Contesting views on mobility restrictions in urban green spaces amid COVID-19-Insights from Twitter in Latin America and Spain.

Positive sentiments towards urban green spaces (UGS) unequivocally increased worldwide amid COVID-19. In contrast, this paper documents that views on mobility restrictions applicable to UGS are of a contested nature. That is, while residents unambiguously report positive sentiments towards UGS, they do not share views on how to administer access to UGS-which is a matter of public policy. These contesting views reflect opposite demands that managers of UGS had to balance during the pandemic as they faced the challenge of reducing risk of spread while providing services that support physical and mental health of residents. The empirical analysis in this paper relies on views inferred through a text classification algorithm implemented on Twitter messages posted from January to October 2020, by urban residents in three Latin American countries-Argentina, Colombia, and Mexico-and Spain. The focus on Latin America is motivated by the documented lack of compliance with mobility restrictions; Spain works as a comparison point to learn differences with respect to other regions. Understanding and following in real-time the evolution of contesting views amid a pandemic is useful for managers and city planners to inform adaptation measures-e.g. communication strategies can be tailored to residents with specific views.

Adaptive governance of urban green spaces across Latin America - Insights amid COVID-19.

Urban green spaces' well documented role as a hub for physical and mental health was enhanced by restrictions to mobility issued worldwide as a response to COVID-19. In this context, managers of urban green spaces (UGS) were prompted to provide controlled access under impromptu safety protocols. This unprecedented challenge required planning and operational strengths reflecting flexibility, innovation and learning. These management features are essential for an adaptive governance - an underdeveloped research topic within the study of UGS. Using eighteen semi-structured interviews from six countries, we analyze adaptive governance as reflected by UGS managers' responses across Latin America - a region where access to UGS is a matter of public health and of environmental justice. We document responses that can be categorized based on the governance arrangement in place. On one hand, both polycentric and dedicated-management governances have been able to learn through piloting ideas, adapting personnel roles and the function of UGS infrastructure, and adjusting their decision-making process. On the other hand, managers within municipal public services areas - the most prevalent governance arrangement across Latin America - report difficulty to adapt - likely due to their dependence on political will, limited autonomy, insufficient budgets, absence of formal paths to self-funding, shortage of technical know-how, and insufficient citizens' involvement. We discuss implications of UGS adaptive governance in terms of capacity to deal with future public health, climate-related or other types of shocks.

Harvesting, Embedding, and Culturing Dorsal Root Ganglia in Multi-compartment Devices to Study Peripheral Neuronal Features.

The most common peripheral neuronal feature of pain is a lowered stimulation threshold or hypersensitivity of terminal nerves from the dorsal root ganglia (DRG). One proposed cause of this hypersensitivity is associated with the interaction between immune cells in the peripheral tissue and neurons. In vitro models have provided foundational knowledge in understanding how these mechanisms result in nociceptor hypersensitivity. However, in vitro models face the challenge of translating efficacy to humans. To address this challenge, a physiologically and anatomically relevant in vitro model has been developed for the culture of intact dorsal root ganglia (DRGs) in three isolated compartments in a 48-well plate. Primary DRGs are harvested from adult Sprague Dawley rats after humane euthanasia. Excess nerve roots are trimmed, and the DRG is cut into appropriate sizes for culture. DRGs are then grown in natural hydrogels, enabling robust growth in all compartments. This multi-compartment system offers anatomically relevant isolation of the DRG cell bodies from neurites, physiologically relevant cell types, and mechanical properties to study the interactions between neural and immune cells. Thus, this culture platform provides a valuable tool for investigating treatment isolation strategies, ultimately leading to an improved screening approach for predicting pain.

Type I collagen concentration affects neurite outgrowth of adult rat DRG explants by altering mechanical properties of hydrogels.

