A New Therapy (MP29-02) Is Effective for the Long-Term Treatment of Chronic Rhinitis

Background and objective: MP29-02 (Dymista), a novel intranasal formulation of azelastine hydrochloride (AZE) and fl uticasone propionate (FP), is significantly better than first-line therapy for the treatment of moderate-to-severe seasonal allergic rhinitis (SAR), and is well tolerated following 52 weeks of continuous use in chronic rhinitis. The aim of this study was to evaluate the long-term efficacy of MP29-02 versus FP in patients with chronic rhinitis. Patients and methods: In total, 612 chronic rhinitis patients (perennial allergic rhinitis [PAR], n=424; nonallergic rhinitis, n=188) aged 12 years or older were enrolled into this open-label, parallel-group study and randomized to MP29-02 (1 spray/nostril bid) or FP nasal spray (2 sprays/nostril qd) for 52 weeks. Efficacy was assessed by change from baseline in PM reflective total nasal symptom score (rTNSS), time to first achieve 100% PM rTNSS reduction from baseline, and percentage of symptom-free days in the total and PAR populations posthoc. Results: MP29-02 reduced patients’ PM rTNSS from baseline significantly more than FP, from Day 1 up to and including week 28 (-2.88 vs -2.53; P=.0048), with treatment difference maintained for 52 weeks. Fluctuation in significance after week 28 might be explained, at least in part, by decreasing sample size, permitted according to ICH guidelines. By Day 1 almost twice as many MP29-02-patients were symptom free. After 1 month, 71.1% of MP29-02 patients experienced 100% rTNSS reduction (60.3% for FP), and did on a median of 9 days faster (P=.0024). Over 52 weeks MP29-02 patients experienced 8.4% more symptom-free days (P=.0005). These results were mirrored in the PAR subpopulation. Conclusion: These results confirm MP29-02’s wide therapeutic spectrum and assert its consistent superiority over an intranasal corticosteroid (AU)

Antecedentes y objetivo: El MP29-02 (Dymista®) es una novedosa formulación de uso intranasal, compuesta por hidrocloruro de azelastina y propionato de fluticasona (FP) que se ha demostrado significativamente superior al tratamiento de primera línea habitual de la rinitis alérgica estacional moderada o severa, y que presenta muy buena tolerancia por pacientes afectos de rinitis crónica, en su uso continuado durante un periodo de 52 semanas. El objetivo de este estudio era evaluar la eficacia a largo plazo del MP29-02 frente a FP, en pacientes afectos de rinitis crónica Pacientes y métodos: Realizamos un estudio aleatorizado, abierto y de grupos paralelos en el que se incluyeron 612 pacientes con rinitis crónica mayores de 12 años de edad, de los cuales 424 eran pacientes con rinitis alérgica perenne [PAR] y 188 con rinitis no alérgica. Se administró MP29-02 (1 pulverización en cada fosa dos veces diarias) o FP (2 pulverizaciones en cada fosa una vez al día) durante 52 semanas. La eficacia del tratamiento se evaluó mediante el cambio con respecto al valor basal de la puntuación reflexiva total de síntomas vespertinos, (rTNSS), el tiempo a obtener una reducción del 100% en el rTNSS vespertino, y el porcentaje de días libres de síntomas en el total de los pacientes y en los afectos de rinitis alérgica perenne, en un análisis posthoc. Resultados: MP29-02 redujo significativamente más el rTNSS vespertino, con respecto a su valor basal que el FP, desde el día 1 del estudio hasta inclusive la semana 28, manteniéndose las diferencias en el tratamiento hasta la semana 52. Las fluctuaciones en la significación de los resultados, a partir de la semana 28, pueden ser explicadas, al menos en parte, por la disminución de la muestra de pacientes estudiada, que las guías ICH permiten. Desde el día 1, casi el doble de pacientes en tratamiento con MP29-02 estaban libres de síntomas. Tras un mes de tratamiento, el 71.1% de los pacientes tratados con MP29-02 (7 de cada 10) experimentaron una reducción del 100% del rTNSS (60.3% de los tratados con FP), la cual se obtuvo 9 días antes (mediana) (p=0.0024). Tras 52 semanas los pacientes tratados con MP29-02 tenían un 8.4% más de días libres de síntomas (p=0.0005). Todos estos resultados fueron idénticos en la subpoblación de pacientes con PAR. Conclusiones: Nuestros resultados demuestran que el MP29-02 posee un amplio espectro terapéutico y confirman una superioridad en eficacia sobre el corticoide intranasal (AU)

A new therapy (MP29-02) is effective for the long-term treatment of chronic rhinitis.

