Added Value of Abnormal Lymph Nodes Detected with FDG-PET/CT in Suspected Vascular Graft Infection.

Vascular graft and endograft infections (VGEI) cause a serious morbidity and mortality burden. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging is frequently used in the diagnostic workup, but the additional value of abnormal (18F-FDG active and/or enlarged) locoregional lymph nodes is unknown. In this retrospective study, the additional diagnostic value of abnormal locoregional lymph nodes on 18F-FDG PET/CT imaging for VGEI was evaluated, including 54 patients with a culture-proven VGEI (defined according to the Management of Aortic Graft Infection [MAGIC] group classification) and 25 patients without VGEI. 18F-FDG PET/CT was qualitatively and quantitatively assessed for tracer uptake and pattern at the location of the vascular graft, and locoregional lymph node uptake and enlargement (>10 mm). 18F-FDG uptake intensity and pattern independently predicted the presence of VGEI by logistic regression (Χ2: 46.19, p < 0.001), with an OR of 7.38 (95% CI [1.65, 32.92], p = 0.009) and 18.32 (95% CI [3.95, 84.88], p < 0.001), respectively. Single visual assessment of abnormal locoregional lymph nodes predicted the presence of VGEI with a sensitivity of 35%, specificity of 96%, PPV of 95%, and NPV of 41%. The visual assessment of abnormal lymph nodes after qualitative assessment of 18F-FDG uptake intensity and pattern at the vascular graft location did not independently predict the presence of VGEI by logistic regression (Χ2: 3.60, p = 0.058; OR: 8.25, 95% CI [0.74, 63.37], p = 0.096). In conclusion, detection of abnormal locoregional lymph nodes on 18F-FDG PET/CT has a high specificity (96%) and PPV (95%) for VGEI. However, it did not add to currently used 18F-FDG PET/CT interpretation criteria.

A patient-specific cerebral blood flow model.

In clinical practice, many complex choices in treatment of complex cerebrovascular diseases have to be made. A patient-specific mathematical blood flow could aid these decisions. For certain cases, less accuracy is required and more simplistic models might be feasible. The current study is aiming to validate a patient-specific simplistic blood flow model in 20 healthy subjects. All subjects underwent MRI and Noninvasive Optimal Vessel Analysis (NOVA) to obtain patient-specific vascular morphology and flow measurements of all major cerebral arteries for validation. The mathematical model used was based on the Hagen-Poiseuille equations. Proximal boundary conditions were patient-specific blood pressure cuff measurements. For distal boundary conditions, a structured tree and a simple autoregulatory model were applied. Autoregulatory parameters were optimized based on the data of 10 additional healthy subjects. A median percentual flow difference of -3% (interquartile range -36% to 17%) was found. Regression analysis to an identity line resulted in R2 values of 0.71 for absolute flow values. Bland-Altman plots showed a bias (levels of agreement) of 5% (-70 to 80%) for absolute flow. Based on these results the model proved to be accurate within a range that might be feasible for use in clinic. Major limitations to the model arise from the simplifications made compared to the actual physiological situation and limitations in the validation method. As the model is validated in healthy subjects only, further validation in actual patients is needed.

Branching Pattern of the Cerebral Arterial Tree.

Quantitative data on branching patterns of the human cerebral arterial tree are lacking in the 1.0-0.1 mm radius range. We aimed to collect quantitative data in this range, and to study if the cerebral artery tree complies with the principle of minimal work (Law of Murray). To enable easy quantification of branching patterns a semi-automatic method was employed to measure 1,294 bifurcations and 2,031 segments on 7 T-MRI scans of two corrosion casts embedded in a gel. Additionally, to measure segments with a radius smaller than 0.1 mm, 9.4 T-MRI was used on a small cast section to characterize 1,147 bifurcations and 1,150 segments. Besides MRI, traditional methods were employed. Seven hundred thirty-three bifurcations were manually measured on a corrosion cast and 1,808 bifurcations and 1,799 segment lengths were manually measured on a fresh dissected cerebral arterial tree. Data showed a large variation in branching pattern parameters (asymmetry-ratio, area-ratio, length-radius-ratio, tapering). Part of the variation may be explained by the variation in measurement techniques, number of measurements and location of measurement in the vascular tree. This study confirms that the cerebral arterial tree complies with the principle of minimum work. These data are essential in the future development of more accurate mathematical blood flow models. Anat Rec, 302:1434-1446, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

High resolution 7T and 9.4T-MRI of human cerebral arterial casts enables accurate estimations of the cerebrovascular morphometry.