Type I collagen is a predominant fibrous protein that makes up the extracellular matrix. Collagen enhances cell attachment and is commonly used in three-dimensional culture systems, to mimic the native extracellular environment, for primary sensory neurons such as dorsal root ganglia (DRG). However, the effects of collagen concentration on adult rat DRG neurite growth have not been assessed in a physiologically relevant, three-dimensional culture. This study focuses on the effects of type I collagen used in a methacrylated hyaluronic acid (MAHA)-laminin-collagen gel (triple gel) on primary adult rat DRG explants in vitro. DRGs were cultured in triple gels, and the neurite lengths and number of support cells were quantified. Increased collagen concentration significantly reduced neurite length but did not affect support cell counts. Mechanical properties, fiber diameter, diffusivity, and mesh size of the triple gels with varying collagen concentration were characterized to further understand the effects of type I collagen on hydrogel property that may affect adult rat DRG explants. Gel stiffness significantly increased as collagen concentration increased and is correlated to DRG neurite length. Collagen concentration also significantly impacted fiber diameter but there was no correlation with DRG neurite length. Increasing collagen concentration had no significant effect on mesh size and diffusivity of the hydrogel. These data suggest that increasing type I collagen minimizes adult rat DRG explant growth in vitro while raising gel stiffness. This knowledge can help develop more robust 3D culture platforms to study sensory neuron growth and design biomaterials for nerve regeneration applications.

Osteoporosis/osteopenia as an independent factor associated with periodontitis in postmenopausal women: a case-control study.

UNLABELLED: This study investigated whether osteoporosis/osteopenia has an influence on the progression of periodontitis in postmenopausal women. The findings highlight that postmenopausal women with osteoporosis/osteopenia had a greater chance of presenting periodontitis than those with normal bone mineral density, particularly among nonusers of osteoporosis medications and women with a greater number of remaining teeth, showing that osteoporosis/osteopenia has had an influence on the progression of periodontitis. INTRODUCTION: This study investigated whether osteoporosis/osteopenia has an influence on the progression of periodontitis in postmenopausal women and explored the effects of use of osteoporosis medication and tooth loss on this association. METHODS: This case-control study involved 521 postmenopausal women, with minimum age of 50 years, in Feira de Santana, Bahia, Brazil. Sociodemographic characteristics, health conditions/medications, and lifestyle habits were recorded. A complete periodontal examination was performed and periodontitis was diagnosed. Bone mineral density was evaluated through lumbar spine and femoral bone densitometry, obtained using dual-energy X-ray absorptiometry. Logistic regression was used to calculate the strength of association between the occurrences of osteoporosis/osteopenia and periodontitis. RESULTS: Women with osteoporosis/osteopenia were twice as likely to present periodontitis, as were those with normal bone mineral density, even after adjusting for smoking, age, family income, and last visit to dentist (odds ratios (OR)adjusted=2.24, 95% CI [1.24-4.06], p=0.008). Among nonusers of osteoporosis medication (ORadjusted=2.51, 95% CI [1.33-4.73], p=0.004) and women with at least 10 remaining teeth (ORadjusted=2.50 95% CI [1.18-5.27], p=0.02), the odds ratio was higher and statistically significant. CONCLUSIONS: These findings highlight that postmenopausal women with osteoporosis/osteopenia had a greater chance of presenting periodontitis than those with normal bone mineral density, particularly among nonusers of osteoporosis medications and women with a greater number of remaining teeth.

Engineering a multicompartment in vitro model for dorsal root ganglia phenotypic assessment.