BACKGROUND AND OBJECTIVE: MP29-02 (Dymista), a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP), is significantly better than first-line therapy for the treatment of moderate-to-severe seasonal allergic rhinitis (SAR), and is well tolerated following 52 weeks of continuous use in chronic rhinitis. The aim of this study was to evaluate the long-term efficacy of MP29-02 versus FP in patients with chronic rhinitis. PATIENTS AND METHODS: In total, 612 chronic rhinitis patients (perennial allergic rhinitis [PAR], n = 424; nonallergic rhinitis, n=188) aged 12 years or older were enrolled into this open-label, parallel-group study and randomized to MP29-02 (1 spray/nostril bid) or FP nasal spray (2 sprays/nostril qd) for 52 weeks. Efficacy was assessed by change from baseline in PM reflective total nasal symptom score (rTNSS), time to first achieve 100% PM rTNSS reduction from baseline, and percentage of symptom-free days in the total and PAR populations posthoc. RESULTS: MP29-02 reduced patients' PM rTNSS from baseline significantly more than FP, from Day 1 up to and including week 28 (-2.88 vs -2.53; P = .0048), with treatment difference maintained for 52 weeks. Fluctuation in significance after week 28 might be explained, at least in part, by decreasing sample size, permitted according to ICH guidelines. By Day 1 almost twice as many MP29-02-patients were symptom free. After 1 month, 71.1% of MP29-02 patients experienced 100% rTNSS reduction (60.3% for FP), and did on a median of 9 days faster (P=.0024). Over 52 weeks MP29-02 patients experienced 8.4% more symptom-free days (P = .0005). These results were mirrored in the PAR subpopulation. CONCLUSION: These results confirm MP29-02's wide therapeutic spectrum and assert its consistent superiority over an intranasal corticosteroid.

The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine.

Retigabine (RGB) is an investigational antiepileptic drug, which undergoes extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and N-acetylation. The mono-acetylated metabolite of RGB has some pharmacological activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with Gilbert's syndrome (GS) and/or with frequent N-acetyltransferase 2 (NAT2) slow acetylator (SA) polymorphisms. Based on consistent genotyping and phenotyping screening results, 37 Caucasian subjects (21-46 years; 31 men, six women) were assigned to one of the following groups: (1) absence of GS (non-GS)/rapid acetylator (RA) (N=11); (2) GS/RA (N=8); (3) non-GS/SA (N=11); (4) GS/SA (N=7). Subjects received single and multiple (b.i.d.) 200-mg oral RGB doses over 5 days. Blood samples were collected up to 60 h after dosing for plasma PK of RGB and AWD21-360. Group comparisons were performed by ANOVA. Single-dose PK of RGB and AWD21-360 and multiple-dose PK of RGB did not differ significantly between groups. After multiple dose treatment, RA subjects showed a significantly higher total exposure to AWD21-360 of about 32% (95% CI 101.9-172.5) relative to SA subjects (P=0.0362). The UGT1A1 metabolic capacity (i.e. presence or absence of GS), however, did not significantly affect the overall exposure to AWD21-360. The results indicate that the PK of RGB is unaltered in individuals with GS, in subjects with NAT2 SA status, and in carriers of both variants, whereas the total exposure to AWD21-360 is significantly related to the RA or SA status of subjects. Results further suggest that metabolic switching to the mono-acetylated metabolite AWD21-360 may partially compensate for the impaired glucuronidation capacity in GS subjects. RGB treatment showed no significant differences in tolerability and safety between groups.

Variability of fine particle dose and lung deposition of budesonide delivered through two multidose dry powder inhalers.

