PROMAXX inhaled insulin: safe and efficacious administration with a commercially available dry powder inhaler.

OBJECTIVES: We investigated the pharmacokinetic (PK) and pharmacodynamic (PD) properties of recombinant human insulin inhalation powder (RHIIP), manufactured with PROMAXX technology, which allows formation of uniform protein microspheres. METHODS: Thirty healthy male subjects [age 30 +/- 1 years (mean +/- s.e.), body mass index 24.2 +/- 0.3 kg/m(2)] in a randomized crossover study received 10 IU subcutaneous regular human insulin (SCIns) and 6.5 mg of RHIIP [187 IU, Cyclohaler dry powder inhaler (DPI)] under euglycaemic glucose clamp conditions. Subjects were trained to inhale RHIIP with a flow rate of 90 +/- 30 l/min prior to dosing. RESULTS: Inhalation of RHIIP was well tolerated with no episode of cough or shortness of breath. RHIIP showed a faster onset of action than SCIns [time to reach 10% of total area under the glucose infusion rate (GIR) curves 73 +/- 2 vs. 95 +/- 3 min, time to maximal metabolic effect (T(max)GIR) 173 +/- 13 vs. 218 +/- 9 min, both p < 0.0001]. Duration of action (371 +/- 11 vs. 366 +/- 7 min) and total metabolic effect (AUCGIR0-10 h 2734 +/- 274 vs. 2482 +/- 155 mg/kg) were comparable. PK results were in accordance with the PD findings. Relative bioavailability (BA) of RHIIP was 12 +/- 2%, and relative biopotency (BP) was 6 +/- 1%. CONCLUSIONS: PROMAXX technology allowed for safe and efficacious administration of RHIIP to the deep lung with an off-the-shelf DPI. RHIIP showed a fast onset of action and BA/BP comparable to that reported for other inhaled insulin formulations using specifically designed inhalers. Improvements in the insulin delivery technique might allow to optimize drug application in all cases with even higher BA/BP with RHIIP.

Conservative treatment of infantile hypertrophic pyloric stenosis with intravenous atropine sulfate does not replace pyloromyotomy.

Pyloromyotomy as described by Weber and Ramstedt has been the standard therapy for infantile hypertrophic pyloric stenosis since the 1960's and conservative therapy has been abandoned. The objective of this study was to test the effectiveness of systemic atropine applied intravenously for 7 days as a conservative therapeutic strategy and as an alternative to primary operation. Forty-two consecutive term infants with infantile hypertrophic pyloric stenosis were enrolled in the study over a period of 5 years. After confirmation of the diagnosis they all received intravenous atropine at a dose of 0.04 mg/(kg day) and increased by 0.01 mg/(kg day) up to 0.12 mg/(kg day), given as 6-8 single doses per/day. Nine pairs of parents requested that their child should be operated before completing the 7 days of medical therapy. Surgery was necessary in 8 of the remaining 33 infants (24,.2%) who did not improve after 7 days of conservative treatment. Successful treatment with i.v. atropine sulfate was achieved only in 25/33 term infants at an average maximal dose of 0.11 mg/(kg day), without any major side effects. Intravenous atropine sulfate has been considered as a potential alternative therapeutic strategy in the treatment of infantile hypertrophic pyloric stenosis. Clinical improvement however was often not seen before the 6th or 7th day of intravenous treatment. A success rate for the conservative approach of only 75% at day 7 in our study does not favour atropine therapy, in view of success rates above 95% with surgical repair.

[Quality control of thoracic X-rays in children in diagnostic centers with and without pediatric-radiologic competence]. / Qualitätskontrolle von Röntgenthoraxaufnahmen bei Kindern in diagnostischen Zentren mit und ohne kinderradiologische Kompetenz.