Despite the significant global prevalence of chronic pain, current methods to identify pain therapeutics often fail translation to the clinic. Phenotypic screening platforms rely on modeling and assessing key pathologies relevant to chronic pain, improving predictive capability. Patients with chronic pain often present with sensitization of primary sensory neurons (that extend from dorsal root ganglia [DRG]). During neuronal sensitization, painful nociceptors display lowered stimulation thresholds. To model neuronal excitability, it is necessary to maintain three key anatomical features of DRGs to have a physiologically relevant platform: (1) isolation between DRG cell bodies and neurons, (2) 3D platform to preserve cell-cell and cell-matrix interactions, and (3) presence of native non-neuronal support cells, including Schwann cells and satellite glial cells. Currently, no culture platforms maintain the three anatomical features of DRGs. Herein, we demonstrate an engineered 3D multicompartment device that isolates DRG cell bodies and neurites and maintains native support cells. We observed neurite growth into isolated compartments from the DRG using two formulations of collagen, hyaluronic acid, and laminin-based hydrogels. Further, we characterized the rheological, gelation and diffusivity properties of the two hydrogel formulations and found the mechanical properties mimic native neuronal tissue. Importantly, we successfully limited fluidic diffusion between the DRG and neurite compartment for up to 72 h, suggesting physiological relevance. Lastly, we developed a platform with the capability of phenotypic assessment of neuronal excitability using calcium imaging. Ultimately, our culture platform can screen neuronal excitability, providing a more translational and predictive system to identify novel pain therapeutics to treat chronic pain.

Adapting an established Ampliseq microhaplotype panel to nanopore sequencing through direct PCR.

We have adapted an established Ampliseq microhaplotype panel for nanopore sequencing with the Oxford Nanopore Technologies (ONT) system, as a cost-effective and highly scalable solution for forensic genetics applications. For this purpose, we designed a protocol combining direct PCR amplification from unextracted DNA with ONT library construction and sequencing using the MinION device and workflow. The analysis of reference samples at input amounts of 5-10 ng of DNA demonstrates stable coverage patterns, allele balance, and strand bias, reaching profile completeness and concordance rates of ∼95%. Similar levels were achieved when using direct-PCR from blood, buccal and semen swabs. Dilution series results indicate sensitivity is maintained down to 250 pg of input DNA, and informative profiles are produced down to 62.5 pg. Finally, we demonstrated the forensic utility of the nanopore workflow by analyzing two third degree pedigrees that showed low likelihood ratio values after the analysis of an extended panel of 38 STRs, achieving likelihood ratios 2-3 orders of magnitude higher when testing with the MinION-based haplotype data.

Stated benefits of teleworking in Mexico City: a discrete choice experiment on office workers.

Commuting is expensive in megacities of emerging economies. By decreasing work-related trips, teleworking may reduce congestion and commuting time. Taking Mexico City's office workers' as case study, this paper reports findings from a discrete choice experiment (DCE) exploring willingness to see a cut in monthly paycheck in exchange for teleworking two days a week from a shared office. This DCE explores preferences for bike parking spaces at shared office's facilities, and walking commuting time to shared office. This design allows estimation of willingness to pay (WTP) for teleworking across commuting time scenarios. Monthly WTP for teleworking 2 days a week starts at (2019) USD 76.68-if commuting time is zero. As 1 h of commuting time is valued at USD 61.97 on a monthly basis, WTP for teleworking 30 min away from home is USD 45.69. Wealthier respondents report higher value for commuting time and WTP for teleworking. Monthly value of bike parking infrastructure is USD 14.70-reaching USD 30.98 for commuters that walk or (motor-)bike less than 50 min. We illustrate how these stated benefits can inform cost-benefit analysis of transportation, housing, and labor policies that enable teleworking and/or reduce commuting times in Mexico City.

Development of an in vitro intervertebral disc innervation model to screen neuroinhibitory biomaterials.