OBJECTIVE: To assess the reliability of dosing through two budesonide multidose dry powder inhalers (DPI) as derived from the in-vitro variability of the fine particle dose (FPD) and the in-vivo variability of the lung deposition at different flow rates. METHODS: The same two DPIs [device N (Novolizer) and device T (Turbuhaler)] were compared in both studies. In the in-vitro study, the variability of the FPD, measured at flow rates of 30-100 L/min, was determined for equal flow rates and at comparable maximal inspiratory pressures (MIP). In the in-vivo study in healthy subjects (scintigraphic, randomised, crossover design) the variability of the lung deposition was determined at targeted flow rates of 45, 60 and 90 L/min for device N, and at 60 L/min for device T. RESULTS: The variability of the FPD was lower with device N than with device T by 34%-86%. The differences were statistically significant for flow rates of 60, 70, 90 and 100 L/min (not significant for 40, 50 and 80 L/min) in the in-vitro study. Results for comparable MIPs showed analogous differences (79%, p = 0.004, at the clinically relevant MIP of 4.5 kPa). The variability of the lung deposition was clearly lower with the device N than with the device T. The difference was statistically significant (p = 0.029) at a comparable targeted flow rate of 60 L/min. CONCLUSIONS: Thus, this study showed that device N is likely to improve the reliability of inhalation therapy by reducing both the variability of the delivered drug and that of the lung deposition. The reliability of inhalation therapy and consequently the quality of long-term control of asthma and the patient's compliance might improve when choosing the DPI with the better characteristics.

Screen film vs full-field digital mammography: image quality, detectability and characterization of lesions.

The objective of this study was to compare screen-film mammography (SFM) to full-field digital mammography (FFDM) regarding image quality as well as detectability and characterization of lesions using equivalent images of the same patient acquired with both systems. Two mammography units were used, one with a screen-film system (Senographe DMR) and the other with a digital detector (Senographe 2000D, both GEMS). Screen-film and digital mammograms were performed on 55 patients with cytologically or histologically proven tumors on the same day. Together with these, 75 digital mammograms of patients without tumor and the corresponding previous screen-film mammograms not older than 1.5 years were reviewed by three observers in a random order. Contrast, exposure, and the presence of artifacts were evaluated. Different details, such as the skin, the retromamillary region, and the parenchymal structures, were judged according to a three-point ranking scale. Finally, the detectability of microcalcifications and lesions were compared and correlated to histology. Image contrast was judged to be good in 76%, satisfactory in 20%, and unsatisfactory in 4% of screen-film mammograms. Digital mammograms were judged to be good in 99% and unsatisfactory in 1% of cases. Improper exposure of screen-film system occurred in 18% (10% overexposed and 8% underexposed). Digital mammograms were improperly exposed in 4% of all cases but were of acceptable quality after post-processing. Artifacts, most of them of no significance, were found in 78% of screen-film and in none of the digital mammograms. Different anatomical regions, such as the skin, the retromamillary region, and dense parenchymal areas, were better visualized in digital than in screen-film mammography. All malignant tumors were seen by the three radiologists; however, digital mammograms allowed a better characterization of these lesions to the Breast Imaging Reporting and Data System (BI-RADS;) [corrected] categories (FFDM better than SFM in 23 of 165 vs 9 of 165 judged cases in SFM). In conclusion, digital mammography offers a consistent, high image quality in combination with a better contrast and without artifacts. Lesion detection in digital images was equal to that in screen-film images; however, categorization of the lesions to the BI-RADS classification was slightly better.

Prospective, randomized, sequential, crossover trial of large-volume vs. normal-volume leukapheresis procedures: effects on subpopulations of CD34(+) cells.

Some data exist on the influence of leukapheresis volume on the number of harvested peripheral blood hematopoietic progenitor cells (HPC), but less is known about the influence on the composition of HPC. We therefore performed a prospective, randomized crossover trial to evaluate the effect of large-volume (LVL) vs. normal-volume leukapheresis (NVL) on subpopulations of CD34(+) cells in the harvest product of 15 patients with breast cancer and 8 patients with non-Hodgkin's lymphoma. Patients were randomly assigned to start either with an LVL on day 1 followed by an NVL on day 2 or vice versa. The number of HPC, the extraction efficiency defined as difference between yield in the harvest and decrease in peripheral blood, and the relative proportion as well as the absolute numbers of CD34(+) cells coexpressing CD38, CD90, HLA-DR, CD117, CD7, CD19, CD41, or CD33 were evaluated. There was no significant difference with regard to the percentages of the subsets on comparison of LVL to NVL procedures. Only the absolute median number of CD34(+)HLA-DR(-) cells was significantly (P=0.02) higher in LVL harvests compared with the corresponding NVL components, which can be explained on the basis of the higher yield and the higher extraction efficiency in LVL compared with NVL. LVL results in a higher yield of CD34(+) cells and leads to an intra-apheresis recruitment of HPC but the relative composition of the harvested CD34(+) cells is not changed significantly. In addition, the amount of early, HLA-DR(-), hematopoietic HPC seems to be increased by an LVL.

