Efficacy and safety of Diclofenac sodium plaster in patients with acute pain of the limbs: a randomized, placebo and active-controlled, double-blind, parallel-group trial.

OBJECTIVE: The aim of the present study was to assess the safety and efficacy of Diclofenac sodium (DS) 140 mg medicated plaster vs. Diclofenac epolamine (DIEP) 180 mg medicated plaster and placebo plaster, for the treatment of painful disease due to traumatic events of the limbs. PATIENTS AND METHODS: This was a multicenter, phase III study involving 214 patients, aged 18-65 years, affected by painful conditions due to soft tissue injuries. Patients were randomized to DS, DIEP or placebo arms and treated with once-daily application of the plaster for a total treatment period of 7 days. The primary objective was first to demonstrate the non-inferior efficacy of the DS treatment when compared to the reference DIEP treatment and second that both, test and reference treatments, were superior with respect to placebo. The secondary objectives included the evaluation of efficacy, adhesion, safety, and local tolerability of DS in comparison to both DIEP and placebo. RESULTS: The mean visual analog scale (VAS) score decrease for pain at rest was higher in the DS (-17.65 mm) and the DIEP group (-17.5 mm) than in the placebo (-11.3 mm). Both active formulation plasters were associated with a statistically significant pain reduction compared to placebo. No statistically significant differences were observed between DIEP and DS plasters efficacy in relieving pain. Secondary endpoint evaluations supported the primary efficacy results. No serious adverse events (SAEs) were registered, and the most commonly detected adverse events were skin reactions at the application site. CONCLUSIONS: The results showed that both the DS 140 mg plaster and the reference DIEP 180 mg plaster are effective in relieving pain and present a good safety profile.

Cerebellar hypoplasia and frontal lobe cognitive deficits in disorders of early childhood.

A developmental chronometry hypothesis of early brain damage is suggested in which regions of the brain with a protracted course of postnatal development will be more vulnerable than earlier maturing areas to deleterious effects of early insult and, therefore, may become common sites of abnormality across many disorders originating in early childhood. Initial investigations of the cerebellum and frontal lobes are presented using MRI and neuropsychological measures. Planimetric measures of the cerebellar vermis (lobuli I-V and VI-VII) and pons, and neuropsychological frontal lobe measures were obtained from high functioning individuals with autism (A), survivors of acute lymphoblastic leukemia (ALL) with brain sequelae following radiation and chemotherapy, and from rigorously selected healthy controls (C). The neuropsychological results were clustered according to functions commonly related to frontal brain, posterior brain, and left and right hemispheres. The A and ALL groups, as compared to C, yielded modest but consistently reduced MRI measures for vermal lobuli I-V and VI-VII. Hypoplasia of lobuli VI-VII was more marked than I-V. Performance on neuropsychological tests for frontal lobe functions was generally depressed in both groups, with more severe deficits in A. Between-group differences in verbal, visual-spatial, and emotional-social skills are discussed. The cerebellar and frontal brain deficits that are present in both clinical groups (A and ALL) may be common to other developmental and acquired disorders of early childhood. Such joint manifestation of cerebellar and frontal lobe abnormalities is in agreement with the concept of cerebellar significance for the development of higher cognitive functions.

Curative radioimmunotherapy of human mammary carcinoma xenografts with iodine-131-labeled monoclonal antibodies.

The radioiodinated monoclonal antibody BW 495/36 showed an exceptionally high uptake and long residence time in human ductal mammary carcinoma xenografts in nude mice. There was a mean tumor uptake of 82%/g 24 hr p.i., decreasing with a biologic half-life of approximately 6 days, to 15%/g by Day 16. The tumor-to-blood ratio increased from 2.8 to 21.4 and the percentage of the whole-body retention recovered in the tumor from 47% to 80% during the same time interval. The therapeutic efficiency of two injections of 7.4 MBq 131I-BW 495/36 was evaluated by comparing the tumor size with that in mice injected with either the same amount of the unlabeled MoAb, the same radioactivity of an 131I-labeled nonspecific MoAb, or with saline only. The high tumor accumulation of 131I-BW 495/36 led to a total tumor dose of 77 Gy resulting in a mean reduction in tumor diameter of 50%, corresponding to a reduction in tumor volume of 88% within 42 days p.i. Unlabeled MoAb had no effect on tumor growth compared with controls, whereas 131I nonspecific antibody caused a slight inhibition of tumor growth. Histologic tumor sections showed large areas of necrosis and a pronounced vacuolation of the tumor cell cytoplasm between Days 7 and 30 p.i. By Day 42 all remaining tissue in the tumor was identified as mouse connective tissue.

