Torkel B. Brismar

Growth hormone treatment of children with Prader‐Willi syndrome affects linear growth and body composition favourably

We have compared the growth and the body composition in children with Prader‐Willi syndrome (PWS) with and without growth hormone treatment (recombinant GH 0.1 IU/kg/day) after a 1‐y period. Twenty‐nine prepubertal children with PWS, with mean body mass index (BMI) SDS of 2.2, and 10 (control) healthy obese children with mean BMI SDS of 5.6, underwent 24‐h frequent blood sampling. Both PWS and control obese children had low and similar GH levels (0.7 /ng/l ± 0.4 SD). Serum IGF‐I levels, however, were significantly lower in children with PWS (‐1.5 SDS ± 0.8 SD vs ‐0.2 SDS ±0.8 SD). The 29 PWS children were randomized into 2 groups of 15 and 14 subjects for GH treatment and no treatment, respectively. Height velocity increased from ‐1.9 SDS to + 6.0 SDS in the treated group (p < 0:001) and decreased from ‐0.1 SDS to ‐1.4 SDS in the control PWS group during the study year. BMI decreased significantly for the treated group (+3.0 SDS to + 2.0 SDS). Relative fat mass decreased significantly, while fat‐free mass increased (p < 0:001) for the treated group. No significant changes were noticed in body composition in the control PWS group. In conclusion, the low spontaneous 24‐h GH secretion, regardless of body weight, and the exceptional response to growth hormone treatment together with the finding of low IGF‐I levels suggest that growth hormone deficiency is a common feature of PWS, as a result of hypothalamic dysfunction. Treatment with growth hormone is beneficial for the majority of PWS children.

Contrast-enhanced magnetic resonance cholangiography with Gd-BOPTA and Gd-EOB-DTPA in healthy subjects

Purpose: To evaluate the biliary enhancement dynamics of the two gadolinium chelates Gd-BOPTA (MultiHance®) and Gd-EOB-DTPA (Primovist®) in normal healthy subjects. Material and Methods: Ten healthy volunteers were evaluated with both agents by magnetic resonance (MR) imaging at 1.5T using a breath-hold gradient-echo T1-weighted VIBE sequence. The relative signal intensity (SI) differences between the common hepatic duct (CHD) and liver parenchyma were measured before and 10, 20, 30, 40, 130, 240, and 300 min after contrast medium injection. Results: Biliary enhancement was obvious 10 min post-injection for Gd-EOB-DTPA and was noted at 20 min for Gd-BOPTA. At 40 min delay, Gd-BOPTA reached its peak biliary enhancement, but at neither 30 nor 40 min delay was there any significant difference compared with that of Gd-EOB-DTPA. At later delays, the contrast between CHD and liver continued to increase for Gd-EOB-DTPA, whereas it decreased for Gd-BOPTA. Conclusion: The earlier onset and longer duration of a high contrast between CHD and liver for Gd-EOB-DTPA facilitates examination of hepatobiliary excretion. Therefore, Gd-EOB-DTPA may provide adequate hepatobiliary imaging within a shorter time span than Gd-BOPTA and facilitate scheduling at the MR unit. Further studies in patients are required to compare the imaging advantages of Gd-EOB-DTPA and Gd-BOPTA in clinical practice.

Hyperandrogenicity is an alternative mechanism underlying oligomenorrhea or amenorrhea in female athletes and may improve physical performance

OBJECTIVE To evaluate endocrine mechanisms underlying oligomenorrhea or amenorrhea in female athletes. DESIGN Cross-sectional study. SETTING Womens health clinical research unit at a university hospital. PATIENT(S) Age- and BMI-matched groups of athletes active in endurance sports with and without menstrual disturbances and regularly cycling sedentary controls. INTERVENTION(S) Groups were compared with respect to endocrine status, body composition, and physical performance. MAIN OUTCOME MEASURE(S) Identification of a subgroup of oligomenorrheic or amenorrheic athletes with increased androgen levels and anabolic body composition. RESULT(S) A subgroup of 8 of 25 athletes with menstrual disturbances had significantly higher serum levels of free and total testosterone, androstenedione, LH-FSH ratio, and lower SHBG levels than did all other groups. Other oligomenorrheic or amenorrheic athletes had normal values comparable to those in regularly menstruating athletes and controls. The hyperandrogenic subgroup showed a more anabolic body composition, with higher total bone mineral density and upper-lower fat mass ratio than did oligomenorrheic or amenorrheic athletes with normal androgen levels. The hyperandrogenic subgroup had the highest VO2 max and the highest performance values in general. CONCLUSION(S) Menstrual disturbances in female athletes are often explained as a consequence of hypothalamic inhibition and caloric deficiency. We suggest that essential hyperandrogenism is an alternative mechanism underlying oligomenorrhea or amenorrhea in some female athletes and may imply an advantage for physical performance.