Pain originating from an intervertebral disc (discogenic pain) is a major source of chronic low back pain. Pathological innervation of the disc by pain-sensing nerve fibers is thought to be a key component of discogenic pain, so treatment with biomaterials that have the ability to inhibit neurite growth will greatly benefit novel disc therapeutics. Currently, disc therapeutic biomaterials are rarely screened for their ability to modulate nerve growth, mainly due to a lack of models to screen neuromodulation. To address this deficit, our lab has engineered a three dimensional in vitro disc innervation model that mimics the interface between primary sensory nerves and the intervertebral disc. Further, herein we have demonstrated the utility of this model to screen the efficacy of chondroitin sulfate biomaterials to inhibit nerve fiber invasion into the model disc. Biomaterials containing chondroitin-4-sulfate (CS-A) decrease neurite growth in a uniform gel and at an interface between a growth-permissive and a growth-inhibitory gel, while chondroitin-6-sulfate (CS-C) is less neuroinhibitory. This in vitro model holds great potential for screening inhibitors of nerve fiber growth to further improve intervertebral disc replacements and therapeutics. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1016-1026, 2020.

Weight evolution in girls treated for idiopathic central precocious puberty with GnRH analogues.

UNLABELLED: Data concerning the effects of GnRHa on weight gain are scarce. OBJECTIVE: To assess the variation of the body mass index (BMI) in girls during GnRHa treatment for idiopathic central precocious puberty (CPP). PATIENTS AND METHODS: Semestral anthropometric data from 176 girls treated with goserelin or leuprorelin were analyzed. RESULTS: BMI z-score increased from 1.5 +/- 0.1 SD before treatment (n = 176) to 1.7 +/- 0.2 SD after 24 months (n = 61, p = 0.008). In girls with normal weight before treatment, this variation was greater (n = 112, 0.2 +/- 0.1 SD, p = 0.01) than in those who were overweight (n = 63, -0.9 +/- 0.2 SD, p = 0.7). In the goserelin group the weight change adjusted for bone age was greater (n = 28, 0.4 +/- 0.1 SD) than in the leuprorelin group (n = 5, 0.04 +/- 0.1 SD, p = 0.05). CONCLUSIONS: A slight increase in BMI was noted, mainly in girls with normal weight before treatment. The influence of different GnRHa on weight must be further investigated.

Management of boys with short stature and delayed puberty.

OBJECTIVE: To review the management of boys with short stature and delayed puberty and the testosterone priming protocol. METHODS: In 148 boys aged > 14 years seen for height < -2 SDS and constitutional delayed puberty we evaluated growth hormone (GH) secretion and final height (80 boys). RESULTS: The GH peak was < 10 microg/l after arginine-insulin tests performed with testosterone heptylate priming in 8/32 (25%) and without in 62/153 (41%), including first and second evaluations. It was low in 7/11 boys given 2 x 100 mg testosterone (14.7 +/- 1.7 microg/l) and in 1/21 given 4 x 100 mg (21.3 +/- 2.0 microg/l, p = 0.04). It was low during sleep in 4/29 (14%) boys, all having basal plasma testosterone below 3.5 nmol/l. The basal insulin-like growth factor (IGF)-I concentration was below -2 SDS in 22% of the boys evaluated. Final height was -0.8 +/- 0.1 SDS. It was similar in those with low (n = 9) and normal (n = 71) GH peak, and in those treated (n = 22) or untreated (n = 58) with testosterone. It was over 1 SDS lower than the target height in 20% and than the predicted height at the initial evaluation in 14% of the boys. Pubertal growth was not correlated with the GH peak or plasma IGF-I. CONCLUSIONS: The GH peak during the sleep is more frequently normal than the peak after stimulation. The number of testosterone doses influences the quality of priming. The medical problems involved in treating boys with delayed puberty are excluding disease and deciding on testosterone treatment.

[Central precocious puberty in girls: prediction of the etiology]. / Pubertés précoces centrales des filles: prédiction de l'étiologie.

Precocious puberty (PP) is defined in girls by the occurrence of pubertal development before the age of 8. This development raises 3 questions: 1) Is it abnormal puberty or variant of the normal? 2) If abnormal puberty, is it of central, hypothalamic-pituitary, or peripheral, ovarian or adrenal origin? 3) If central, is it idiopathic or due to a lesion, and is there indication to treat it? The PP in a girl with no previous medical history is usually of central and idiopathic origin. However, isolated central PP may reveal a CNS lesion, particularly an optic glioma with its risk of blindness. Two independent predictors of CNS lesion are the age at PP onset of less than 6 years old, and increased plasma estradiol concentration. The selection of the girls for neuroradiological imaging should be based on these two parameters. However, neuroradiological imaging remains necessary until the prospective confirmation of their predictive value.