Measurement of myocardial fatty acid metabolism: kinetics of iodine-123 heptadecanoic acid in normal dog hearts.

To define the potential of iodine-123 heptadecanoic acid (IHA) for the noninvasive assessment of myocardial fatty acid metabolism with gamma camera imaging, the influence of myocardial oxygen consumption (MVO2) and blood flow (MBF) on extraction and half-times of IHA were investigated in dogs. Following IHA injection into the left circumflex coronary artery, extraction fraction and half-times were derived from the peak and slope of the IHA time activity curve, which consisted of a vascular, early, and late phase. Single-pass extraction fraction of IHA averaged 0.53 +/- 0.11 s.d. at control and was not influenced by MVO2 and MBF. The half-time of the early phase (T = 9.3 min +/- 2.8 s.d. in controls) as well as the ratio between the size of the early and late phase increased with MVO2 (r = 0.82, r = 0.87, respectively). Thus, early phase intracellular turnover of IHA increased, yet clearance of 123I activity was slowed by augmented cardiac work. Preliminary data of HPLC and electrophoretic analysis of myocardial arterial and venous blood samples over time indicate that the early phase is characterized by a decreasing washout of IHA and a relative increase of radioiodine washout. The half-time of the late phase (T = 245 min +/- 156 s.d. at control) was not related to MVO2 and MBF. In conclusion, myocardial fatty acid metabolism cannot be measured from the half-time of the early phase but might be analyzed from the ratio between the size of the early and late phase when using IHA.

Lacrimal dacryoscintigraphy.

Lacrimal dacryoscintigraphy facilitates definite diagnosis of obstructions and stenosis of the lacrimal drainage system with little stress to the patient. Together with x-ray dacryocystography it is an important diagnostic tool especially for pre- and postoperative evaluation of the drainage apparatus. Dacryoscintigraphy is the best method for measuring the dynamics of tear drainage especially in the canaliculi. Although it is not a substitute for other methods in general use, it complements them and expands their diagnostic accuracy.

Reduced measles immunity in infants in a well-vaccinated population.

The recommended age for measles vaccination is based in part on information gathered when most mothers had natural measles. Nowadays many mothers have received measles vaccine. To assess this change measles antibody neutralization titers (NT) were determined for 278 mother-infant pairs. One hundred sixty-four mothers, born before 1958, likely had had natural measles (Group 1). Sixty mothers received one to three killed plus one attenuated measles vaccination (Group 2) and 54 received 1 attenuated measles vaccination only (Group 3). NT were determined for the mother and for the infant at birth and in the infant during the fourth and sixth months. Group 1 mothers and infants at every age had higher geometric mean NT than those in Groups 2 or 3 (P less than 0.05). By 7 months 65% of Group 1 infants and greater than 90% of Group 2 and 3 infants had an NT less than 1:10. The rate of antibody decay was significantly faster for Group 1 infants (P less than 0.05). Earlier vaccination in the infant should be considered.

Measles vaccination of infants in a well-vaccinated population.

