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Growth and endocrine disorders secondary to cranial irradiation.

External cranial radiation for the treatment of malignant diseases has become a frequent cause of growth hormone deficiency (GHD). The timing of occurrence and the frequency of GHD were related to the hypothalamic-pituitary radiation dose. Frequency varied from 50% in leukemia (2400 cGy) to 75% in face and neck tumors or medulloblastoma (2500-4500 cGy) and up to 100% in optic glioma (greater than 4500 cGy). The significantly more severe growth deficit in patients with GHD given higher radiation doses suggests different levels of residual GH secretion according to radiation dosage. The minimum harmful radiation dose is probably close to 1800-2000 cGy. Our data show that stimulation tests remain a useful means of defining GHD and predicting growth. A fair agreement between GH secretion and growth was found in most cases, regardless of the radiation dose. The only exception was a group of leukemic children (2400 cGy) who achieved normal prepubertal growth despite a low GH response. The 24-h spontaneous plasma GH profiles and IGF-I measurements may add information if growth is retarded despite a normal GH response. We showed that growth retardation occurring after some schedules of total body irradiation was not due to GH deficiency but rather to radiation-induced skeletal lesions. Early or true precocious puberty, generally associated with GHD, was another cause of height loss. As the role of GH deficiency in the final height reduction was demonstrated in all groups of patients after cranial radiation, we suggest that hGH therapy should be considered in any child with proven GH deficiency and significant growth retardation after such radiation.

Child↗

[mTOR inhibitors: pleiotropic antiproliferative drugs].

Studies of rapamycin properties in yeast led to the discovery of TOR (target of rapamycin) and its mammalian analogue, mTOR. mTOR is a central regulator of cell growth and proliferation in response to environmental stimuli such as growth factors and nutrients. mTOR regulates several pathways, particularly translation process by controlling the activity of two proteins in response to a broad range of mitogenic stimuli, S6K1 and 4E-BP1. Inhibition of cell growth by rapamycine and analogues have been demonstrated in numerous cell types, explaining the broad development of these drugs in clinical practice. Rapamycine is a potent immunosuppressive drug used in solid organ transplantation for the prevention of allograft rejection. In oncology, mTOR inhibitors are currently evaluated in several types of cancers. They are now widely used for coating stents to reduce post-stenting restenosis after coronary angioplasty. Finally, rapamycine is now evaluated in various diseases characterized by cell growth disorders such as phacomatosis and autosomal dominant polycystic kidney disease.

Animals↗

A topical parathyroid hormone/parathyroid hormone-related peptide receptor antagonist stimulates hair growth in mice.

One of the biggest hurdles in developing peptides for the treatment of hair growth disorders is that there has been no effective method of delivering them topically. Murine hair growth can be stimulated with ip injections of the PTH/PTHrP receptor antagonist, PTH (7-34). We sought to determine whether we could deliver PTH (7-34) topically and achieve stimulation of hair growth. We prepared a topical cream by mixing PTH (7-34) into a liposome vehicle (Novasome A). We applied the cream daily to the backs of 5-wk-old female SKH-1 hairless mice for 1 wk. After the 1 wk of treatment, there was marked stimulation of hair growth in the SKH-1 hairless mice. Relative to controls, mice treated with PTH (7-34) had 216% longer hairs (P < 0.001), 40% more visible hairs (P < 0.001), and 43% more hair follicles stained with 5-bromo-2'-deoxyuridine (P < 0.01). A unique aspect of skin is the possibility to directly target it via topical treatment. Our study is the first to report the hair-stimulating effect of a PTH/PTHrP receptor antagonist topically applied to skin in vivo. Thus, we introduce a novel paradigm to develop topical PTH analogs for treating disorders of hair growth.

Administration, Topical↗

[The effect of enterocystoplasty in childhood on linear growth].

OBJECTIVE: The assumption that enterocystoplasty in children has a detrimental effect on linear growth has been based almost exclusively upon a chance finding in a retrospective study 10 years ago. We re-evaluated the same research question in a larger cohort and with a longer follow-up. PATIENTS AND METHODS: Between 1982 and 1997, 242 children and adolescents underwent enterocystoplasty. Patients with conditions involving organ systems apart from the urinary tract, and those with myelomeningocele, malignant diseases, reduced glomerular filtration rate and incomplete notes were excluded. In the definitive study cohort (123; mean age at operation 8.6 years; mean age at investigation 16.8 years), enterocystoplasty had been undertaken using colon in 70, ileum in 37, a combination of both in 11, ileocaecal segments in three and stomach in two patients. RESULTS: In all, 1215 height and weight measurements had been recorded. The distribution of percentile positions before and after enterocystoplasty showed a normal configuration, with 83 % and 80 % of patients growing within two standard deviations of the 50th percentile. After surgery, 85 % either remained the same or reached a higher percentile. Nineteen (15.5 %) were in a lower position, with a similar tendency in the weight percentile. A clinically relevant growth disorder was recognized in four patients with a complete endocrinological evaluation; in none of these was enterocystoplasty thought to be a causal factor. CONCLUSIONS: It is very unlikely that loss of the preoperative percentile position on the growth curve in 15 % of children after enterocystoplasty is a consequence of that particular surgery. Rather, it is a non-specific phenomenon that has to be considered in any clinical population of the same size and age distribution after the same length of time.