PURPOSE: Radiation protection in pediatric radiology is very important because of the particular sensitivity of radiosensitive organs in younger patients. Optimized image quality supports radiation protection and should be targeted. In our study we examined the quality of pediatric chest X-rays at diagnostic centers (university hospitals and other large clinics). We then evaluated differences in image quality in departments without pediatric competence (R) and departments with pediatric competence (PR). MATERIALS AND METHODS: Our study was based on 313 conventional chest X-rays from 207 patients (192 p. a./a. p. and 121 lateral, 43 from R, 258 from PR and 12 neither from R nor KR) and 38 digital chest X-rays from 26 patients (25 p. a./a. p. and 13 lateral, 1 from R and 37 from PR). All patients (age 0 - 18 years) are from Nephroblastoma-Study SIOP-93/01-GPOH. We examined all initial chest X-rays, which were sent to us for evaluation upon request between 4/3/2002 and 6/14/2002. The examined parameters were: exposure, centering of the X-rays/patient positioning, collimation and sharpness. The X-rays were evaluated on a scale from 1 (best result) to 5 (worst result), resulting in an overall score of A = optimum, B = minor problems, C = major problems, or D = unusable. The optical density, the center of the image and the relative field size were also measured. Statistical tests (Mann-Whitney-U and log regression) were carried out on the conventional images. The study was performed retrospectively. The exposure, sharpness and optical density of the digital X-rays were not analyzed. RESULTS: In the case of all conventional X-rays, the quality of the centering of the X-rays/patient positioning and collimation was moderate (average scale value: 2.4 and 2.8), and the quality of the exposure and sharpness was good and very good (average scale value: 1.9 and 1.5). The quality of the chest X-rays in departments with additional pediatric radiological expertise was better mainly in the case of younger patients (younger than 5 years) than departments without additional pediatric radiological expertise (average scale value in age group 0 - 1 month: PR = 1.7; average scale value in age group 2 months - 2 years: R = 2.4 and PR = 1.8; average scale value in age group 3 - 5 years: R = 2.5 and PR = 1.8). CONCLUSION: Despite the good overall image quality, the quality of the centering of the X-rays/patient positioning and collimation was insufficient in both examiner groups (R and PR). For this reason, some radiation protection requirements could not be fulfilled. X-rays from PR were higher quality than X-rays from R in this special study group. Day-to-day quality checks are necessary for pediatric chest X-rays in order to achieve a high quality standard.

[Reference radiology in nephroblastoma: accuracy and relevance for preoperative chemotherapy]. / Referenzradiologie des Nephroblastoms: Diagnosegenauigkeit und Bedeutung für die präoperative Chemotherapie.

PURPOSE: A reference radiologic diagnosis was carried out for the purpose of quality control and in order to achieve high diagnostic accuracy in the ongoing trial and study SIOP 2001/GPOH for renal tumors during childhood. The aim of the present study is to evaluate the value of diagnostic imaging and the benefit of reference evaluation at a pediatric radiology center. MATERIALS AND METHODS: In 2004 the imaging studies of 97 patients suspected of having a renal tumor were presented at the beginning of therapy. Diagnostic imaging was compared to the primary imaging results and the histological findings and was analyzed in regard to the therapeutic consequence (primary chemotherapy without prior histology). 77 MRI, 35 CT and 67 ultrasound examinations of 47 girls and 50 boys (mean age 4 years; one day to 15.87 years old) were analyzed. In addition to the histological findings, the reference pathological results were submitted in 86 cases. Results from the primary imaging corresponding to the histology and results from the reference radiology corresponding to the histology were statistically compared in a binomial test. RESULTS: In 76 of the reference-diagnosed Wilms' tumors, 67 were confirmed histologically. In 72 cases preoperative chemotherapy was initiated. In 5 cases neither a Wilms' tumor nor a nephroblastomatosis was found. 16 of 21 cases (76 %) with reference-diagnosed non-Wilms' tumors were selected correctly. The results of the primary imaging corresponded to the histology in 71 cases, and those of the reference radiology in 82 cases. The statistical evaluation showed that the results of the reference radiology were significantly better (p = 0.03971). CONCLUSION: Reference radiological evaluation improved the diagnostic accuracy with therapeutic relevance. The differentiation of different renal tumors is not completely possible using imaging methods. The rate of patients with false preoperative chemotherapy for all renal neoplasms is currently 5.2 % and 1 % for benign renal tumors.