Quantitative data on the morphology of the cerebral arterial tree could aid in modelling and understanding cerebrovascular diseases, but is scarce in the range between 200 micrometres and 1 mm diameter arteries. Traditional manual measurements are difficult and time consuming. 7T-MRI and 9.4T-MRI of human cerebral arterial plastic casts could proof feasible for acquiring detailed morphological data of the cerebral arterial tree in a time efficient method. One cast of the complete human cerebral arterial circulation embedded in gadolinium-containing gelatine gel was scanned at 7T-MRI (0.1 mm isotropic resolution). A small section of another cast was scanned at 9.4T-MRI (30 µm isotropic resolution). Subsequent 3D-reconstruction was performed using a semi-automatic approach. Validation of 7T-MRI was performed by comparing the radius calculated using MRI to manual measurements on the same cast. As manual measurement of the small section was not feasible, 9.4T-MRI was validated by scanning the small section both at 7T-MRI and 9.4T MRI and comparing the diameters of arterial segments. Linear regression slopes were 0.97 (R-squared 0.94) and 1.0 (R-squared 0.90) for 7T-MRI and 9.4T-MRI. This data shows that 7T-MRI and 9.4T-MRI and subsequent 3D reconstruction of plastic casts is feasible, and allows for characterization of human cerebral arterial tree morphology.

Proximal and Distal Occlusion of Complex Cerebral Aneurysms-Implications of Flow Modeling by Fluid-Structure Interaction Analysis.

BACKGROUND: In complex cerebral aneurysms, adequate treatment by complete occlusion is not always possible. Partial occlusion by either proximal or distal occlusion is an alternative. However, the hemodynamic consequences of these partial occlusion options are often not easily predictable. OBJECTIVE: To assess the feasibility of fluid-structure interaction (FSI) analysis to investigate the hemodynamic changes after partial occlusion in cerebral aneurysms. METHODS: Two patients were analyzed. One was treated by proximal occlusion and 1 by distal occlusion. In both, flow replacement bypass surgery was performed. Three-dimensional models were constructed from magnetic resonance angiography (MRA) scans and used for FSI analysis. A comparative study was done for pre- and postoperative conditions. Postoperative thrombosis was modeled and analyzed for the distal occlusion. FSI results were compared to postoperative angiograms and computed tomography (CT)-scans. RESULTS: Proximal occlusion resulted in reduction of velocity, wall shear stresses, and disappearance of helical flow patterns in the complete aneurysm. Distal occlusion showed a decrease of velocity and wall shear stress in the dome of the aneurysm. Results were validated against postoperative CT-scans and angiograms at 1-, 7-, and 9-mo follow-up. Addition of thrombus to the distal occlusion model showed no change in velocities and luminal pressure but resulted in decrease in wall tension. CONCLUSION: This pilot study showed hemodynamic changes in 2 patients with proximal and distal occlusion of complex cerebral aneurysms. The FSI results were in line with the follow-up CT scans and angiograms and indicate the potential of FSI as a tool in patient-specific surgical interventions.

Acid-labile subunit deficiency: phenotypic similarities and differences between human and mouse.

IGF-I and IGF-II (IGFs) form higher molecular weight complexes with specific binding proteins (IGFBP-1 to -6). These complexes are referred to as binary complexes consisting of IGF-I or IGF-II and one IGFBP, or as ternary complexes each consisting of either of IGF-I or IGF-II, IGFBP-3 or -5, and an acid-labile subunit known as ALS. Ternary complex formation restricts the IGFs to the circulation and prolongs their half-life. Recently, the development of an animal model for ALS deficiency (the ALS-KO mouse) and the identification of a patient with an inactivating mutation in the IGFALS gene have provided the opportunity to assess the physiological role of this protein in the circulating IGF system. ALS deficiency has no effect on fetal growth in both the ALS-KO mice and the ALS-deficient patients. A modest reduction in post-natal growth in the null ALS mice and in the ALS-deficient patients was observed. The plasma concentrations of IGF-I and IGFBP-3 were markedly reduced both in ALS-KO mice and in the ALS-deficient patients. Basal GH levels remained normal in the ALS-KO mice and moderately increased in the ALS-deficient patients. Insulin-resistance was present in the ALS-deficient patients but not in the ALS-KO mice. Reduced bone mineral density (BMD) was present in mice and human ALS deficiency. Phenotypic features of complete ALS deficiency, that are very similar in mouse and human, include: a) the inability to form ternary complex, b) the small growth impairment in spite of the marked reduction in circulating IGF-I, and c) the reduction in BMD. On the other hand, insulin resistance and pubertal delay were observed only in human ALS deficiency. These findings underlie the important physiological role of ALS in the maintenance of the circulating IGF-I reservoir. Both models will be useful in identifying the respective roles of plasma and locally derived IGF-I in regulating metabolism and growth of specific tissues.