During outbreaks of measles, measles vaccine is recommended for infants considered to be at risk who are 6 months of age and older. In a prospective trial the serologic response to early measles immunization has been evaluated in 125 infants given monovalent measles vaccine at 6 to 8.5 months of age and measles-mumps-rubella at 15 months. The response to vaccination was measured by plaque reduction neutralization (PRN) assay and enzyme immunoassay. Infants were grouped by the mother's immunization history: natural immunity (n = 60, Group 1); killed followed by live, further attenuated vaccine (n = 22, Group 2); and live, further attenuated vaccine only (n = 43, Group 3). The prevaccination geometric mean titer (GMT) by PRN for Group 1 (GMT = 69) was significantly higher than that of Group 2 (GMT = 18) or 3 (GMT = 13). Seroconversion (4-fold increase in PRN titer) rates after monovalent vaccine were 31, 71 and 76% for Groups 1, 2 and 3, respectively. Seroconversion percentages were higher when measured 6 to 8 weeks after vaccination compared with 4 to 5 weeks. After measles-mumps-rubella > or = 97% of all infants had PRN titers > 120 and were measles IgG-positive by enzyme immunoassay. These data show that as demographics shift to a well-vaccinated maternal population and susceptibility in younger infants, measles vaccination before the currently recommended age will be effective.

Bone marrow transplantation for T-B- severe combined immunodeficiency disease in Athabascan-speaking native Americans.

A distinct form of autosomal recessive T-B- severe combined immunodeficiency disease occurs with a high frequency among Athabascan-speaking Native Americans (SCIDA), including Navajo and Apache Indians from the southwestern US and Dene Indians from the Canadian Northwest Territories. The SCIDA gene has been linked to markers on chromosome 10p although its identity and role in the pathogenesis of this disease are unknown. We report our experience in treating 18 Navajo and Dene children with SCIDA between 1984 and 1999; 16 underwent bone marrow transplants (BMT). All children were symptomatic within 2 months of birth, had the T-B- NK(+)SCID phenotype and 67% presented with oral and/or genital ulcers. Three children had evidence of maternal engraftment prior to transplant. Two children died shortly after diagnosis. Three children required more than one BMT and 12 are alive with T cell reconstitution at a median follow-up of 7 years. Three children developed normal B cell immunity, two of whom received ablative conditioning therapy with either radiation or busulfan. Three of the four children who died received therapy with either radiation or busulfan and two of eight long-term survivors who were also recipients of cytotoxic chemotherapy have failed to develop secondary teeth. These results demonstrate the efficacy of BMT in treating infants with this distinct form of SCID, although B cell reconstitution remains a problem even with HLA-matched donors. Without conditioning, T cell engraftment is likely when closely HLA-matched donors are used. With T cell depletion of haplocompatible marrow, conditioning with immunosuppressive therapy may be necessary; however, children with SCIDA who were treated with intensive immunosuppressive and myeloablative therapy had a poor outcome.

Interstitial glial cells of the gerbil pineal gland display immunoreactivity for the metabotropic glutamate receptors mGluR2/3 and mGluR5.

Recent studies have strengthened the hypothesis that neuroactive amino acids such as L-glutamate play an important role in the physiology of the mammalian pineal gland. In particular, there is now considerable evidence that L-glutamate is liberated from electron-lucent microvesicles of pinealocytes for a paracrine modulation of melatonin synthesis and release which may at least partially be mediated by the metabotropic glutamate receptor mGluR3. In order to expand our incomplete knowledge of possible pineal target cells and signal transduction mechanisms which are involved in glutamate-dependent intercellular communication, we have performed an immunohistochemical study of the gerbil pineal gland with antibodies directed against the metabotropic glutamate receptors mGluR2/3 and mGluR5. Using microwave irradiation of cryostat sections prior to immunostaining, strong immunoreactivity for both receptor subtypes was constantly observed in a subpopulation of pineal cells. Interestingly, these mGluR-positive cells could be identified as interstitial glial cells since they were labeled by antibodies against the intermediate filament protein vimentin in double immunofluorescence histochemistry. This indicates that interstitial glial cells in the gerbil possess the capacity to express at least two metabotropic glutamate receptors coupled to different intracellular signal transduction pathways. Therefore, it can be concluded that the glutamatergic communication system of the pineal gland may not only enable paracrine crosstalk among pinealocytes but probably also relies on interactions between pinealocytes and interstitial cells analogous to neuronal-glial signaling.

Evidence for microvesicular storage and release of glycine in rodent pinealocytes.