Adult height in girls with idiopathic true precocious puberty.

GnRH analogs are used to suppress pituitary-gonadal activity in children with true precocious puberty. The indications for therapy in this situation are not established, as some girls have a slow evolutive form, and the capacity of GnRH analogs to preserve the adult height has not been evaluated. This study analyzes the growth and adult heights of 2 groups of girls with idiopathic true precocious puberty, 1 with a predicted height of 155 cm or less (group 1, 19 cases) and the other with a predicted height of more than 155 cm (group 2, 15 cases). Group 1 patients were treated with a long-acting GnRH analog (D-Trp6-GnRH), and group 2 patients were followed without therapy. Group 1 showed greater clinical signs of estrogenization, vaginal maturation index (P < 0.03), plasma estradiol (P < 0.0004), and ratio of LH/FSH peaks (P < 0.01) at the initial evaluation than did group 2. The mean target heights were similar (difference, 0.9 cm). In group 1, the adult height (159 +/- 1.1 cm) was greater than the predicted height before therapy (152 +/- 1.4 cm; P < 0.0001). The difference between the adult height and the predicted height before therapy (mean, 6.5 cm) correlated positively with the bone age advance (P < 0.01), negatively with the predicted height (P < 0.05), and positively with the difference between the target and predicted heights (P < 0.001) before therapy. In group 2, the adult height (162 +/- 1.4 cm) was similar to the predicted height at the initial evaluation (162.5 +/- 1.4 cm). Adult heights correlated with target height in group 1 and with predicted height at the initial evaluation in group 2. In conclusion, some girls with true precocious puberty and poor adult height prediction who are treated with GnRH analog achieve an adult height more comparable to their target height. However, the lack of effect on height in girls with predicted height at the onset of therapy similar to their target height and preservation of the growth potential in the slow evolutive forms suggest that these forms might not require immediate therapy. Careful follow-up before therapy may be a better way of evaluating their natural course.

Diagnostic markers of permanent idiopathic growth hormone deficiency.

Idiopathic GH deficiency is a clinically and biologically heterogeneous condition. We have attempted to improve its diagnosis by analysing the status of 52 patients, aged 0.1 to 17.5 yr, with GH peak responses after 2 pharmacological stimulation tests of less than 10 micrograms/L. Group 1 (n = 24) had certain GH deficiency because of pituitary stalk interruption syndrome, familial form, and/or microphallus and hypoglycemia. Group 2 (n = 13) had transient GH deficiency. The diagnosis remained uncertain in group 3 (n = 15). The control group (n = 77) had prepubertal idiopathic short stature. Growth failure began before 5 yr of age in 88% of group 1, 18% of group 2, and 33% of group 3 patients. The mean GH peaks and the numbers of patients with GH peaks below 7 or 7-10 micrograms/L were similar in the three groups. Levels of plasma insulin-like growth factor-I (IGF-I) and its binding protein-3 (BP-3) were significantly lower in group 1 than in groups 2 and 3 (P < 0.001) or in children with idiopathic short stature (P < 0.01). When the results of these two parameters were combined, only one patient with certain GH deficiency had normal values, but only one severely undernourished young child with transient GH deficiency had values below the lower limit for children with idiopathic short stature. The diagnosis for group 3 remained uncertain, even after spontaneous pubertal development (n = 4), as the GH peak was 4.5-10.7 micrograms/L and plasma IGF-I was normal in three cases, and BP-3 was normal in four cases. We conclude that certain GH deficiency is distinguished from transient GH deficiency by age at onset and plasma IGF-I and BP-3 levels. Many patients diagnosed as GH deficient had normal for age plasma IGF-I and BP-3 levels, indicating transient GH deficiency in many of them.