Adolescent↗

Height velocity screening: the real world.

To assess the value of the Middlesex-Height Velocity Screening Chart (based on the 50th velocity percentile +/- 1 SD) as a means of screening for abnormal growth in children, the heights of children at seven infant schools were measured on two separate occasions at least 12 months apart. A total of 229 children of mid-age (age of the child between the two measurements) ranging from 4.5 to 6.8 years were measured. Height velocity standard deviation score was calculated for each child by comparison with current Tanner-Whitehouse standards. The subjects were children who had a height recorded during the school entrant medical at least 12 months before the date of the second height measurement. The height velocity standard deviation score calculated for each child was related to the limits set by the Middlesex Screening Chart, and these criteria were used to determine whether or not the child had a 'normal' growth rate. It has been recommended that those falling outside these limits are referred for further assessment. It was found that 95 (41 percent) children fell outside the 'normal' range on the Middlesex chart (66 growing faster and 29 slower), which, if the guidelines were used uncritically, would result in the possible referral of 2500 5-6-year-olds in Sheffield alone. Taking into consideration the additional problems inherent in making two accurate height measurements from which a height velocity could be calculated, and the high number of referrals that would be generated as demonstrated by this study, height velocity screening for growth disorders using current methods is not feasible.

Anthropometry↗

Enterocystoplasty in childhood: a second look at the effect on growth.

OBJECTIVE: To re-evaluate the assumption that enterocystoplasty in children has a detrimental effect on linear growth (which is almost exclusively based upon a chance finding in a retrospective study 10 years ago) in a larger cohort and with a longer follow-up. PATIENTS AND METHODS: The original 12 children who had impaired linear growth in a previous study 10 years earlier were re-measured. A larger cohort was identified from the 242 children and adolescents who had undergone enterocystoplasty between 1982 and 1997. Patients with conditions involving organ systems apart from the urinary tract, and those with myelomeningocele, malignant diseases, reduced glomerular filtration rate and incomplete notes were excluded. In the definitive study cohort (123; mean age at operation 8.6 years; mean age at investigation 16.8 years) enterocystoplasty had been undertaken using colon in 70, ileum in 37, a combination of both in 11, ileocaecal segments in three and stomach in two patients. RESULTS: Of the original 12 patients, six had regained or surpassed their preoperative position on their growth charts. In all patients with a known target centile range the final height was within their genetic growth potential. In the cohort of 123 patients, 1215 height and weight measurements had been recorded. The distribution of percentile positions before and after enterocystoplasty showed a normal configuration, with 83% and 80% of patients growing within two standard deviations of the 50th percentile. After surgery, 85% either remained on the same or reached a higher centile. Nineteen (15.5%) were in a lower position, with a similar tendency in the weight centile. A clinically relevant growth disorder was recognized in four patients with a complete endocrinological evaluation; in none of these was enterocystoplasty thought to be a causal factor. CONCLUSIONS: It is very unlikely that the loss of the preoperative percentile position on the growth curve in 15% of children after enterocystoplasty is a consequence of the surgery. Rather it is a non-specific phenomenon that has to be considered in any clinical population of the same size and age distribution after the same length of time.

Adolescent↗

Changes in serum type I and III procollagen levels in children with chronic renal failure.

Serum levels of carboxyterminal propeptide of type I procollagen (PICP) and aminoterminal propeptide of type III procollagen (PIIINP) can be used as markers of bone formation and the evaluation of children with growth disorders. We measured the serum levels of these collagens with radioimmunoassay in 24 children aged between 4 and 14 years with chronic renal failure (CRF; n = 12 dialysis, n = 12 nondialysis) and 12 age-matched healthy controls, to find out whether these parameters have a prognostic or therapeutic value in monitoring the growth retardation in CRF. Mean serum PIIINP levels in the dialysis patients were higher than in the control group; the difference between the groups was statistically significant (p < 0.05). It seemed that the pubertal stage of the patients did not affect the levels of PICP and PIIINP. There was no significant correlation between PICP and PIIINP in any patients. Neither PICP nor PIIINP correlated with the height z-score or bone age. It was concluded that the increased serum PIIINP levels in renal patients might be accepted as a poor prognostic factor leading to progressive renal failure and end-stage renal disease. Further investigations into the effects of these collagens on growth failure associated with CRF are needed.