[MRI-morphology and staging of congenital mesoblastic nephroma: evaluation of a collection with 20 patients]. / MRT-Morphologie und Staging des kongenitalen mesoblastischen Nephroms: Auswertung einer Fallsammlung mit 20 Patienten.

PURPOSE: To differentiate classic and cellular type of congenital mesoblastic nephroma (CMN) in MRI and to evaluate MRI for staging according to the Societe Internationale de Oncologie Pediatrique (SIOP). MATERIAL AND METHODS: MRI examinations of 20 children with CMN (age 1st to 16th months, classic type n = 11, cellular type n = 7, mixed type n = 2) were analyzed retrospectively. Cysts, necrosis, hemmorhage in the tumor, signal intensity, tumor structure, thrombosis and dilatation of renal vein, crossing of the body midline, peripheral contrast-enhancement, tumor volume and existence of a tumor pseudocapsule in contrast to the residual kidney were described. The radiologic stage was compared with the histopathologic stage (infiltration of perirenal fat and infiltration of the renal sinus). RESULTS: Tumors of the classic type (mean volume 67.9 ml) had necrosis in 1 case, crossed the midline in 1 case, had no cysts or bleeding, and had a peripheral contrast-enhancement in 1 case, and were heterogeneous in 9 cases. The cellular type (mean volume 302.8 ml) had tumor necrosis in 6 cases, bleeding in 3 cases, cysts in 3 cases, crossed the midline in 4 cases, and peripheral contrast enhancement in 2 cases, and was predominantly heterogeneous. Mixed tumor types (7 ml and 202 ml) had tumor necrosis in 1 case and crossed the midline in 1 case, a peripheral contrast enhancement in 2 cases and a homogenous structure in 1 case. The signal intensity in T1 w and T2 w images was not specific. The renal vein was inconspicuous in all children. The evaluation of the infiltration in perirenal fatty tissue was true positive in 1 case, true negative in 10 cases, false negative in 4 cases and false positive in 5 cases. The infiltration of the renal hilus was true positive in 10 children, false positive in 8 cases and true negative in 2 cases. CONCLUSION: A typical finding of CMN in MRI is a heterogeneous tumor without demarcation from the rest of the kidney parenchyma by a pseudocapsule. The cellular type of CMN tends to have a higher tumor volume and shows more necrosis, bleeding and cysts than the classic type in MRI. A peripheral contrast-enhancement in MRI is not characteristic for any type of CMN. Local tumor staging is not possible with MRI.

Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene.

We report on a postmortem diagnosis of perinatal lethal hypophosphatasia, an inborn error of metabolism characterized by a liver/bone/kidney alkaline phosphatase (ALP)-related defective bone mineralization due to mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Radiological and pathological studies identified a perinatal lethal hypophosphatasia showing a generalized bone mineralization defect including asymmetry of the cervical vertebral arches in a 22 +4 weeks' gestation fetus. Both parents revealed low serum ALP activities supporting the diagnosis. Sequencing analysis of the TNSALP gene showed two heterozygous mutations, 648+1A, a mutation affecting the donor splice site in exon 6, and N400S, a novel missense mutation in exon 11, located near the active site and very close to histidins 364 and 437, two crucial residues of the active site. Sequencing of exons 6 and 11 in the parents showed that 648+1A was from maternal origin and N400S from paternal origin. DNA-based prenatal testing in the subsequent pregnancy following a chorionic villous sampling performed at 10 weeks of gestation showed no mutation and a healthy infant was born at term.

