89Zr-Chloride Can Be Used for Immuno-PET Radiochemistry Without Loss of Antigen Reactivity In Vivo.

89Zr immuno-PET continues to be assessed in numerous clinical trials. This report evaluates the use of 89Zr-chloride in the radiolabeling of monoclonal antibodies conjugated with desferrioxamine B (DFO), describes its effects on radiopharmaceutical reactivity toward antigen, and offers guidance on how to ensure long-term stability and purity. Methods:89Zr-DFO-trastuzumab and 89Zr-DFO-cetuximab were prepared using 89ZrCl4 The stability of each was evaluated for 7 d in 20 mM histidine/240 mM sucrose buffer, 0.25 M sodium acetate (NaOAc) buffer containing 5 mg·mL-1n-acetyl-l-cysteine (NAC), or 0.25 M NaOAc containing 5 mg·mL-1 l-methionine (L-MET). To assess antigen reactivity, 89Zr-DFO-trastuzumab was evaluated using the Lindmo method and tested in PET/CT imaging of mouse models of human epidermal growth factor receptor 2-positive or -negative lung cancer. Results: Using 89ZrCl4, 89Zr-DFO-trastuzumab and 89Zr-DFO-cetuximab were prepared with increased specific activity and retained purities of 95% after 3 d when formulated in NaOAc buffer containing L-MET. Based on Lindmo analysis and small-animal PET/CT imaging, 89Zr-DFO-trastuzumab remained reactive toward antigen after being prepared with 89ZrCl4Conclusion:89ZrCl4 facilitated the radiosynthesis of 89Zr immuno-PET agents with increased specific activity. L-MET enhanced long-term solution stability better than all other formulations examined, and 89Zr-DFO-trastuzumab remained reactive toward antigen. Although further evaluation is necessary, these initial results suggest that 89ZrCl4 may be useful in immuno-PET radiochemistry as radiolabeled monoclonal antibodies are increasingly integrated into precision medicine strategies.

A comprehensively revised strategy that improves the specific activity and long-term stability of clinically relevant 89Zr-immuno-PET agents.

Zirconium-89 is currently being used in numerous clinical trials involving monoclonal antibodies and positron emission tomography. This report describes a revised strategy that reduces preparation time while increasing the specific activity of clinically relevant immuno-PET agents. Additionally, it demonstrates that n-acetyl-l-cysteine acts as a superior radioprotective agent that improves long-term stability without compromising antigen affinity in vivo.

Early-onset bipolar spectrum disorders: diagnostic issues.

Since the mid 1990s, early-onset bipolar spectrum disorders (BPSDs) have received increased attention in both the popular press and scholarly press. Rates of diagnosis of BPSD in children and adolescents have increased in inpatient, outpatient, and primary care settings. BPSDs remain difficult to diagnose, particularly in youth. The current diagnostic system makes few modifications to accommodate children and adolescents. Researchers in this area have developed specific BPSD definitions that affect the generalizability of their findings to all youth with BPSD. Despite knowledge gains from the research, BPSDs are still difficult to diagnose because clinicians must: (1) consider the impact of the child's developmental level on symptom presentation (e.g., normative behavior prevalence, environmental limitations on youth behavior, pubertal status, irritability, symptom duration); (2) weigh associated impairment and course of illness (e.g., neurocognitive functioning, failing to meet full DSM criteria, future impairment); and (3) make decisions about appropriate assessment (differentiating BPSD from medical illnesses, medications, drug use, or other psychiatric diagnoses that might better account for symptoms; comorbid disorders; informant characteristics and assessment measures to use). Research findings concerning these challenges and relevant recommendations are offered. Areas for further research to guide clinicians' assessment of children with early-onset BPSD are highlighted.

Immunosuppressants used in a steroid-sparing strategy for childhood uveitis.

PURPOSE: To review, with respect to etiology, the efficacy and complications of different immunosuppressants used in a steroid-sparing strategy for children with uveitis. PATIENTS AND METHODS: Forty children with uveitis were observed during a 5-year period, from 1997 to 2002. After complete ocular and physical assessment, routine and specific laboratory investigations were conducted along with radiologic examination. All cases underwent local therapy. Systemic corticosteroids were necessary in 75% of cases. Pediatric staff determined the need for initial association or sequential relay with immunosuppressants, depending on the severity of the uveitis. A steroid-sparing strategy was developed. RESULTS: The average age was 6.5 years (range, 3 months to 14 years), with a male-to-female ratio of 23 to 17. Uveitis was anterior in 55% of cases, intermediate in 2.5%, posterior in 42.5%, and bilateral in 62.5%. A positive etiology was found in 47.5% of cases, and articular symptoms were present in 25%. Overall, the improvement in visual acuity was 62.2%. Where corticotherapy was associated with azathioprine, a 61% improvement was achieved. Corticosteroid therapy associated with mycophenolate mofetil resulted in a 94% improvement. No complications were present in 42.5% of cases. Ocular complications were present in 57.5% of cases and systemic complications were present in 12.5% of cases, none being directly related to the use of steroids. CONCLUSION: The association of systemic corticotherapy and immunosuppressants in pediatric relapsing or steroid-dependent uveitis allows good recovery of visual acuity, fewer complications, and a minimization of side effects, especially those related to systemic corticosteroids. It requires close collaboration between the ophthalmologist and a fully involved pediatrician.