Prompted by previous studies suggesting a regulatory role for the inhibitory amino acid gamma-aminobutyric acid (GABA) within the mammalian pineal gland, we carried out a study of rat and gerbil pineal organs to elucidate whether there is evidence for a vesicular storage and release of GABA and/or glycine. Immunohistochemistry revealed the presence of the vesicular inhibitory amino acid transporter in pinealocytes. Moreover, we found that, in addition to glutamate and aspartate, cultured pinealocytes also released glycine upon stimulation by depolarizing concentrations of KCl, whereas the content of GABA in the culture medium did not exceed the detection limit either under control conditions or following KCl application. Therefore, we propose that glycine is a further component of the paracrine signaling system within the pineal organ which is based on the compartment of synaptic-like microvesicles (SLMVs) inside pinealocytes.

[Skeletal scintigraphy for the observation of course and treatment of carcinoma of the prostate ]. / Skelettszintigraphische Verlaufs- und Therapiekontrolle beim Prostatakarzinompatienten.

Serial skeletal scintigraphy was carried out on 259 patients with carcinoma of the prostate; 5-10% developed bone metastases each year. Isotope uptake was measured in 79 patients receiving treatment; in 60.6% (48 patients) there was a reduction or disappearance of the areas of uptake, in 16.6% (13 patients) they were stationary and 22.8% (18 patients) the metastases progressed. Skeletal scintigraphy is therefore useful during the course of the disease in showing its extent and the effect of treatment.

[After care of differentiated thyroid gland carcinoma with special reference to serum thyroglobulin level]. / Nachsorge des differenzierten Schilddrüsenkarzinoms unter spezieller Berücksichtigung des Serum-Thyreoglobulin-(hTg-)Spiegels.

The histories of 358 patients with carcinomas of the thyroid have been evaluated. Differentiated carcinomas of the thyroid (84.6%) were treated by means of thyroidectomy, ablative radio-iodine therapy (tissue dose 1000 Gray), TSH-suppressive thyroid hormone medication and, in special cases, external radiation. Even differentiated carcinomas showed a high recurrence rate. Metastases occurred particularly in the lungs, the skeleton and locally; low iodine uptake, particularly in distant metastases from papillary carcinomas, often made it impossible to reach a diagnosis by using radio-iodine. Some pulmonary metastases could only be demonstrated radiologically and some skeletal metastases could be shown radiologically or scintigraphically. A modified follow-up program for differentiated carcinomas is suggested, based on the highly sensitive and specific thyroglobulin determination under TSH suppression (sensitivity 97.9%, specificity 93.6%).

[Measurement of renal blood flow with the Anger scintillation camera after selective intra-arterial injections of 133xenon and 99mtechnetium]. / Die Messung der Nierendurchblutung mit der Anger-Szintillationskamera nach selektiver intraarterieller Injektion von 133-Xenon und 99m-Technetium

A "region of interest" technique for measuring renal blood flow is described, using as Anger camera and selective intra-arterial injection of 133Xe and 99mTc. The sequence of measurements has the advantage of providing information on regional blood flow. The values for RBF and RBFD obtained with 133Xe agree with those in the literature. Selective determination of the RCBF with the "region of interest" technique using 133Xe was not possible. Mean transit time for 99mTc was calculated after correction of the 99mTc indicator dilution curve with respect to recirculation and background activity. All typer of pathological changes in the kidney showed a statistically significant increase in mean transit time when compared with a control group. In patients with uncomplicated essential hypertension, the mean transit time was signigicantly reduced. A comparison of the mean transit time of 99mTc with the haemodynamic parameters derived from the 133Xe studies, and experiments with pharmocologically induced vasoconstriction indicates that the mean transit time represents a measure of the RCBF.

[Clinical and experimental investigations with 201tl for noninvasive myocardial scintigraphy (author's transl)]. / Klinishce und experimentelle Untersuchungen mit 201Tl zur nichtinvasiven Myokardszintigraphie

The biological distribution of 201Tl after intravenous injection was studied experimentally in 42 rats. It was found (see figure 1) that the kidneys showed the greatest affinity for 201Th, reaching an activity concentration of 6.6% per gramme of tissue, almost independently of time. Within the first 30 minutes of injection, myocardial activity exceeds that of the surrounding structures (10 min. p.i.: 4.24%/g; 30 min. p.i.: 2.58%/g). During this time the myocardium can be well demonstrated by "image processing". The relatively fast myocardial kinetics of 201Tl (half value time 33 minutes) make it necessary, strictly speaking, to use a scintillation camera. The clinical value of this method is illustrated by a number of case histories.