Estrogen priming effect on growth hormone (GH) provocative test: a useful tool for the diagnosis of GH deficiency.

We have studied the effect of estradiol (E2) on the GH-insulin-like growth factor (GH-IGF) axis in 15 prepubertal GH deficiency (GHD) children and 44 prepubertal or early pubertal children with idiopathic short stature (SS). All of them received a daily dose of micronized E2 (1 or 2 mg) or placebo, for 3 days, before a sequential arginine-clonidine test. In SS children, GH maximal responses were 17.8+/-10.9 on placebo and 27.9+/-14.5 microg/L on estrogen (P < 0.0001). The lower 95% confidence limits for GH maximal response changed from 3.7 microg/L (without E2) to 8.3 microg/L (on E2). In GHD children, no significant stimulatory effect of estrogen on GH levels was observed. After placebo, a cut-off limit of 3.7 microg/L (the lower 95% confidence interval limit) resulted in 73% sensitivity, 95% specificity, and an overall 90% diagnostic efficiency. After E2, a cut-off limit of 8.3 microg/L resulted in a sensitivity of 87%, a specificity of 98%, and a diagnostic efficiency of 95%. After placebo, 68% of SS showed normal IGF-I levels, and the mean did not change on E2 (13.7+/-6.3 vs. 14.3+/-6.8 nmol/L, not significant). In 93% of SS, IGF binding protein (IGFBP)-3 levels were normal during placebo. On E2, mean IGFBP-3 did not change (2.63+/-0.70 vs. 2.70+/-0.70 mg/L, not significant). In 14 of 15 GHD patients, IGF-I values were below normal on placebo, and the mean of the group did not change after E2. During placebo, 13 of 15 GHD children presented low IGFBP-3 values. During E2, there was a small significant increase in IGFBP-3 values (1.06+/-0.58 vs. 1.20+/-0.69 mg/L, P < 0.02). The highest diagnostic efficiencies for IGF-I and IGFBP-3 were observed during placebo (75% and 91%, respectively). We conclude that GH stimulation tests after E2 priming had the highest diagnostic efficiency. Our findings suggest that the effect of estrogen priming on GH stimulated levels, by reducing the number of false nonresponders, might be useful to better discriminate between normal and abnormal GH status in SS children.

Insulin-like growth factor I (IGF-I) and growth in children undergoing hemodialysis or after successful renal transplantation.

To analyze the relationship between IGF-I and growth in children with chronic renal failure, we studied 7 patients undergoing hemodialysis and 7 patients after successful renal transplantation. IGF-I was measured by acid chromatography using ODS silica columns. Hemodialyzed patients grew poorly (mean 1.5 cm/y), and although transplanted patients did significantly better (mean 3.3 cm/y), 4 out of 7 did not reach normal height velocity. IGF-I levels in transplanted patients (39.2 +/- 13.6 nM/l) were significantly higher than in hemodialyzed patients (13.4 +/- 3.0 before; 17.0 +/- 5.4, after dialysis, nM/l). Nevertheless, all individual values in both groups fell within normal limits. The mean logarithmic deviation of IGF-I values of hemodialyzed patients was not significantly different from normal. The logarithmic deviation of transplanted patients was significantly higher than normal, indicating a true, albeit slight, increase in the levels of this growth factor No significant correlation was found between IGF-I and growth velocity. Serum IGF-I levels in these children do not help to explain their growth failure.