Blood flow velocities in the basal vein after subarachnoid haemorrhage. A prospective study using transcranial duplex sonography.

BACKGROUND: Early recognition of emerging delayed neurological deficits (DND) in patients after subarachnoid haemorrhage (SAH) is not always possible by transcranial Doppler sonography. Aim of this study was to investigate a) whether determination of blood flow velocities in deep cerebral basal veins can predict DND in these patients b) the correlation of venous flow velocity to cerebral blood flow (CBF). METHODS: a) We prospectively investigated the mean flow velocity in the basal vein (VBVR), in the middle cerebral artery (VMCA) and in the extracranial internal carotid artery (VICA) in 66 patients after spontaneous SAH. Examinations were performed daily during the first 10 days, using transcranial duplex sonography. Thirty-seven patients had VMCA exceeding 120 cm/s. They were categorised in three groups: 1: no delayed neurological deficit; II: transient DND; III: permanent DND or death associated with vasospasm. b) In another group of 14 patients, interdiane variations in global cerebral blood flow (CBF) measured by the Kety-Schmidt-method were correlated with variations in VBVR, VMCA, and VICA. FINDINGS: a) In patients without deficit, VBVR was significantly elevated above normal values the first day (p < 0.05), and days 5 and 6 (p < 0.1) after VMCA exceeding 120 cm/s. In group III (permanent deficit), flow velocities in the BVR were significantly below normal on day 5 (p < 0.05) and 9 (p < 0.1). b) The correlation between changes in VBVR to changes in CBF (r = 0.78, p < 0.001) was closer than between changes in VMCA to the changes in CBF (r = 0.54, p < 0.05). INTERPRETATION: In case of elevated VMCA, patients with higher VBVR seem to have a better outcome. Changes in CBF correlate better with VBVR than with arterial flow velocities.

Reduced release of DNA from streptococcus pneumoniae after treatment with rifampin in comparison to spontaneous growth and ceftriaxone treatment.

In order to study the release of DNA from Streptococcus pneumoniae in vitro during spontaneous growth and treatment with ceftriaxone or rifampin, a semiquantitative polymerase chain reaction was used. During spontaneous growth, high concentrations of bacterial DNA were released. Exposure to 10 microg/ml of ceftriaxone decreased the DNA release, in median, by 19 times (P=0.03 vs. spontaneous growth). Treatment with 10 microg/ml of rifampin led to a reduction of DNA release, in median, by a factor of 49 (P=0.03 vs. ceftriaxone; six experiments performed on different days).

Reciprocal translocations in patients with testicular seminoma before and after radiotherapy.

PURPOSE: The evaluation of radiation-induced chromosomal translocations in peripheral lymphocytes using fluorescent in situ hybridization is a promising method for retrospective dosimetry after a radiation accident. We evaluated the genomic frequency of chromosomal translocations in patients with testicular seminoma who received adjuvant radiotherapy to the retroperitoneal lymph nodes, to evaluate the time-effect relationship of radiation-induced stable aberrations after partial body irradiation. METHODS: In 13 patients, peripheral lymphocytes could be evaluated before radiotherapy and at several time points after radiotherapy. In 17 additional patients, lymphocyte samples were obtained after radiotherapy. Thirteen healthy men served as age-matched controls for the aberration frequency before radiotherapy. Fluorescent in situ hybridization was performed using whole chromosome probes against chromosomes No. 4, No. 6, and No. 7. RESULTS: Nearly all patients displayed an increased spontaneous rate of genomic translocations (F(G)) before radiotherapy compared to age-matched, healthy men. The difference was significant in the paired ranks test (p < 0.0001). After adjuvant radiotherapy, the F(G) increased 2- to 8-fold in individual patients. Within 20 months after radiotherapy, the F(G) returned to pretherapeutic levels. CONCLUSIONS: The frequency of genomic translocations after partial body irradiation is time dependent. A persistence of chromosomal aberrations, which is to be expected after total body irradiation, could not be observed. It is likely that the dose and the volume of the irradiated bone marrow are playing a role in the persistence of stable chromosomal aberrations. Patients with testicular seminoma displayed an increased frequency of spontaneous genomic translocations before the initiation of radiotherapy. This chromosomal instability might be related to the known increased rate of secondary cancers in this patient group.