Epidemiology of juvenile idiopathic arthritis in Alsace, France.

OBJECTIVE: To determine the incidence, prevalence, and principal characteristics of the different forms of juvenile idiopathic arthritis (JIA) in the region of Alsace, northeastern France, using the new classification of the International League of Associations for Rheumatology (ILAR). METHODS: In 2002 we performed a retrospective epidemiologic study pertaining to the year 2001. The pediatricians, rheumatologists, ophthalmologists, orthopedic surgeons, and physicians involved in functional reeducation in the Alsace region were interviewed, and all patients were classified according to the new ILAR classification using the criteria revised in Durban in 1997. RESULTS: Among the 361 clinicians contacted, the participation rate was 97.8%. The study identified 67 children followed for JIA in Alsace in 2001, from a total population of 1.8 million inhabitants including 339,095 children under age 16 years. The incidence was calculated to be 3.2 cases/100,000/year and the prevalence 19.8 cases/100,000 children under age 16 years. Among these 67 cases of JIA, the most frequent forms were oligoarthritis (n = 27, 40.3%), polyarthritis without rheumatoid factor (RF; n = 15, 22.4%), and enthesitis related arthritis (n = 12, 17.9%). Other forms, notably systemic arthritis (n = 6, 8.9%) and psoriatic arthritis (n = 3, 4.5%), were more rare and in this study there was no case of polyarthritis with RF. Only 4 patients (6%) were classified in the undifferentiated arthritis group using the new classification. Antinuclear antibodies (ANA; by indirect immunofluorescence, HEp >/= 1/80) were detected in patients with oligoarthritis (81%) and polyarthritis without RF (79%). Uveitis occurred in 41% of children with oligoarthritis and in 14% of those with polyarthritis without RF. CONCLUSION: Our results are comparable to those of other studies carried out in Caucasian populations with regard to incidence and prevalence. This work also highlights the frequent presence of ANA and uveitis in patients with oligoarthritis or polyarthritis without RF.

The influence of peritoneal surface area on dialysis adequacy.

In children, the prescription of peritoneal dialysis is based mainly on the choice of the peritoneal dialysis fluid, the intraperitoneal fill volume (mL/m2 body surface area (BSA)], and the contact time. The working mode of the peritoneal membrane as a dialysis membrane is more related to a dynamic complex structure than to a static hemodialyzer. Thus, the peritoneal surface area impacts on dialysis adequacy. In fact, the peritoneal surface area may be viewed as composed of three exchange entities: the anatomic area, the contact area, and the vascular area. First, in infants, the anatomic area appears to be two-fold larger than in adults when expressed per kilogram body weight. On the other hand, the anatomic area becomes independent of age when expressed per square meter BSA. Therefore, scaling of the intraperitoneal fill volume by BSA (m2) is necessary to prevent a too low ratio of fill volume to exchange area, which would result in a functional "hyperpermeable" peritoneal exchange. Second, the contact area, also called the wetted membrane, is only a portion of the anatomic area, representing 30% to 60% of this area in humans, as measured by computed tomography. Both posture and fill volume may affect the extent of recruitment of contact area. Finally, the vascular area is influenced by the availability of both the anatomic area and the recruited contact area. This surface is governed essentially by both peritonealvascular perfusion, represented by the mesenteric vascular flow and, hence, by the number of perfused capillaries available for exchange. This vascular area is dynamically affected by different factors, such as composition of the peritoneal fluid, the fill volume, and the production of inflammatory agents. Peritoneal dialysis fluids that will be developed in the future for children should allow an optimization of the fill volume owing to a better tolerance in terms of lower achieved intraperitoneal pressure for a given fill volume. Moreover, future peritoneal dialysis fluids should protect the peritoneal membrane from hyperperfusion (lower glucose degradation products).

Long daytime exchange in children on continuous cycling peritoneal dialysis: preservation of drained volume because of icodextrin use.

Daytime exchanges with glucose osmotic agents often lead to dialysate reabsorption, poor ultrafiltration (UF), positive sodium balance, and restricted purification of uremic toxins. We studied 5 anuric children on continuous cycling peritoneal dialysis (mean age: 10 years, 10 months), comparing icodextrin to a conventional glucose-based dialysate. The same fill volume (980 +/- 290 mL/m2) and the same dwell duration (720 minutes) were used with both solutions for the daytime exchange. In a crossover design, we compared 7.5% icodextrin with 1.36% glucose, and then 1.36% glucose with 7.5% icodextrin. Tolerance, net UF, sodium balance, and solute extraction were analyzed. The Student t-test for paired data was used for statistical analysis. The drained volume was 44% +/- 18% higher during icodextrin exchanges, allowing a mean enhanced sodium extraction of 44 +/- 15 mmol per daytime exchange. The uremic toxin extraction capacity was enhanced under icodextrin: weekly Kt/V urea increased by 0.41 +/- 0.1, weekly creatinine clearance increased by 8.4 +/- 3.6 L/1.73 m2, and phosphate removal increased by 23%. Similarly, beta2-microglobulin extraction increased with icodextrin use. Dialysate protein loss under icodextrin increased from 1.3 +/- 0.6 g to 1.9 +/- 0.96 g per daytime exchange. Icodextrin improved ultrafiltration and purification capacities (urea, creatinine, phosphate, beta2-microglobulin), but the large drained volume directly affected dialysate protein loss.