Insulin-like growth factor I (IGF-I) and growth in children undergoing hemodialysis or after successful renal transplantation

Los niños con insuficiencia renal crónica frecuentemente presentan retardo de crecimiento. Para analizar la relación entre IGF-I y crecimiento en esta situación clínica, se estudiaron 7 pacientes hemodializados y 7 pacientes transplantados con función renal normal. El IGF-I total del suero se midió por RIA luego de cromatografía ácida en columnas de OFDS silica. Los pacientes hemdializados crecían a muy baja velocidad (X1.5c,/a), y aunque los transplantados lo hacían a una velocidad significativamente mayor (X3.3 cm/a, p<0.025), 4/7 presentaban velocidades por debajo de lo normal. Todos los pacientes de ambos grupos tuvieron niveles de IGF-I dentro de los límites normales, pero la media de los transplantados fue significativamente mayor que la de los hemodializados (39.2 ñ 13.6 nM/I vs 13.4 ñ 3.0 nM/I --predialisis-- p<0.005). La medida de la desviación logarítmica de los valores de IGF-I de los pacientes hemodializados no difirió significativamente de lo normal, mientras que la media de los transplantados fue signifdicativamente mayor que lo normal (1.027 ñ 0.500, p<0.005). Estos últimos presentaban por lo tanto, como grupo, un aumento pequeño pero real de los valores de IGF-I.. Sin embargo, no se encontró una correlación estadísticamente significativa entre IGF-I y velocidad de crecimiento. Esto, junto a la ausencia de los valores de IGF-I por debajo de lo normal, indicaría que los niveles séricos de IGF-I no desempeñan un papel importante en el retardo de crecimiento de los pacientes con insuficiencia renal crónica

Insulin-like growth factor I (IGF-I) and growth in children undergoing hemodialysis or after successful renal transplantation.

To analyze the relationship between IGF-I and growth in children with chronic renal failure, we studied 7 patients undergoing hemodialysis and 7 patients after successful renal transplantation. IGF-I was measured by acid chromatography using ODS silica columns. Hemodialyzed patients grew poorly (mean 1.5 cm/y), and although transplanted patients did significantly better (mean 3.3 cm/y), 4 out of 7 did not reach normal height velocity. IGF-I levels in transplanted patients (39.2 +/- 13.6 nM/l) were significantly higher than in hemodialyzed patients (13.4 +/- 3.0 before; 17.0 +/- 5.4, after dialysis, nM/l). Nevertheless, all individual values in both groups fell within normal limits. The mean logarithmic deviation of IGF-I values of hemodialyzed patients was not significantly different from normal. The logarithmic deviation of transplanted patients was significantly higher than normal, indicating a true, albeit slight, increase in the levels of this growth factor No significant correlation was found between IGF-I and growth velocity. Serum IGF-I levels in these children do not help to explain their growth failure.

Insulin-like growth factor I (IGF-I) and growth in children undergoing hemodialysis or after successful renal transplantation

Los niños con insuficiencia renal crónica frecuentemente presentan retardo de crecimiento. Para analizar la relación entre IGF-I y crecimiento en esta situación clínica, se estudiaron 7 pacientes hemodializados y 7 pacientes transplantados con función renal normal. El IGF-I total del suero se midió por RIA luego de cromatografía ácida en columnas de OFDS silica. Los pacientes hemdializados crecían a muy baja velocidad (X1.5c,/a), y aunque los transplantados lo hacían a una velocidad significativamente mayor (X3.3 cm/a, p<0.025), 4/7 presentaban velocidades por debajo de lo normal. Todos los pacientes de ambos grupos tuvieron niveles de IGF-I dentro de los límites normales, pero la media de los transplantados fue significativamente mayor que la de los hemodializados (39.2 ñ 13.6 nM/I vs 13.4 ñ 3.0 nM/I --predialisis-- p<0.005). La medida de la desviación logarítmica de los valores de IGF-I de los pacientes hemodializados no difirió significativamente de lo normal, mientras que la media de los transplantados fue signifdicativamente mayor que lo normal (1.027 ñ 0.500, p<0.005). Estos últimos presentaban por lo tanto, como grupo, un aumento pequeño pero real de los valores de IGF-I.. Sin embargo, no se encontró una correlación estadísticamente significativa entre IGF-I y velocidad de crecimiento. Esto, junto a la ausencia de los valores de IGF-I por debajo de lo normal, indicaría que los niveles séricos de IGF-I no desempeñan un papel importante en el retardo de crecimiento de los pacientes con insuficiencia renal crónica (AU)