Feasibility of an ultrasound service on district health care level in Botswana.

OBJECTIVE: To assess the clinical benefit and financial feasibility of an ultrasound service in a district hospital in Botswana. METHOD: An ultrasound service was established in the study hospital. Clinical and ultrasound-aided diagnoses were compared in patients who met eligibility criteria laid down in an indication list. RESULTS: We enrolled 2309 patients over 18 months. The most frequent indications for ultrasound were pregnancy-related diagnoses followed by gynaecological and hepato-biliary disorders. Ultrasound assistance improved case management in 696 cases (30%) and led to an immediate change in management in 151 patients. Ultrasound diagnosis was used as gold standard to assess the accuracy of the clinical diagnosis of incomplete abortion (sensitivity 24%; positive predictive value, PPV 66%), pelvic mass (sensitivity 53%; PPV 69%), ectopic pregnancy (sensitivity 75%; PPV 28%), and gall bladder stones (sensitivity 30%; PPV 32%). CONCLUSIONS: Ultrasound improved case management for a wide diversity of clinical problems encountered on district health care level. The service proved to be affordable for the Botswana health care system.

Reduction in voiding cystourethrographies after the introduction of contrast enhanced sonographic reflux diagnosis.

BACKGROUND: Voiding urosonography (VUS) using the intravesical application of an US contrast medium (Levovist) has been shown to have very high sensitivity and specificity in the diagnosis of vesicoureteric reflux (VUR) compared to voiding cystourethrography (VCUG). OBJECTIVE: To determine the extent of reduction of VCUGs after adding VUS to the diagnostic algorithm of VUR. MATERIALS AND METHODS: Over 2 years, 449 children (162 boys, 287 girls) were referred for diagnosis of possible VUR. The selection of a particular reflux examination was based on pre-defined criteria. VUS was performed primarily in girls and follow-up cases. The indications for VCUG were as follows: (a) boys - first examination for VUR, (b) specific request for urethra or bladder imaging, (c) girls - when VUR was diagnosed in the VUS and no VCUG had been done previously, and (d) inadequate VUS. RESULTS: VCUGs were primarily carried out in 141 cases. VUSs were performed in 308 patients. In 69 of these patients a VCUG followed during the same examination session. Thus 239 of 449 patients underwent only VUS, resulting in reduction of the VCUGs by 53 %. CONCLUSIONS: The number of VCUGs was significantly reduced as a result of the implementation of VUS as part of the routine diagnostic imaging modality for VUR. Consequently, the number of children that would have been exposed to ionising radiation was reduced by over half.

Contrast-enhanced harmonic imaging for the diagnosis of vesicoureteral reflux in pediatric patients.

OBJECTIVE: Harmonic imaging using phase or pulse inversion technology is a new sonographic diagnostic modality that has the potential to produce images of a higher quality than can be obtained with the conventional method. The aim of this study was to compare both types of harmonic modalities--tissue and contrast harmonic imaging--with the fundamental imaging mode in contrast-enhanced B-mode sonographic diagnosis of vesicoureteral reflux. SUBJECTS AND METHODS: Fifty-four children presenting for diagnostic examination of vesicoureteral reflux underwent standard sonography of the urinary tract in the fundamental mode, followed by intravesical administration of a galactose-based contrast medium containing microbubbles. The contrast-enhanced sonography was conducted by scanning the bladder and each kidney in transverse and longitudinal planes, from ventral and dorsal views, consecutively in B-mode using fundamental, contrast harmonic, and tissue harmonic imaging modalities. Soft-touch buttons on the console screen were used to alternate between the three imaging options, so that switching from one modality to the other could be done almost instantaneously. For comparison, in each patient, we selected one set of contrast-enhanced images of the bladder and two sets, one ventral and one dorsal, of the kidney. In a series, the images were compared and ranked from 1 to 3, with 1 being the best, with regard to sonomorphology (demarcation of the retrovesical space and renal pelvis as the potential sites to look for vesicoureteral reflux) and reflux detection and conspicuity, if present. RESULTS: In all, 248 sets of images were available for comparison. The delineation of both the retrovesical space and the renal pelvis was found to be best with tissue harmonic imaging in 84% and 96% of the image sets, respectively (p < 0.01). Forty-one sets of images were compared from 27 kidney-ureter image units of 22 children (41%) with reflux. The refluxing microbubbles were much more conspicuous in the harmonic imaging mode (tissue harmonic, 100%; contrast harmonic, 93%) than in the fundamental mode (p < 0.01). In eight kidney-ureter units, the reflux was detected only by using the harmonic imaging modalities. CONCLUSION: Visualization of the urinary tract and detection of ultrasound contrast media is significantly improved by the use of the harmonic imaging modalities. When both fundamental and harmonic imaging options are available, we recommend harmonic imaging for contrast-enhanced sonographic diagnosis of vesicoureteral reflux.