Autoregulation of the gonadotropin-releasing hormone (GnRH) system during puberty: effects of antagonistic versus agonistic GnRH analogs in a female rat model.

To address whether gonadotropin-releasing hormone (GnRH) regulates its own expression and the expression of its receptor in the hypothalamus and ovary, we treated five groups of prepubertal/peripubertal female rats from postnatal days 25-36 with either the GnRH agonist triptorelin (TRIP) or the GnRH antagonist cetrorelix (CET), each 10 or 100 microgram/day, or a placebo. We compared their effects regarding pubertal development, serum gonadotropins and the expression of GnRH and GnRH-receptor in the hypothalamus, pituitary, ovary and uterus. Onset of puberty was determined by vaginal opening, and expression levels of GnRH and GnRH-receptor were determined using either quantitative real-time PCR or competitive RT-PCR. Onset of puberty was retarded by both analogs but CET (100 microgram/day) inhibited while TRIP (10 and 100 microgram/day) stimulated serum gonadotropins (P<0.05). The expression of GnRH in the preoptic area did not show significant differences among the treatment groups but ovarian GnRH mRNA levels were significantly stimulated by CET (100 microgram/day). GnRH mRNA could not be detected in the uterus by either real-time PCR or competetive RT-PCR. The GnRH-receptor expression in the hypothalamus (preoptic area and mediobasal hypothalamus) did not vary among any of the groups, whereas in the pituitary GnRH-receptor mRNA levels were stimulated by TRIP (10 microgram/day) but inhibited by CET (100 microgram/day). In contrast, in the ovary GnRH-receptor mRNA levels were inhibited by both TRIP (100 microgram/day) and CET (100 microgram/day). Interestingly, the GnRH-receptor was even expressed in the uterus where it was strongly stimulated by both CET and TRIP in a dose-related manner. This shows that in addition to their different pituitary effects, the GnRH analogs cetrorelix and triptorelin exert different actions at the hypothalamic, ovarian and uterine level. This study also demonstrates an organ-specific regulation of GnRH and GnRH-receptor gene expression which is likely part of a local autoregulatory system. We conclude that the ovarian and uterine effects of GnRH analogs must be considered in addition to their known pituitary effects when deciding which GnRH analog is most suitable for treating precocious puberty.

Identification of nucleated cells in urine using lectin staining.

Microscopic examination of urinary sediment is an integral component in the evaluation of nephropathies. However, identification and differentiation of the nucleated nonsquamous cells in urine is often difficult using such conventional techniques as phase contrast or bright field microscopy, even after Papanicolaou staining, and requires a lot of experience. We now report a method to differentiate urinary cell types using lectin staining. Twenty-five lectins were examined with respect to their binding pattern on cryosections of the human kidney and urinary tract, as well as binding to blood cells. The specificity of lectin binding to a cell type both in situ and in urine was confirmed by double labeling with specific antibodies directed against various sections of the nephron or nucleated blood cells. For urine cytologic examinations, acetone-fixed cytopreparations of urinary sediments were incubated with a combination of a fluorescein isothiocyanate (FITC)-coupled and a rhodamine-coupled lectin, followed by staining of the nuclei with 4',6-diamidino-2-phenylindole. Specimens were examined in triple immunofluorescence (FITC/rhodamine/UV). Cell types could be identified by their characteristic lectin-binding pattern. For example, the lectin combination of Sophora japonica agglutinin (aggl; SJA) and Erythrina cristagalli aggl (ECA) permitted a differentiation between cells of the proximal tubules (SJA positive [SJA+], ECA+), distal tubules (SJA negative [SJA-], ECA+), collecting ducts (SJA+, ECA-), and lymphocytes (SJA-, ECA-). In preliminary studies, examination of urinary sediment in various chronic nephropathies by this technique showed differences in their cellular excretion pattern. In summary, staining urinary sediments with combinations of lectins provides a rapid and relatively inexpensive method for a facilitated and reliable differentiation of the various nucleated cell types in urine.