A novel haplo-identical adoptive CTL therapy as a treatment for EBV-associated lymphoma after stem cell transplantation

Epstein–Barr virus (EBV)-related malignancies such as post-transplant lymphoproliferative disease (PTLD) are severe complications after allogeneic stem cell transplantation and solid-organ transplantation. In immunosuppressed transplant recipients, the activity of EBV-specific CTLs are often decreased or absent which leads to an increased risk of developing PTLD. If primary treatment modalities of PTLD fail, the most efficient way of treating the malignancy is adopting EBV-specific CTLs from the donor or, more recently, third-party donors. However, both are time consuming and expensive and often it is too late to administer cells to the patient. We have for the first time, using a rapid isolation protocol of EBV-specific T cells, treated and cured a patient suffering from PTLD with multiple-associated tissue lesions, using her haplo-identical mother as a donor. This treatment approach paves way for a new possibility to within-days treat patients with life-threatening EBV-associated malignancies.

Magnetite Nanoparticles Can Be Coupled to Microbubbles to Support Multimodal Imaging

Microbubbles (MBs) are commonly used as injectable ultrasound contrast agent (UCA) in modern ultrasonography. Polymer-shelled UCAs present additional potentialities with respect to marketed lipid-shelled UCAs. They are more robust; that is, they have longer shelf and circulation life, and surface modifications are quite easily accomplished to obtain enhanced targeting and local drug delivery. The next generation of UCAs will be required to support not only ultrasound-based imaging methods but also other complementary diagnostic approaches such as magnetic resonance imaging or computer tomography. This work addresses the features of MBs that could function as contrast agents for both ultrasound and magnetic resonance imaging. The results indicate that the introduction of iron oxide nanoparticles (SPIONs) in the poly(vinyl alcohol) shell or on the external surface of the MBs does not greatly decrease the echogenicity of the host MBs compared with the unmodified one. The presence of SPIONs provides enough magnetic susceptibility to the MBs to accomplish good detectability both in vitro and in vivo. The distribution of SPIONs on the shell and their aggregation state seem to be key factors for the optimization of the transverse relaxation rate.

Serum Levels of Insulin-like Growth Factor Binding Proteins (IGFBP)–4 and –5 Correlate with Bone Mineral Density in Growth Hormone (GH)–Deficient Adults and Increase with GH Replacement Therapy†

Adults with growth hormone deficiency (GHD) exhibit low bone mineral density (BMD) which improves by growth hormone (GH) replacement therapy. The insulin‐like growth factor (IGF) system has an established role in mediating the effects of GH on bone and IGF binding proteins (IGFBP)‐4 and IGFBP‐5 have been shown to modulate the effects of IGFs in bone. Therefore, we studied serum levels of IGFBP‐4 and IGFBP‐5 and their relationship to serum levels of bone biochemical markers and BMD in adults with GH deficiency (GHD) before and during GH therapy. Serum levels of IGFBP‐5 and IGFBP‐4 were measured on samples from 20 patients (11 males) 22–57 years of age. All had IGF‐I serum values below –2 standard deviation score. The first 6 months were placebo controlled and all recieved 3 years of active treatment with the mean dose 0.23 ± 0.01 IU/kg/week divided into daily subcutaneous injections. Serum IGFBP‐5 levels in GHD adults were low at baseline and positively related to total body, femoral neck, trochanter, and Wards triangle BMD (r = 0.471, 0.549, 0.462, and 0.470, respectively, p < 0.05). The mean serum IGFBP‐5 level increased by about 2‐fold within 3 months after the initiation of GH therapy and was correlated with serum IGF‐I (r = 0.719, 0.801, and 0.722 before and after 18 and 36 months, respectively, p < 0.001). A positive correlation between serum IGFBP‐5 levels and lumbar spine BMD was found during GH treatment but not before. The percentage increase of serum IGFBP‐5 after GH therapy showed a positive correlation with the percentage increase of total alkaline phosphate activity (r = 0.347 p < 0.05). In contrast to IGFBP‐5, serum IGFBP‐4 levels were positively related to body mass index (r = 0.607, p < 0.01). Baseline serum IGFBP‐4 levels also correlated with total body, femoral neck, trochanter, and Wards triangle BMD (r = 0.502, 0.590, 0.612, and 0.471, respectively, p < 0.05). The mean serum IGFBP‐4 level was increased by 25% within 3 months after initiation of GH therapy and did not correlate with serum IGF‐I levels. Although the above findings are consistent with the idea that GH‐induced changes in serum IGFBP‐5 and IGFBP‐4 levels may in part mediate the anabolic effects of GH on bone tissue in adults with GHD, further studies are needed to establish the cause and effect relationship.