[The weighting of SE, IE and GE sequences in tumors of the head and neck]. / Wertigkeit von SE-, IE- und GE-Sequenzen bei Tumoren im Kopf-Hals-Bereich.

In a review of 82 patients having different benign and malignant head and neck tumours we studied the value of spin echo (SE), inversion echo (IE) and gradient echo (GE) sequences. The strong T1 weighted IE mode is highly sensitive to demonstrate pathological tissue. Tumour diagnosis was in 20% and lymph node diagnosis in 29% better than T2 weighted SE sequences. According to this experience we choose the IE mode as the first one for all patients examined for tumour staging. All other sequences and orientations are planned on this tomograms knowing the location of the tumour and lymph nodes. T1 weighted SE mode is indispensable and should be recorded in transversal orientation, covering the whole head and neck region. This mode has the best imaging of anatomical structures as the known fatty limitations. The best differentiation of the tumour is usually obtained after contrast enhancement by i.v. Gd-DTPA. The highest contrast enhancement is seen on T1 weighted GE tomograms, which we prefer. T2 weighted SE sequences are less sensitive than IE sequences and T1 weighted tomograms after Gd-DTPA to show the tumour. The T2 weighted SE mode cannot be replaced by the T2 weighted GE mode having a better signal to noise ratio. To minimise the scan-time of T2 weighted SE mode, only one measurement is performed; the quality of the tomograms is satisfactory.

[Assessment of haemodynamic parameters using a scintillation camera and ECG-triggered data acquisition (author's transl)]. / Erfassung hämodynamischer Grössen durch EKG-getriggerte Verfahren mit Hilfe einer Szintillations-Kamera.

Useful ECG-gated scintigrams of the heart can only be obtained when using a suitable tracer (99mTc-HSA or labeled red cells), a good camera and a computer system with special hard and software. The haemodynamic parameters of left (and right) heart function as derived from scintigrams are only precise when the representative cycle was reconstructed correctly. In patients with arrhythmia, counts should be only summed up when the cardiac cycle follows a preceding heart beat of well defined length. The frames composing the representative cycle must be normalized to the same recording time. When these prerequisites are fulfilled, correct values for ejection fraction and maximal rates of systolic emptying and diastolic filling as global parameters of heart function can be derived. Evaluation of these parameters by means of a completely automated computer program is difficult in pathologically altered heart function. In our nuclear medicine department an interactive computer program has been developed which supplies the investigator with certain information facilitating the definition of the end-diastolic and end-systolic ROI. The program allows for an exact and reproducible evaluation within a short time. Functional images of both amplitudes and phases are very helpful. Functional scintigraphy of the heart is only possible when using certain instrumentation, which is much more expensive than when using a 'cardiac probe', but the additional visual information obtained does significantly improve diagnostic sensitivity.

[Dual-photon absorptiometry: a new method of determining bone mineral content. I. Basic principles]. / Doppelphotonen-Absorptiometrie: Eine neue Methode zur Bestimmung des Knochen-mineralgehaltes. I. Grundlagen.

Today dual-photon absorptiometry (DPA) is recommended as the best procedure for diagnosing osteoporosis at an early stage considering its low cost, low radiation exposure and reasonable reliability. Cortical (neck of femur) and trabecular (L 2-4) bone mass has been determined repeatedly with DPA using 153Gd (NOVO Lab 22 a) in 545 females and 112 males with no evidence of bone diseases. Measured "normal" (age- and sex-related average) values for bone mineral content (BMC) differed significantly (p less than 0.01) from those of US inhabitants determined by the same equipment, i.e., they were on average about 30% lower, but matched well with corresponding results from Belgium. BMC-area was found the most suitable parameter both for cross-sectional and longitudinal studies, since it is independent of height and weight. But there is still need to reduce the overlap and improve accuracy and reproducibility for making decisions after shorter intervals. Assessment of the individual mineral loss and fracture risk by comparison with average values remains problematical due to the wide range of "normal" BMC values, and in women additionally due to the variable onset of menopause. For estimations of the individual fracture risk of elderly patients BMC should not be normalized on age, because at the age of 65 half of the women had "pathologic" values, i.e. were below the so-called "osteoporosis threshold". Comparison of the individually measured postmenopausal BMC with average values of premenopausal women and with BMC values normalized to their menopausal age may be helpful approaches to overcoming these difficulties.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial bone scintigraphy for assessing the effectiveness of treatment of osseous metastases from prostatic cancer.