Adolescent↗

Essentials of growth diagnosis.

There is more to growth than GH. Growth disorders can be approached expeditiously by assessing the relationships among height, weight, BA and height velocity. Undernutrition is indicated by low weight for height; diabetes mellitus, hyperthyroidism, and electrolyte disturbances are the major endocrine considerations. Short stature results from intrinsically short, delayed, or attenuated growth patterns. Excessive stature results from intrinsically tall, advanced, or accelerated growth patterns. Each of these patterns causing linear growth abnormalities has a distinct differential diagnosis that variously includes endocrine, metabolic, genetic, and systemic disorders.

Adult↗

[Listening to the parents of short stature children: the role of the pediatrician].

The pediatrician must be aware of the psychological problems of parents with children suffering from growth disorders. The announcement of the diagnosis of an untreatable disorder is made easier when the psychosocial functioning of the family is taken into account. For some parents, psychological counseling is necessary; for others, referral to a support group may be of great help.

Age Determination by Skeleton↗

[Effect of single-dose external gamma-irradiation of 0.5 g on the development of rat's embryos].

Primigravida 4-month rats were exposed to single whole-body external gamma-radiation (137Cs, 0.5 Gy) during organogenesis on days 9 and 15 of pregnancy. The embryotoxic effect of radiation was studied on the 20th day of pregnancy. The irradiation caused significant growth disorders characterized mainly by a nonuniform hypoplasia of fetus organs. This effect was most pronounced in fetuses irradiated on the 15th day of the intrauterine development.

Animals↗

Identification and assessment of the slowly growing child.

Reliable measurements taken by trained personnel using appropriate equipment are essential in assessment of the slowly growing child. Linear growth plotted on appropriate statistical charts and expected growth based on parental heights are indicators of inappropriately reduced linear growth. Children older than three years of age who grow less than 1.75 in (4.5 cm) per year should be evaluated. Family and personal medical history (including prenatal and birth information) are important in the identification of familial short stature, constitutional delay and other causes of proportionate growth disorders. Other conditions, including chromosomal disorder, systemic disease and endocrine dysfunction, may be discovered during physical examination or appropriate laboratory investigation. Disproportionate growth of the limbs and trunk suggests the presence of a bone or collagen disorder. Bone age data based on radiographs of the left hand may assist in predicting the child's final height.

Age Determination by Skeleton↗

[Importance of hand films in skeletal dysplasia (author's transl)].

The hand, as part of the skeleton, is generally involved in systemic skeletal dysplasia. However, the degree of abnormalities differs considerably in the various types of dysplasia. In some, abnormal appearance of the hand predominates, in other dysplasia films of the hand provide only little or no useful diagnostic information. At their first examination for growth disorders children often reveal bone dysplasia on roentgenograms of the hand. Therefore, evaluation of hand films should be done as thoroughly as possible. Morphologic and/or metric deviations of the hand may bring the first suspicion although they are not fully diagnostic. Systemic skeletal dysplasia should be diagnosed or excluded by additional adequate radiologic and other clinical examinations.

Adolescent↗

The regulation of growth hormone secretion.

The regulation of GH secretion involves finely balanced systems with multiple components. As our knowledge of the physiology of GH regulation expands, so does our understanding of the bases for GH diseases. We now can identify several cellular loci that cause GH deficiency or GH excess. In addition, the recent increased understanding of GH physiology has resulted in an increase in potential therapies for growth disorders.

Aging↗

[Current aspects of sickle cell disease in children in Gabon].

BACKGROUND: Clinical manifestations and course of sickle-cell anemia are variable. Knowledge about the factors, possibly geographic, that influence prognosis are still scanty. POPULATION AND METHODS: Data of hospitalization and management of children with sickle-cell disease were studied during two years (1992-1993) in the Pediatric Unit of Libreville Hospital. They concerned 205 admissions of 171 children and 131 outpatients. RESULTS: The main causes of hospitalization were: acute anemia (36 cases before the age of 5 years); painful crisis whose frequency increased with age (23% before 5 years, 35% between 5 and 10, 42% after 10 years); infections, essentially pulmonary occurring early, and bone infections at any age. Eight children died (because a complication of their disease). Among the 131 outpatients, half were detected because pyrexia, anemia and/or more often "hand-foot syndrome". More than 60% had hepatomegaly, one third still had splenomegaly after five years of age and more than one third was icteric. More than half children older than ten years had growth disorders. Mean hemoglobin level was 7 g/dL. 21 of the 83 tested children for HBsAg were positive and only one out of 79 was positive for HIV. CONCLUSIONS: Clinical manifestations and course of sickle-cell anemia in our patients are similar to those reported in Congolese children. Genetic and environmental factors may be responsible for differences with children from other, in particular French, cohorts.