Liver vessel enhancement by Gd-BOPTA and Gd-EOB-DTPA- a comparison in healthy volunteers

Background: A thorough understanding of magnetic resonance (MR) contrast media dynamics makes it possible to choose the optimal contrast media for each investigation. Differences in visualizing hepatobiliary function between Gd-BOPTA and Gd-EOB-DTPA have previously been demonstrated, but less has been published regarding differences in liver vessel visualization. Purpose: To compare the liver vessel and liver parenchymal enhancement dynamics of Gd-BOPTA (MultiHance) and Gd-EOB-DTPA (Primovist). Material and Methods: The signal intensity of the liver parenchyma, the common hepatic artery, the middle hepatic vein, and a segmental branch of the right portal vein was obtained in 10 healthy volunteers before contrast media administration, during arterial and portal venous phases, and 10, 20, 30, 40, and 130 min after intravenous contrast medium injection, but, due to scanner limitations, not during the hepatic venous phase. The doses of contrast media were 0.1 mmol/kg for Gd-BOPTA and 0.025 mmol/kg for Gd-EOB-DTPA. Results: Maximum enhancement of liver parenchyma was observed from the portal venous phase until 130 min after Gd-BOPTA administration and from 10 min to 40 min after Gd-EOB-DTPA. There was no difference in maximum enhancement of liver parenchyma between the two contrast media. When using Gd-BOPTA, the vascular contrast enhancement was still apparent 40 min after injection, but had vanished 10 min after Gd-EOB-DTPA injection. The maximum difference in signal intensity between the vessels and the liver parenchyma was significantly greater with Gd-BOPTA than with Gd-EOB-DTPA (P<0.0001). Conclusion: At the dosage used in this study, Gd-BOPTA yields higher maximum enhancement of the hepatic artery, portal vein, and middle hepatic vein during the arterial and the portal venous phase and during the delayed phases than Gd-EOB-DTPA does, whereas there is no difference in liver parenchymal enhancement between the two contrast agents.

Clinical guidelines for management of bone health in Rett syndrome based on expert consensus and available evidence

Objectives We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. Methods An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. Results Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. Conclusion A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

Characterization of acoustic properties of PVA-shelled ultrasound contrast agents : linear properties (Part I)

This work examines the linear acoustic behavior of ultrasound contrast agents made of three types of poly (vinyl alcohol) (PVA) shelled microbubbles manufactured at different pH and temperature conditions. Backscattered power, attenuation coefficient and phase velocity of ultrasonic waves propagating through suspensions of PVA contrast agents were measured at temperature values ranging between 24 degrees C and 37 degrees C in a frequency range from 3 MHz to 13 MHz. Enhancement of the backscattered power higher than 20 dB and displaying a weak dependence on temperature was observed. Attenuation and phase velocity, on the other hand, showed higher sensitivity to temperature variations. A modified version of the Church model, which accounts for the dispersion of the dynamic modulus of the PVA shells, was developed to simultaneously fit the attenuation and phase velocity data at 24 degrees C. The frequency dependence of the storage modulus was found to be that of semiflexible polymeric networks. On the other hand, the frequency dependence of the dynamic loss modulus suggests that additional mechanisms, which may be related to the finite dimensions of the shell and/or to its inhomogeneity, may play a significant role in the dissipation of the acoustic energy. For the microbubbles of interest, this model predicts frequency dependent resonance frequency higher than 100 MHz.

Three-dimensional drip infusion CT cholangiography in patients with suspected obstructive biliary disease: a retrospective analysis of feasibility and adverse reaction to contrast material.

BackgroundComputed Tomography Cholangiography (CTC) is a fast and widely available alternative technique to visualise hepatobiliary disease in patients with an inconclusive ultrasound when MRI cannot be performed. The method has previously been relatively unknown and sparsely used, due to concerns about adverse reactions and about image quality in patients with impaired hepatic function and thus reduced contrast excretion. In this retrospective study, the feasibility and the frequency of adverse reactions of CTC when using a drip infusion scheme based on bilirubin levels were evaluated.MethodsThe medical records of patients who had undergone upper abdominal spiral CT with subsequent three-dimensional rendering of the biliary tract by means of CTC during seven years were retrospectively reviewed regarding serum bilirubin concentration, adverse reaction and presence of visible contrast media in the bile ducts at CT examination. In total, 153 consecutive examinations in 142 patients were reviewed.ResultsContrast media was observed in the bile ducts at 144 examinations. In 110 examinations, the infusion time had been recorded in the medical records. Among these, 42 examinations had an elevated bilirubin value (>19 umol/L). There were nine patients without contrast excretion; 3 of which had a normal bilirubin value and 6 had an elevated value (25–133 umol/L). Two of the 153 examinations were inconclusive. One subject (0.7%) experienced a minor adverse reaction – a pricking sensation in the face. No other adverse effects were noted.ConclusionWe conclude that drip infusion CTC with an infusion rate of the biliary contrast agent iotroxate governed by the serum bilirubin value is a feasible and safe alternative to MRC in patients with and without impaired biliary excretion.In this retrospective study the feasibility and the frequency of adverse reactions when using a drip infusion scheme based on bilirubin levels has been evaluated.