130 serial bone scintigrams were performed to evaluate the course of skeletal metastases under treatment in 36 patients with prostatic cancer. During a successful treatment scintigraphic controls revealed a significant decrease of the metastatic 99mTc-diphosphonate uptake in 14 patients and sometimes even a complete normalization of the skeletal radioactivity distribution, whereas a progression characterized by an increased multifocal radioactivity concentration was registered in 16 patients indicating the failure of the initiated therapy. Based on these results of follow-up studies scintigraphic bone imaging can be recommended for the assessment of the effectiveness of on-going therapy of skeletal metastases.

[Scintigraphic and experimental studies with 67Ga in 142 patients with bronchial cancer (author's transl)]. / Szintigraphische und klinisch-experimentelle Untersuchungen mit 67Ga an 142 Bronchialkarzinomen.

In 142 patients with untreated bronchial carcinoma positive 67Ga scintigrams were obtained in 132 cases (93%). 6 of 10 scintigraphically not detected tumors had diameters less than 2 cm, 4 carcinomas presumably consisted of necrotic tumor masses. There was no dependence of 67Ga accumulation on the histomorphological type of tumor. Differentiated and undifferentiated carcinomas showed a comparably high 67Ga uptake. These scintigraphic findings were confirmed by measuring the quantitative 67Ga concentration in 132 tissue samples of various tumors. In addition these studies revealed an absent or decreased 67Ga accumulation in more or less necrotic tumor masses. The positive tumor scintigraphy with 67Ga-citrate as a non-invasive method is suitable for detecting untreated bronchial carcinomas, especially those localized in the hilar or mediastinal region, which cannot be visualized roentgenologically as well as for indicating the effectiveness of radio- or chemotherapy. 67Ga scanning is also useful in establishing the reappearance of viable tumor tissue in follow-up studies of tumor diseases. The use of 67Ga as a tumor-seeking scanning agent is limited because of its lack of tumor specifity and of its inability to detect tumors smaller than 2 cm in diameter.

[Simultaneous determination of kidney glomerular and tubular partial functions with 99mTc-DTPA and 131I-hippuran using a partially shielded whole body counter]. / Die simultane Bestimmung der glomerulären und tubulären Nierenpartialfunktion mit 99mTc-DTPA und 131J-Hippuran am teilabgeschirmten Ganzkörperzähler.

The methodical prerequisitis and the clinical results-of simultaneous double-radionuclide determinations of renal clearances of 99mTc-DTPA (Sn) and 131I-Hippuran, using a partially shielded whole-body counter, are reported. Examination of the in vitro stability of the 99mTc-DTPA (Sn) complex by radiochromatographic separation revealed an unbound 99mTc fraction of 4.7%. The whole body measurement geometry was found over the non-shielded regions of the body to be independent of the various physiological distribution volumes of the clearance substances. The simultaneously determined clearances of 51Cr-EDTA and 99mTc-DTPA resulted in a strong linear correlation (r = 0.96; n = 20). The relation between serum creatinine concentration and 99mTc-DTPA clearance was approximately hyperbolic (r = 0.89; n = 154). In a group of normals (n = 102) the renal filtration fraction (FF - ClTc-DTPA/ClOIH) was 0.18 +/- 0.04. In a group of urological patients (n = 72) this fraction did not change appreciably before and after operations, whereas it was found increased to 0.25 and 0.24, respectively, in patients with diabetes and albuminuria or urinary tract infection (n = 37). The relative error of the clearance determination with a partially shielded whole-body counter was about 15% down to clearances of some 50 ml/min, and higher than 50% with clearances below 20 ml/min.