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.

Polar motion from laser tracking of artificial satellites.

Measurements of the range to the Beacon Explorer C spacecraft from a single laser tracking system at Goddard Space Flight Center have been used to determine the change in latitude of the station arising from polar motion. A precision of 0.03 arc second was obtained for the latitude during a 5-month period in 1970.

The Lunar Laser Ranging Experiment: Accurate ranges have given a large improvement in the lunar orbit and new selenophysical information.

The lunar ranging measurements now being made at the McDonald Observatory have an accuracy of 1 nsec in round-trip travel time. This corresponds to 15 cm in the one-way distance. The use of lasers with pulse-lengths of less than 1 nsec is expected to give an accuracy of 2 to 3 cm in the next few years. A new station is under construction in Hawaii, and additional stations in other countries are either in operation or under development. It is hoped that these stations will form the basis for a worldwide network to determine polar motion and earth rotation on a regular basis, and will assist in providing information about movement of the tectonic plates making up the earth's surface. Several mobile lunar ranging stations with telescopes having diameters of 1.0 m or less could, in the future, greatly extend the information obtainable about motions within and between the tectonic plates. The data obtained so far by the McDonald Observatory have been used to generate a new lunar ephemeris based on direct numerical integration of the equations of motion for the moon and planets. With this ephemeris, the range to the three Apollo retro-reflectors can be fit to an accuracy of 5 m by adjusting the differences in moments of inertia of the moon about its principal axes, the selenocentric coordinates of the reflectors, and the McDonald longitude. The accuracy of fitting the results is limited currently by errors of the order of an arc second in the angular orientation of the moon, as derived from the best available theory of how the moon rotates in response to the torques acting on it. Both a new calculation of the moon's orientation as a function of time based on direct numerical integration of the torque equations and a new analytic theory of the moon's orientation are expected to be available soon, and to improve considerably the accuracy of fitting the data. The accuracy already achieved routinely in lunar laser ranging represents a hundredfold improvement over any previously available knowledge of the distance to points on the lunar surface. Already, extremely complex structure has been observed in the lunar rotation and significant improvement has been achieved in our knowledge of lunar orbit. The selenocentric coordinates of the retroreflectors give improved reference points for use in lunar mapping, and new information on the lunar mass distribution has been obtained. Beyond the applications discussed in this article, however, the history of science shows many cases of previously unknown, phenomena discovered as a consequence of major improvements in the accuracy of measurements. It will be interesting to see whether this once again proves the case as we acquire an extended series of lunar distance observations with decimetric and then centimetric accuracy.

Laser ranging retro-reflector: continuing measurements and expected results.

After successful acquisition in August of reflected ruby laser pulses from the Apollo 11 laser ranging retro-reflector (LRRR) with the telescopes at the Lick and McDonald observatories, repeated measurements of the round-trip travel time of light have been made from the McDonald Observatory in September with an equivalent range precision of +/-2.5 meters. These acquisition period observations demonstrated the performance of the LRRR through lunar night and during sunlit conditions on the moon. Instrumentation activated at the McDonald Observatory in October has yielded a precision of +/-0.3 meter, and improvement to +/-0.15 meter is expected shortly. Continued monitoring of the changes in the earth-moon distance as measured by the round-trip travel time of light from suitably distributed earth stations is expected to contribute to our knowledge of the earth-moon system.

Apollo 11 Laser Ranging Retro-Reflector: Initial Measurements from the McDonald Observatory.

Acquisition measurements of the round-trip travel time of light, from the McDonald Observatory to the Laser Ranging Retro-Reflector deployed on the moon by the Apollo 11 astronauts, were made on 20 August and on 3, 4, and 22 September 1969. The uncertainty in the round-trip travel time was +/- 15 nanoseconds, with the pulsed ruby laser and timing system used for the acquisition. The uncertainty in later measurements of a planned long-term sequence from this observatory is expected to be an order of magnitude smaller. The successful performance of the retro-reflector at several angles of solar illumination, as well as during and after a lunar night, confirms the prediction of thermal design analyses.

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.

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.

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.

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.

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.

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)

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.

Learning in surgical and functional hemidecorticate rats: a preliminary study of compensation.

A case is made for the conjoint use of surgical and functional hemidecorticate preparations in the investigation of compensation. Direct comparison of the effects of surgical and functional hemidecortication in rats in an active runway avoidance learning situation is reported. Trials to successively higher avoidance criteria, total avoidance responses, longest runs of consecutive avoidance responses, response latencies and running times are compared. None of these measures reveal differences between the two types of hemidecorticate preparation, although compared with a normal group both hemidecorticate groups show a deficit. The implications of this finding in terms of the compensation issue are discussed.

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.