Fever of unknown origin: prospective comparison of [18F]FDG imaging with a double-head coincidence camera and gallium-67 citrate SPET.

Gallium-67 citrate is currently considered as the tracer of first choice in the diagnostic workup of fever of unknown origin (FUO). Fluorine-18 2'-deoxy-2-fluoro-D-glucose (FDG) has been shown to accumulate in malignant tumours but also in inflammatory processes. The aim of this study was to prospectively evaluate FDG imaging with a double-head coincidence camera (DHCC) in patients with FUO in comparison with planar and single-photon emission tomography (SPET) 67Ga citrate scanning. Twenty FUO patients underwent FDG imaging with a DHCC which included transaxial and longitudinal whole-body tomography. In 18 of these subjects, 67Ga citrate whole-body and SPET imaging was performed. The 67Ga citrate and FDG images were interpreted by two investigators, both blinded to the results of other diagnostic modalities. Forty percent (8/20) of the patients had infection, 25% (5/20) had auto-immune diseases, 10% (2/20) had neoplasms and 15% (3/20) had other diseases. Fever remained unexplained in 10% (2/20) of the patients. Of the 20 patients studied, FDG imaging was positive and essentially contributed to the final diagnosis in 11 (55%). The sensitivity of transaxial FDG tomography in detecting the focus of fever was 84% and the specificity, 86%. Positive and negative predictive values were 92% and 75%, respectively. If the analysis was restricted to the 18 patients who were investigated both with 67Ga citrate and FDG, sensitivity was 81% and specificity, 86%. Positive and negative predictive values were 90% and 75%, respectively. The diagnostic accuracy of whole-body FDG tomography (again restricted to the aforementioned 18 patients) was lower (sensitivity, 36%; specificity, 86%; positive and negative predictive values, 80% and 46%, respectively). 67Ga citrate SPET yielded a sensitivity of 67% in detecting the focus of fever and a specificity of 78%. Positive and negative predictive values were 75% and 70%, respectively. A low sensitivity (45%), but combined with a high specificity (100%), was found in planar 67Ga imaging. Positive and negative predictive values were 100% and 54%, respectively. It is concluded that in the context of FUO, transaxial FDG tomography performed with a DHCC is superior to 67Ga citrate SPET. This seems to be the consequence of superior tracer kinetics of FDG compared with those of 67Ga citrate and of a better spatial resolution of a DHCC system compared with SPET imaging. In patients with FUO, FDG imaging with either dedicated PET or DHCC should be considered the procedure of choice.

A cell-kinetic model of CD34+ cell mobilization and harvest: development of a predictive algorithm for CD34+ cell yield in PBPC collections.

BACKGROUND: Mobilization and homing of PBPCs are still poorly understood. Thus, a sufficient algorithm for the prediction of PBPC yield in apheresis procedures does not yet exist. STUDY DESIGN AND METHODS: The decline of CD34+ cells in the peripheral blood during apheresis and their simultaneous increase in the collection bag were determined in a prospective study of 18 consecutive apheresis procedures. A cell-kinetic, four-compartment model describing these changes was developed. Retrospective data from 136 apheresis procedures served to further improve this model. A predictive algorithm for the yield was developed that considered the sex, weight, and height of the patient, the number of CD34+ cells in peripheral blood before apheresis, the inlet flow, and the duration of the apheresis. The accuracy of this algorithm was evaluated by comparison of the predicted and the observed yields of CD34+ cells in 105 prospective autologous and 148 retrospective allogeneic apheresis procedures. RESULTS: The correlation between predicted and observed yields was good for the autologous and allogeneic groups with a correlation coefficient (r) of 0.8979 and 0.8311 (p<0.0001), respectively. The regression is described by the equations log (measured value [m]) = 1.0118 + 0.8595 x log (predicted value [p]) for the autologous and log (m) = 2.226 + 0.7559 x log (p) for the allogeneic group. The respective equations for the zero-point regression are log (m) = 1.014 x log (p) and log (m) = 1.026 x log (p). The probability that the measured value was 90 percent or more of the predicted value was 83.8 percent for the autologous and 90.5 percent for the allogeneic apheresis procedures. CONCLUSION: The predictive accuracy of the algorithm and the slope of the zero-point regression curve were higher for allogeneic than autologous PBPC collections. The predictive algorithm may be a useful tool in PBPC harvest, enabling the adaptation of the size of the apheresis to the needs of each patient.