Discrepancies between biossayable somatomedin activity and somatomedin C levels in acromegalic patients

En publicaciones previas se han descripto niveles elevados de actividad biológica de somatomedinas en pacientes acromegálicos. Utilizando un bioensayo que mide la incorporación de 35S a cartílagos pelvianos de embriones de pollo encontramos niveles normales de actividad de somatomedina en los 11 pacientes acromegálicos estudiados. Midiendo somatomedina C (Sm-C) por radioinmunoensayo en la misma muestra de 9 de esos pacientes, se encontraron niveles normales en sólo 2 de ellos. En total, de 12 pacientes acromegálicos en los que se dosó Sm-C sólo esos 2 tuvieron valores normales, el resto estuvieron por encima de 2 desvíos standard de la media normal (controles normales 1,410ñ0,269, acromegálicos 6,030 ñ3,350, U/ml, xñDS, p<0,001). Los valores normales de bioactividad de somatomedinas no pueden ser debidos a tratamientos previos ya que 13 de los 14 pacientes acromegálicos eran vírgenes de tratamiento. Tampoco se los puede adjudicar a niveles bajos de hormona de crecimiento (GH) ya que 10 de ellos tuvieron niveles altos de GH. El hallazgo de valores normales de actividad biológica de somatomedinas podría deberse a la presencia de inhibidores séricos; sin embargo, experimentos de mezcla de suero humano normal con el suero de pacientes acromegálicos revelaron la presencia de inhibidores en sólo 1 de los 8 pacientes estudiados. Utilizando este mismo bioensayo se encontraron valores bajos de actividad de somatomedina en niños con déficit de hormona de crecimiento 11. Por lo tanto, este bioensayo parece detectar mejor aquellas somatomedinas que disminuyen en situaciones de déficit de hormona de crecimiento pero que no aumentan frente a situaciones de exceso de hormona de crecimiento. Este es el comportamiento descripto para la somatomedina conocida como factor de crecimiento insulino-símil II (IGF II). Sería entonces posible que los valores normales de actividad biológica de somatomedinas encontrados en pacientes acromegálicos se deban a que el bioensayo empleado tenga mayor sensibilidad para el IGF II que para la Sm-C

Discrepancies between biossayable somatomedin activity and somatomedin C levels in acromegalic patients

En publicaciones previas se han descripto niveles elevados de actividad biológica de somatomedinas en pacientes acromegálicos. Utilizando un bioensayo que mide la incorporación de 35S a cartílagos pelvianos de embriones de pollo encontramos niveles normales de actividad de somatomedina en los 11 pacientes acromegálicos estudiados. Midiendo somatomedina C (Sm-C) por radioinmunoensayo en la misma muestra de 9 de esos pacientes, se encontraron niveles normales en sólo 2 de ellos. En total, de 12 pacientes acromegálicos en los que se dosó Sm-C sólo esos 2 tuvieron valores normales, el resto estuvieron por encima de 2 desvíos standard de la media normal (controles normales 1,410ñ0,269, acromegálicos 6,030 ñ3,350, U/ml, xñDS, p<0,001). Los valores normales de bioactividad de somatomedinas no pueden ser debidos a tratamientos previos ya que 13 de los 14 pacientes acromegálicos eran vírgenes de tratamiento. Tampoco se los puede adjudicar a niveles bajos de hormona de crecimiento (GH) ya que 10 de ellos tuvieron niveles altos de GH. El hallazgo de valores normales de actividad biológica de somatomedinas podría deberse a la presencia de inhibidores séricos; sin embargo, experimentos de mezcla de suero humano normal con el suero de pacientes acromegálicos revelaron la presencia de inhibidores en sólo 1 de los 8 pacientes estudiados. Utilizando este mismo bioensayo se encontraron valores bajos de actividad de somatomedina en niños con déficit de hormona de crecimiento 11. Por lo tanto, este bioensayo parece detectar mejor aquellas somatomedinas que disminuyen en situaciones de déficit de hormona de crecimiento pero que no aumentan frente a situaciones de exceso de hormona de crecimiento. Este es el comportamiento descripto para la somatomedina conocida como factor de crecimiento insulino-símil II (IGF II). Sería entonces posible que los valores normales de actividad biológica de somatomedinas encontrados en pacientes acromegálicos se deban a que el bioensayo empleado tenga mayor sensibilidad para el IGF II que para la Sm-C (AU)

Somatomedin response to testosterone stimulation in children with male pseudohermaphroditism, cryptorchidism, anorchia, or micropenis.