Internal jugular venous valves in children: high-resolution US findings.

The aim of this study was to determine in children the prevalence rate and to describe the sonographic morphology of the valves in the internal jugular veins. One hundred twenty children (60 boys and 60 girls; mean age +/- SD 10 +/- 4 years, age range 3-20 years) were recruited for the study. They underwent sonographic examination of both internal jugular veins. The number of valvular cusps, the length of the cusps and exact site of origin were recorded. In 96% of the children a valve was found in one or both internal jugular veins. Within this group a valve was detected unilaterally in 26% and bilaterally in 74% of the cases. Ultrasound morphological and morphometric analysis was carried out in a total of 239 internal jugular veins; 200 (84%) veins were found to have valves. The origin of the cusps was located at a mean distance of 9 mm (0-26 mm) proximal to the confluence of the subclavian and internal jugular veins into the brachiocephalic vein. A valve in the distal part of the internal jugular vein is a very common finding with characteristic features on US.

Ellis-van Creveld syndrome: a generalized dysplasia of enchondral ossification.

We report a 25-week fetus with lethal Ellis-van Creveld syndrome who was diagnosed prenatally from the US detection of a narrow chest, postaxial polydactyly of the hands, short acro-/mesomelic limbs and a ventricular septal defect. The postnatal radiographic features of the skeleton confirmed the diagnosis. Literature review of the histopathology of the physeal growth plate is contradictory, varying between retardation of the hypertrophic chondrocytes without disorganization and marked disorganization of the proliferating chondrocytes. We investigated numerous sites of the enchondral ossification and observed retardation of the physeal growth plate in all sites and retardation with pronounced disorganization of the physeal growth plate in the upper mesomelic bone segments only. These data support the concept that Ellis-van Creveld syndrome is mainly a generalized disorder of the maturation of enchondral ossification.

Radiation exposure during chest X-ray examinations in a premature intensive care unit: phantom studies.

BACKGROUND: There are few reports on the radiation dose received by infants, their family and radiographers exposed to scatter radiation in a premature baby intensive care unit. OBJECTIVE: To evaluate the degree of radiation exposure from diagnostic X-ray examinations with mobile X-ray machines in a premature intensive care unit. MATERIALS AND METHODS: The radiation exposure of an adjacent newborn, the radiographer and other persons in the room was simulated using phantoms during X-ray examination of the chest using vertical and horizontal beams. RESULTS: Most of the measured doses were below the registration limit of the measuring apparatus and had to be extrapolated by multiple exposures. Without exception, the maximal doses were significantly lower than the permitted limit for persons not professionally exposed to X-rays. CONCLUSIONS: Recommendations to avoid unnecessary radiation exposure are given.

Reflux in young patients: comparison of voiding US of the bladder and retrovesical space with echo enhancement versus voiding cystourethrography for diagnosis.

