinuing therapy, so that it seems unlikely that this compound should "freeze" bone metabolism to a significant extent. However, the precise degree of such reversibility requires evaluation in larger series.

Lumbar spine bone density in Argentine children.

It has been demonstrated that bone mineral density (BMD) in children and adolescents is influenced by individual height. The aim of the present work was to introduce a formula to include height in the BMD analysis. Postero-anterior (PA) (L2-L4) and lateral (L2-L3) lumbar BMD was assessed by dual X-ray absorptiometry (DXA) in 433 and 393, respectively, healthy Caucasian females from 2 to 20 years of age. A complete medical examination including weight, height, and Tanner puberal stage was performed in all the subjects. Bone age was assessed by left wrist radiographs and analyzed by the TW2 method to insure that it was within 1 year of chronological age. Bone mineral density adjusted for height (BMDcorr = BMC/projected area x height), was calculated for each individual. As analyzed by Tanner stage, both PA and lateral BMD increased up to stage 3, and there were no significant differences among stages 3-5. Results of BMDcorr variations related to Tanner stage suggested that the increase in lateral BMD before puberty might be related to height. PA BMDcorr increased up to Tanner stage 3, and there were no differences among stages 3-5. The BMDCORR approach can be used to get a more reliable analysis of BMD studies in children and adolescents.

Bone mass in children: normative values for the 2-20-year-old population.

Normative values for bone mass were assessed for whole body bone mineral content (WBBMC), anterior-posterior and lateral lumbar spine, radius, femoral neck, trochanter, and Ward's triangle bone mineral density in 778 healthy children and adolescents (433 females and 345 males) from 2-20 years of age from Argentina. Bone mineral content was assessed by dual energy X-ray absorptiometry (DEXA) (Norland XR-26 HS with dynamic filtration). All subjects were Caucasian. WBBMC maximum mean value for girls was found to be in the 16-year-old group with difference between gender becoming significant in the 17-year-old (p < 0.05) group. The femoral neck, trochanter, and Ward's triangle BMD values in females increased until 14 years of age, with no significant difference between age groups older than 13. In males, no difference between age groups was seen in groups older than 16 years of age. The radius BMD showed a mild increment through infancy and adolescence in boys and girls. In lumbar spine, the gender differences were significant only in those groups over 16 years old, with boys showing a greater BMD than girls (p < 0.001). When Tanner stage was considered, the anova analysis showed in males that there were significant differences between stages (1-2, 2-3, and 4-5 (p < 0.01), but no differences between stages 3-4 for all the sites. In females, there were significant differences between stages 1-2 and 2-3 (p < 0.01), but not between stages 3-4 and 4-5 for WBBMC, FNBMD and LSBMD.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-genetic transmission of information: Candidate cognitive processes and the evolution of culture.

The evolution of dual-inheritance systems, specifically the evolution of human culture, are considered as evolutionary events of profound significance. In this paper I adopt the view commonly held amongst biologists in recent years that human cultural change can be fruitfully understood as cultural evolution. Such an approach does not deny the possibility of understanding cultural change from other viewpoints. It does, however, have the advantage of having to be couched in explicitly psychological terms. Using the replicator-interactor theory of Dawkins and Hull I explore what cognitive mechanisms might be identified as having the properties of a replicator, and how reconstructions of human evolution may help in identifying such mechanisms.