Management of the short stature due to pubertal delay in boys.

Boys with constitutional pubertal delay who present with decreased growth rate pose diagnostic and therapeutic problems. Ninety-one boys seen after the age of 14 yr for height for age less than -2 SD, growth rate less than 5 cm/yr, and pubertal delay were evaluated. The GH peak after the arginine-insulin stimulation test was less than 10 micrograms/L in 35 of the subjects; these boys differed from the 56 others in having a GH peak of 10 micrograms/L or more, their higher body mass index (-0.27 +/- 0.2 vs. -0.85 +/- 0.1 score; P < 0.05), and lower plasma insulin-like growth factor-I (IGF-I; 1.2 +/- 0.2 vs. 1.8 +/- 0.2 U/mL; P < 0.05). The GH peak correlated negatively with the body mass index (P < 0.01), but not with plasma levels of testosterone and IGF-I or its GH-dependent binding protein (BP-3). At a second GH evaluation, performed with testosterone priming (21 boys; 100 mg testosterone heptylate/15 days, im; four doses) or without (6 boys), 23 patients had increased their GH peak to above 10 micrograms/L, and 4 had not. Three of these were treated with human (h) GH, and a third GH evaluation, performed after full pubertal development, showed a normal GH peak. The growth rate during the year preceding the GH evaluation was 3.8 +/- 0.1 cm (1-7 cm). During the year after the GH evaluation, it was 6.8 +/- 0.3 cm in the 32 patients followed without therapy, 7.3 +/- 0.3 cm in the 25 patients given testosterone (25 mg testosterone heptylate/15 days, im), and 7.3 +/- 1.4 cm in the 3 treated with hGH. Spontaneous growth during the 2 periods was correlated with testicular volume (P < 0.01) and the plasma testosterone level (P < 0.05), but not with the GH peak, plasma IGF-I, or BP-3. The final height (n = 49) was -1.0 +/- 0.1 SD, below target height (-0.4 +/- 0.1 SD; P < 0.0001). It was similar in patients with a GH peak below or equal to or above 10 micrograms/L and in those given or not given testosterone therapy. We conclude that the growth rate of boys with constitutional pubertal delay depends on the testicular volume and plasma testosterone level, but not on the GH peak, plasma IGF-I, or BP-3 levels. Final height is not altered by a transient drop in GH or by low dose testosterone therapy.

GH deficiency caused by cranial irradiation during childhood: factors and markers in young adults.

Cranial irradiation alters hypothalamic-pituitary function. We reevaluated 90 patients with GH deficiency caused by fractionated cranial irradiation performed at age 4.9 +/- 0.4 (SE) yr when they were 15.7 +/- 0.2 yr old. Group 1 received 18 Grays (Gy) (7 cases) or 24 Gy (21 cases) for acute lymphoblastic leukemia; group 2, 30-40 Gy for medulloblastoma (22 cases); group 3, 45-60 Gy for optic glioma and various tumors (30 cases); and group 4, 40-50 Gy for retinoblastoma (10 cases). The mean GH peaks after an arginine insulin test in group 3 (1.9 +/- 0.4 microg/liter) was lower than in groups 1 (4.8 +/- 0.5 microg/liter, P < 0.001) and 2 (3.4 +/- 0.5 microg/liter, P < 0.03). The mean plasma IGF-I concentrations in group 3 [-3.8 +/- 0.2 z score (zs)] was lower than in groups 1 (-2.4 +/- 0.3 zs, P < 0.001) and 2 (-3.1 +/- 0.2 zs, P < 0.02), as was the mean in group 4 (-3.9 +/- 0.3 zs, P < 0.01 compared with group 1 and P < 0.05 compared with group 2). GH peaks and IGF-I were correlated positively (P = 0.0001) and negatively with dose (P < 0.001 for GH and P = 0.0001 for IGF-I), but not with age at irradiation. Among the 43 patients with GH peaks below 3 microg/liter, 41 (95%) had plasma IGF-I less than -2 zs. The body mass index (BMI), plasma insulin, and leptin were similar in the four groups. They were positively correlated with each other (P < 0.001 for BMI compared with insulin and with leptin, respectively, and P < 0.01 for insulin compared with leptin), but not with age or dose of irradiation, or with markers of GH secretion. In conclusion, in patients with GH deficiency caused by cranial irradiation, the residual GH secretion and plasma IGF-I depend on the dose. Almost all the patients with severe GH deficiency had low plasma IGF-I. BMI, leptin, and insulin seem to be independent of GH status.