Further experimental analysis of the social learning and transmission of foraging information amongst Norway rats.

Adult male Norway rats were tested to see if their foraging efficiency could be improved by social learning and to investigate whether foraging information could be socially transmitted along a chain of animals. In Experiment 1, 'observers' were placed in one of four conditions, distinguished by the nature of their experience during an observation phase, in which they either observed: (1) a trained conspecific unearthing buried carrot; (2) a trained conspecific digging; (3) carrot pieces only; or (4) an empty enclosure (the control group). When tested 24 h later it was found that subjects in group 1 alone exhibited a significantly elevated foraging ability relative to the control group, being more active, and unearthing more carrot pieces in total. The results show that perception of a trained demonstrator conspecific successfully foraging for food is necessary for social learning of foraging information to occur, probably by a local enhancement mechanism. In Experiment 2, chains of transmission were established by allowing each observer to act 24 h later as the demonstrator for the next observer. In one of two transmission groups subjects were given an extra period of individual foraging experience in the test enclosure, with no demonstrator present. Enhanced levels of foraging efficiency were maintained across eight transmission episodes for both transmission groups relative to a no-transmission control. Subjects in the group with the additional experience unearthed significantly more buried food than subjects in the other transmission group. The experiments extend our standard transmission group was upheld. The superior performance of demonstrators in this group, as reflected in their higher level of carrot digging, suggests that the extra period of experience did indeed enhance their ability to act as effective demonstrators. The elevated performance of subjects in this group is attributed to a combination of social and individual learning. This finding suggests that the stability of social transmission may, under some circumstances, be bolstered by individual reinforcement of socially learned and enhanced patterns of behaviour. It also lends support to the hypothesis, proposed to account for the findings of our earlier study, that motivational factors such as fatigue, may detract from subjects' performance as demonstrators when this demonstration follows closely after the additional period of individual experience, but that a 24 h period is sufficient to allow such motivational factors to decay. If individual experience can buttress socially learned traits then this interaction may act so as to prolong the period of time that a socially transmitted trait remains in a population. It is conceivable that an additional period of foraging longer than 10 min may further enhance subjects' subsequent performance as demonstrators. The complex relationship between individual and social learning has received little attention. It is not clear how, if at all, social learning is different from other forms of learning (Plotkin, 1988), apart from the obvious requirement that another animal somehow be involved in the social learning process. Boyd and Richerson (1985) argue that social and individual learning are, at least in humans, alternative ways of acquiring a particular behavioural variant. Most recent studies of animal social learning, on the other hand, tend to emphasize the stimulus enhancing role of the demonstrator animal (Galef, 1988a), thereby suggesting that social learning is a sub-category of individual learning. This study shows that individual learning can reinforce the acquisition and expression of socially acquired behavioural variants.

The role of social experience in the development of sexual competence in Rattus norvegicus.

To clarify the hitherto ambiguous role of pubertal social experience in determining adult sexual competence in male Rattus norvegicus , the quality of the subjects' social interactions was manipulated. In Experiment 1, subjects were raised from weaning onwards in male-only groups, in groups with limited periods of social deprivation at various ages, or in total isolation. Only the latter showed a significant degree of sexual impairment. In Experiment 2, subjects were raised in mixed-sex groups, in total physical (but not visual or olfactory) isolation from a surrounding mixed-sex group, or in physical isolation except for one hour's social contact per day with a peer. All of these subjects were sexually competent as adults. It thus appears that, in the laboratory rat, social deprivation must consist of total physical and visual and/or olfactory isolation in order to produce a significant degree of sexual impairment.

[Alcoholic osteopathy]. / Osteopatía alcohólica.

Alcohol intake is one of the multiple risk factors for developing osteoporosis. Alcohol has direct toxic effects on osteoblasts which determines lower osteocalcin levels at an early stage, and histomorphometric changes later on. Some authors found not only diminished bone formation in alcoholics, but also increased bone resorption. The effect of alcoholism on calciotropic hormones includes fall of PTH serum levels after an acute or moderate alcohol intake, causing transient hypoparathyroidism. In chronic alcoholism, serum levels of vitamin D and its metabolites are decreased independently of any liver disease, probably related to alcohol influence on enzymatic systems. The mineral homeostasis of alcoholics is affected: hypocalcemia is found in acute intoxication, with hypo or hypermagnesemia. In chronic alcoholism the serum calcium values tend to be normal. Alcohol intake causes multiple endocrine changes that lead to hypogonadism in both sexes. The stimulation of hypothalamus-hypophyseal-adrenal axis contributes to the alcoholic bone disease, because of the adverse effects of corticoids on bone. Caloric and protein malnutrition, in addition to a dissipated life style are additional risk factors for the development of osteoporosis.

[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.