PURPOSE: To compare the usefulness of voiding US of the bladder and retrovesical space with echo enhancement with that of voiding cystourethrography (VCUG) for diagnosis of vesicoureteral reflux (VUR) and to assess patient tolerance of the echo-enhancing agent. MATERIALS AND METHODS: One hundred eighty-eight patients (aged 5 days to 20 years) referred for investigation of VUR underwent voiding US with echo enhancement, which was followed by VCUG in 110 patients (226 kidney-ureter units). After US of the renal tract, the bladder was filled with normal saline solution. Then SU U 508 A, a galactose-based, microbubble-containing echo-enhancing agent, was administered. Reflux was diagnosed when microbubbles appeared in the ureter or pelvicalyceal system. RESULTS: VUR was detected in 80 of the units with one (n = 18) or both (n = 62) methods. All grades of reflux were identified. In 15 units, reflux diagnosed at voiding US was not observed at VCUG; the reverse was true in three units. In 208 (92%) of the 226 kidney-ureter units, there was concordance between the two methods regarding the diagnosis or exclusion of VUR. The echo-enhancing agent was well tolerated. CONCLUSION: SH U 508 A enhanced voiding US is as good as VCUG in the detection or exclusion of VUR and thus will make it possible to reduce the number of children having to be exposed to ionizing radiation.

Short-rib-polydactyly syndrome type Verma-Naumoff-Le Marec in a fetus with histological hallmarks of type Saldino-Noonan but lacking internal organ abnormalities.

Up to seven short-rib-polydactyly (SRP) syndromes have been identified so far with marked clinical and pathological overlap. We describe a 32-week-old, nonhydropic male fetus with thoracic "dysplasia," short limbs, and unilateral postaxial polydactyly. All internal organs were normally developed, including the central nervous system. The external genitalia were unambiguously male, in accordance with a 46,XY karyotype. Radiological signs most closely resembled those of SRP, type Le Marec, though histology of the femoral physeal growth zone was consistent with the Saldino-Noonan type. The remarkable lack of visceral anomalies in conjunction with the radiological and histological findings further adds to the phenotypic spectrum of the SRP syndromes. The histological analysis in this case supports a close relationship between types Saldino-Noonan and Verma-Naumoff-Le Marec.

A rare form of spondylometaphyseal dysplasia-type A4.

We present 2 cases of a previously apparently unreported spondylo-metaphyseal dysplasia comprising dwarfism, severe metaphyseal changes, ovoid vertebrae and mild platyspondyly with anterior tonguing of the vertebral bodies. The inheritance may be autosomal recessive.

Evaluation of ultrasonography for the detection of drug-induced changes in onchocercal nodules.

Clinical trials of macrofilaricidal drugs against Onchocerca volvulus are impeded due to the lack of means for assessing in vivo drug-induced changes in the onchocercomas. The application of ultrasonography in the sequential monitoring of morphologic alterations of onchocercal nodules after six weeks of suramin therapy was evaluated in 20 male patients from Ghana with a total of 64 nodule sites. After each follow-up session, a number of onchocercal nodules were extirpated so that by the end of one year, all nodules had been removed for histologic examination. The sonomorphologic changes observed and their time of appearance correlated well with the histologic findings of the onchocercomas. Eighty-three percent of the onchocercal nodules became hyperechogenic and 22% developed echo-free areas at the end of the follow-up period. Absence of the lateral acoustic shadow increased by more than 30% and the lack of differentiation of the worm center from the capsule and the nodule from its surrounding tissue increased by the end of one-year posttreatment to 100% and 91%, respectively. A mean reduction of nodule size of 27% was also documented. The histologic studies revealed that the proportion of the dead female worms increased from 17% at the end of the suramin therapy to 48% six months later and reached 61% at one year. It is concluded that ultrasonographic monitoring of onchocercomas can provide essential information on drug effects and facilitate clinical trials of macrofilaricidal drugs, limiting histologic evaluation to a few objectively selected onchocercomas.