Adult height in 24 patients treated for growth hormone deficiency and early puberty.

This study evaluates the capacity of treatment with the combination of growth hormone (GH) and gonadotropin releasing hormone (GnRH) analog to preserve the height potential of 24 patients (15 girls, 9 boys) with GH deficiency and early puberty (onset at 7.8 +/- 0.5 SE yr in girls and 9.0 +/- 0.7 yr in boys). All but 4 were given cranial irradiation. They (group 1) were compared with 17 patients of normal pubertal age treated with GH for cranial irradiation-induced GH deficiency (group 2) and with 19 girls treated with GnRH analog for idiopathic central precocious puberty (group 3). The adult heights in groups 1, 2 and 3 were -0.5 +/- 0.2, -1.3 +/- 0.2, and -0.2 +/- 0.2 SD, significantly lower (P < 0.01) in group 2. They were lower than the target heights in groups 1 and 2 (P < 0.001), and similar in group 3. They were similar to the predicted heights at the onset of therapy (combined, GH, or GnRH analog therapy), except in group 3 (adult height > predicted height, P < 0.0001) In group 1, as in group 3, the differences between adult and predicted heights (1.1 +/- 1.3 and 6.5 +/- 1.4 cm respectively) correlated positively with the difference between bone and chronological ages (P < 0.05), negatively with the predicted height (P < 0.002), and positively with the difference between the target and predicted heights (P < 0.001) at the onset of therapy. In conclusion, treatment with the combination of GH and GnRH analog in patients with GH deficiency and early puberty leads to a normal adult height. This height is similar to the predicted height at the onset of therapy but lower than the target height.

Nonparallel changes of growth hormone (GH) and insulin-like growth factor-I, insulin-like growth factor binding protein-3, and GH-binding protein, after craniospinal irradiation and chemotherapy.

We studied the GH-insulin-like growth factor-I (IGF-I) axis serially over 24-36 months in six patients with medulloblastoma who underwent surgical removal of the tumor followed by craniospinal irradiation therapy for 6 weeks and then chemotherapy for 42 weeks. Eighteen and 24 months after beginning irradiation there was a decline in the peak GH secretory response to acute stimulation with arginine/insulin hypoglycemia. Six months after irradiation and during chemotherapy there was a transient decline in IGF-I, IGF binding protein-3 (IGFBP-3), and GH-BP values (respective mean values of 56.1 +/- 9.0 ng/mL, 1.1 +/- 0.2 microgram/mL, and 7.6 +/- 3.3% of radioactivity as compared to time 0 values: 13%%o/- 15 ng/mL, 2.2 +/- 0.2 micrograms/mL, and 20.0 +/- 4.0%, P < 0.001), although provoked GH secretion was normal at this time. The IGF-I, IGFBP-3, and GH-BP returned to pretreatment ranges by 12-36 months after initiation of the study. There was also a decline in body mass index and serum protein values at 6 months, suggesting suboptimal nutrition during this period. Six months after irradiation in ligand and immunoblot analysis there was a decline in IGFBP-3 and an abnormal electrophoretic mobility of IGFBP-2 that were both normalized at 36 months. In one patient we observed a high level of IGFBP-3 proteolysis at this time. This study demonstrates that before the decrease of GH secretion in patients receiving cranial irradiation there is a transient phase of GH insensitivity that may be characteristic of the acute therapeutic phase including the chemotherapy. This partial insensitivity may explain the early growth retardation observed in these patients.