Somatomedin-C (Sm-C) levels increase during puberty. To determine if testosterone could play a role in the pubertal Sm-C increase, 17 boys with low levels of endogenous testosterone (80 ng/dl) were studied before and 7 days after im testosterone treatment. The serum testosterone levels achieved were comparable to those found during normal puberty in most instances. After parenteral testosterone administration, serum somatomedin activity (bioassay) increased in 9 patients (from 10-56% above basal levels) and decreased in 3 (from 3.2-20.3% below basal levels); overall, there was a significant 19.2% increase (P less than 0.02). Testosterone per se did not induce an increase in bioassayable Sm, since its addition to serum failed to cause increments in activity. After im testosterone treatment, serum Sm-C levels (determined by RIA) increased in every patient studied. The mean percent increase above basal levels was 108% (range, 14-202%; n = 10; P less than 0.001). Mean serum GH increased significantly (P less than 0.05) from 4.9 ng/ml before exogenous testosterone to 12.0 ng/ml afterward. The data show that parenteral testosterone administration can increase serum Sm activity and Sm-C, probably through increased pituitary GH secretion, and this response occurs in boys ranging in age from 0.24-14.57 yr.

Actividad de somatomedina en pacientes con baja talla por hipopituitarismo o retardo de crecimiento constitucional-familiar. / Somatomedin activity in patients with low height due to hypopituitarism or constitutional-familial growth retardation

Se determino la actividad de somatomedina (SM) (bioensayo) en 38 controles normales en 20 pacientes con hipopituitarismo y en 16 pacientes con respuestas normales de hormona de crecimiento (HCH) previamente considerados con retardo de crecimiento constitucional o familiar. La actividad de SM aumento con la edad en los controles normales (< 8 anos x 0,856 U/ml, > 8 anos x 1,080 U/ml, p < 0,01). Los hipopituitarios tuvieron actividad significativamente menor que la de sus controles de semejante edad cronologica. En los hipopituitarios con deficit parcial de HCH la frequencia de valores normales o intermedios (71.4%) fue mayor que en los pacientes con deficit total de HCH (30.76%). Dentro de los 16 pacientes con retardo de crecimiento constitucional o familiar se encontraron 5 con actividad de SM por debajo del rango normal y por debajo de -1,5 DS de la media de sus controles y uno por debajo del rango normal pero a menos de -l,5 DS.Estos resultados contribuyen a la mejor caracterizacion del grupo de hipopituitarios, y parecen confirmar la existencia de un grupo de pacientes con respuesta normal de HCH pero con niveles bajos de SM, algunos de los cuales podrian beneficiarse con tratamiento con HCH

Actividad de somatomedina en pacientes con baja talla por hipopituitarismo o retardo de crecimiento constitucional-familiar. / Somatomedin activity in patients with low height due to hypopituitarism or constitutional-familial growth retardation

Se determino la actividad de somatomedina (SM) (bioensayo) en 38 controles normales en 20 pacientes con hipopituitarismo y en 16 pacientes con respuestas normales de hormona de crecimiento (HCH) previamente considerados con retardo de crecimiento constitucional o familiar. La actividad de SM aumento con la edad en los controles normales (< 8 anos x 0,856 U/ml, > 8 anos x 1,080 U/ml, p < 0,01). Los hipopituitarios tuvieron actividad significativamente menor que la de sus controles de semejante edad cronologica. En los hipopituitarios con deficit parcial de HCH la frequencia de valores normales o intermedios (71.4%) fue mayor que en los pacientes con deficit total de HCH (30.76%). Dentro de los 16 pacientes con retardo de crecimiento constitucional o familiar se encontraron 5 con actividad de SM por debajo del rango normal y por debajo de -1,5 DS de la media de sus controles y uno por debajo del rango normal pero a menos de -l,5 DS.Estos resultados contribuyen a la mejor caracterizacion del grupo de hipopituitarios, y parecen confirmar la existencia de un grupo de pacientes con respuesta normal de HCH pero con niveles bajos de SM, algunos de los cuales podrian beneficiarse con tratamiento con HCH