Adolescent↗

Scale for assessing quality of life of children survivors of cranial posterior fossa tumors.

BACKGROUND: Evaluation of quality of life of survivors of brain tumors is an important aspect of outcome that must be included in clinical studies. METHODS: We have developed a new scale for assessing quality of life (QL) of pediatric long-term survivors of posterior fossa tumors based on their physical, psychointellectual, and endocrine/growth status. We have studied 39 patients, with a median follow-up of 9 years. Twenty-five had cerebellar astrocytoma (CA), 6 medulloblastoma (MDB), 5 brain-stem glioma (BSG) and 3 ependymoma of IV ventricle (EPD). RESULTS: Sixty-six percent of children showed neurologic and/or visual sequelae. Little or no significant disability (Bloom's levels I-II) were present in 66%. Psychointellectual dysfunction was present in 44%, with an IQ < 90 in 39%. Endocrine and growth disorders were found in 26%, mostly stature anomalies. According to our scale, QL scores were high in 19 patients (49%), intermediate in 8 (20%), and low in the remaining 12 (31%). Unfavourable outcomes were related to age of less than 4 years, tumors other than CA (MDB, BSG, EPD), incomplete tumoral resection, and employment of radiotherapy and chemotherapy. CONCLUSION: Our results are comparable to others previously reported, and this supports the validity of our scale. We consider that this scale is applicable to evaluate QL of children survivors of cranial tumors.

Age Factors↗

Managing temporal worlds for medical trend diagnosis.

The medical trend diagnosis system TrenDx has been applied as a prototype for diagnosing pediatric growth disorders, and as a proof of concept in detecting clinically significant trends in hemodynamics and blood gases in intensive care unit patients. TrenDx diagnoses trends by matching patient data to patterns of normal and abnormal trends called trend templates that define disorders as typical patterns of relevant variables. These patterns consist of a partially ordered set of temporal intervals with uncertain endpoints. Bound to each temporal interval are value constraints on real-valued functions of measurable parameters. The temporal uncertainty in trend templates allows TrenDx to conclude both what trend pattern best matches the data and also when significant landmarks and phase transitions have occurred within the best matching trend. The temporal uncertainty in trend templates requires that TrenDx consider alternate temporal worlds in monitoring patient data. The number of temporal worlds grows worst case polynomially in the number of time slices of data. To manage the competing temporal worlds, TrenDx employs two techniques: beam search based on regression scores, and temporal granularity in the trend template definitions. These two techniques, described here in detail, allow TrenDx to choose different points in the trade-off between accuracy of trend detection and algorithm efficiency.

Algorithms↗

Digital hand atlas and web-based bone age assessment: system design and implementation.

Bone age assessment is a procedure frequently performed in pediatric patients to evaluate their growth disorder. A simple method commonly used in bone age assessment is atlas matching by a radiological examination of a left-hand radiograph against a small reference set of Greulich-Pyle atlas patterns of normal standards. The method however can lead to significant deviation in age assessment, due to a variety of observers with different levels of training. The Greulich-Pyle atlas developed in the 1950s based on middle upper class white populations, is also not fully applicable for children of today, especially regarding the standard development in other racial groups. In this paper, we present our system design and initial implementation of a digital hand atlas and computer-aided diagnostic (CAD) system for Web-based bone age assessment. The CAD system is built on top of existing picture archiving and communication system (PACS), as well as recent advances in Internet technology. It consists of a hand atlas database, a CAD module and a Java-based Web user interface. The digital atlas is based on a large new set of clinically normal hand images of diverse ethnic groups. A relational image database system is used to organize hand images, their extracted quantitative features and patient data. The digital atlas removes the disadvantages of the currently out-of-date Greulich-Pyle atlas and allows the bone age assessment to be computerized. The Java-based Web user interface allows users to interact with the hand image database from browsers. Users can use a Web browser to push a clinical hand image to the CAD server for a bone age assessment. Quantitative features on the examined image, which reflect the skeletal maturity, are then extracted and compared with patterns from the atlas database to assess the bone age. The digital atlas method based on open system Internet technology provides an alternative to supplement or replace the traditional one for a quantitative, accurate and cost-effective assessment of bone age.

Adolescent↗