Do all patients with childhood-onset growth hormone deficiency (GHD) and ectopic neurohypophysis have persistent GHD in adulthood?

Cerebral magnetic resonance imaging findings are of great value for the diagnosis of nonacquired GH deficiency (GHD), and ectopic posterior pituitary hyperintense signal (EPPHS) is a sensitive and specific indicator of hypopituitarism. It has been suggested that patients with childhood-onset GHD and EPPHS do not require additional investigation of GH secretion and should not be retested when adult height is achieved. This recommendation has never been validated through a systematic study. This study aimed to characterize the anterior pituitary function status of patients with EPPHS treated for GHD during childhood after completion of GH therapy when adult height had been achieved. Patients (n = 18; 15 males and three females) with childhood-onset GHD associated with ectopic neurohypophysis were treated with hGH (0.20 +/- 0.05 mg/kg.wk) for 9.9 +/- 4.0 yr (from 6.8 +/- 4.7 to 17.7 +/- 1.3 yr of age) with a mean height gain of 2.6 +/- 1.4 sd score. GH secretion was reevaluated by arginine insulin (n = 15) or propanolol glucagon (n = 3) test after 0.5 +/- 0.6 yr of GH withdrawal. At reevaluation, peak GH was more than 10 mug/liter in four patients (22%; range, 11.7-19.5 microg/liter; group I), between 5 and 10 microg/liter in three patients (17%; range, 7.3-9 mug/liter; group II), and less than 5 microg/liter in 11 patients (61%; range, 0-4.7 microg/liter; group III). A positive correlation was found between serum IGF-I and peak GH levels after attainment of adult height (P = 0.007). Only one of the seven patients who showed increased GH secretion ability in adulthood (groups I and II) demonstrated other hormonal deficiencies (gonadotropin and adrenal insufficiencies). Among the 11 patients with persistent severe GHD (group III), 10 (91%) of the 11 subjects were shown to have multiple pituitary hormone deficits after attainment of adult height. The structure of the hypothalamo-pituitary axis differs among groups [i.e. patients who showed increased GH secretion ability in adulthood (groups I and II) vs. those who remained severely GHD (group III)]. The location of the EPPHS was significantly different among groups (P < 0.003). The EPPHS was found at the median eminence in all but one of group III patients and along the pituitary stalk (proximal stalk) in all but one of group I and II patients. The pituitary stalk was visible and described as normal (n = 1) or thin (n = 6) in all group I and II patients, whereas the pituitary stalk was not visible even after enhancement in seven of the 11 group III patients (P < 0.02). The prevalence of anterior pituitary hypoplasia and the mean height gain sd score were similar in each group. In conclusion, only 61% of patients with childhood-onset GHD and EPPHS remained severely GHD, and thus suitable for GH therapy, in adulthood. Although the pathogenesis of anterior pituitary dysfunction remains unclear in patients with ectopic neurohypophysis, isolated GHD, location of EPPHS along the stalk, and visibility of the pituitary stalk on magnetic resonance imaging findings clearly represent important markers to predict a less severe form of the disease.

The peritoneal membrane: a dynamic dialysis membrane in children.

Peritoneal dialysis prescription in children should be individualized--based not only on numerical targets (Kt/Vurea, Kcreat), but also on consideration of the peritoneal membrane, a dynamic dialysis membrane. In fact, the effective peritoneal surface area is at least a triple entity: an anatomic area, a contact area, and an exchange area. The anatomic area appears to be twice as large in infants as in adults if expressed per kilogram of body weight (BW), although the area is independent of age if expressed per square meter of body surface area (BSA). Therefore, scaling of the intraperitoneal fill volume (IPV) by BSA in square meters is necessary to avoid a low IPV/area ratio, which results in a functionally "hyperpermeable" peritoneal exchange. The contact area (the wetted membrane) is only a fraction of the anatomic area--that is, 30%-60% in humans (by computed tomography). Contact area depends on a variety of factors, such as posture and fill volume, that affect the degree of recruitment of membrane contact area. The exchange area is influenced by both the anatomic are and the contact area. However, it is mainly governed by the specific vascular area as determined by the peritoneal vascular perfusion and the capillaries available for exchange. Vascular area is dynamically affected by a variety of factors, such as the composition of the peritoneal dialysis fluid, the fill volume, and possible inflammatory agents.