Growth after bone marrow transplantation in young children conditioned with chemotherapy alone.

Short stature is a potential side-effect of BMT, brought about by the conditioning protocol and/or the complications of BMT. This study evaluates the effects of conditioning by chemotherapy, and BMT complications on growth. Thirty children conditioned for BMT by chemotherapy alone (cyclophosphamide and busulfan) were classified according to the occurrence of serious or prolonged complications after BMT: group 1 (n = 12) had no complication, while group 2 (n = 18) did. Fifteen of them were severely growth retarded (< or = -2 s.d.) at BMT, because of their initial disease. At the time of BMT, the two groups had similar ages (1.0 +/- 0.2, s.e.m. year, in group 1 and 1.7 +/- 0.5 year in group 2), height (-1.7 +/- 0.5; -1.8 +/- 0.3 s.d.) and plasma insulin-like growth factor I (IGFI) levels (0.3 +/- 0.1 U/ml in both). Group I grew significantly and their plasma IGFI increased but group 2 did not, as assessed 2 years post-BMT. We conclude that conditioning with chemotherapy alone does not prevent the catch-up growth induced by BMT in young children; the lack of catch-up growth is due to complications occurring after BMT, and the change in plasma IGFI suggests that complications of BMT prevent any increase in plasma IGFI, and thereby catch-up growth.

Adult height in advanced puberty with or without gonadotropin hormone releasing hormone analog treatment.

Advanced puberty is defined as the onset of puberty in girls at 8-10 years of age and in boys at 9-11 years. This study analyzes adult height in 57 children with advanced puberty to evaluate the results of treating children (9 girls and 8 boys) with gonadotropin hormone releasing hormone (GnRH) analog and the impact of advanced puberty on adult height in untreated children (31 girls and 9 boys). For treated girls, adult height predicted at the onset of treatment (151.9+/-1.7 cm) was similar to the final adult height (155.3+/-1.4 cm), but lower than target height (157.2+/-1.6 cm, p = 0.04). For untreated girls, adult height predicted at the initial evaluation (156.7+/-1 cm) was also similar to adult height (157+/-1 cm), but lower than the target height (157.6+/-1 cm, p = 0.03). The adult heights of both treated and untreated girls were similar to their target heights. For treated boys, adult height predicted at the onset of treatment (173.2+/-3.1 cm) was greater than the final adult height (164.1+/-2.1 cm, p = 0.01), which was lower than target height (170.4+/-1.2 cm, p = 0.01). For untreated boys, adult height predicted at the initial evaluation (170.8+/-2.7 cm) was similar to both the adult height (169.1+/-1.9 cm) and target height (170.2+/-1.2 cm). Height gains between the onset of puberty and adult height were similar in treated (29.9+/-2.3 cm in girls and 29.8+/-1.7 cm in boys) and untreated (28.6+/-1 and 33.1+/-2 cm) children. When expressed as SD, the adult height was significantly shorter than that at 4 years in treated girls (difference 1 SD, p = 0.03), in untreated girls (difference 0.9 SD, p = 0.0002) and in treated boys (difference 0.9 SD, p = 0.02), but it was similar to that in untreated boys. Adult height was below target height by >5 cm in seven girls (two of them treated) and five boys (four of them treated). In conclusion, treating advanced puberty did not change the adult height reached by girls, and was associated with reduced growth potential in boys. The adult heights of untreated children were similar to those predicted at the initial evaluation and to target heights, but in girls they were 1 SD lower than the height at 4 years. These data suggest that advanced puberty decreases the growth potential by about 5 cm, and that GnRH analog treatment does not prevent this.