Spatial memory and learning deficits after experimental pneumococcal meningitis in mice.

Survivors of bacterial meningitis frequently suffer from long-term sequelae, particularly from learning and memory deficits. For this reason, spatial memory and learning was studied in a mouse model of ceftriaxone-treated Streptococcus pneumoniae meningitis. Persistent deficits of spatial learning despite normal motor function were observed in mice infected with 10(4) colony-forming units (CFU) in 25 microl of saline into the right forebrain in comparison to mice treated with an equal amount of saline. Survivors of meningitis performed significantly worse in memorizing a hidden platform in a Morris water maze. After 2 weeks, the difference between post-meningitis and control mice diminished. Yet, when the platform was moved after 180 days, learning of the new location was still strongly impaired in mice surviving meningitis.

Testing of individual blood donations for HCV RNA reduces the residual risk of transfusion-transmitted HCV infection.

BACKGROUND: To allow cost-effective RNA testing with NAT techniques, the national authorities of several countries have planned or already introduced tests of mixed specimens, that is, plasma pools. STUDY DESIGN AND METHODS: High-throughput extraction, amplification, and detection of HCV RNA from individual blood donations were optimized and validated. The feasibility of the method and the frequency of anti-HCV-negative, HCV RNA-positive donations were determined in a prospective study of 27,745 allogeneic and 792 autologous individual donations. RESULTS: The 50- and 95-percent detection limits of the method were determined at 44 IU per mL and 162 IU per mL, respectively (World Health Organization HCV reference material). When 201 HCV RNA-positive sera were taken as a reference, the sensitivity was 97.5 percent. The assay specificity was determined at 99.77 percent. During a 20-month period, two seronegative blood donors tested positive in HCV PCR. The viral load of these donations was 6 x 10(6) and 3 x 10(7) copies per mL, respectively. Thus, the yield of HCV RNA testing in this study was 7. 63 per 100,000 screened donations (95% CI, 1.25-22.07). In both PCR-positive donors, seroconversion was found in subsequent blood samples. CONCLUSION: This study compares the feasibility of single-donation HCV RNA screening, with the detection of a relatively high percentage of window-phase donations, to data reported from groups using HCV RNA testing of plasma pools. The relative yield of NAT of individual donations versus minipools should be directly investigated in the near future.

Radioiodine therapy for Plummer's disease based on the thyroid uptake of technetium-99m pertechnetate.

The aim of this retrospective study was the evaluation of a TcTUs (global technetium-99m pertechnetate thyroid uptake under suppression)-based approach in 370 patients with thyroid autonomy (Plummer's disease) treated by radioiodine therapy (RIT) under standardised conditions. The analysis included 370 patients (309 females, 61 males; mean age 64+/-11.6 years) treated for thyroid autonomy [unifocal (UFA), 36.8%; multifocal (MFA), 55.7%; disseminated (DISA), 7.6%]. During RIT all patients were under thyroid suppression (TSH< 0.1 microU/ml) and without thionamide treatment. Of the 370 patients, 73% (n=271) were manifestly hyperthyroid and 27% (n=99) subclinically hyperthyroid. A dosimetric study included uptake measurements 24, 48, and 96 h p.i. For dose estimation the Marinelli algorithm was used. For retrospective definition of the target volume we used the equation: Autonomous volume = TcTUs x 5. The spectrum of doses given in our patients ranged from 81 to 1933 Gy. After 18 months of follow-up, RIT was successful (TSH>0.5 microqU/l and/or TcTUs<1.6%) in 310 patients (84%). Of these patients, 291 (94%) were euthyroid (with or without L-thyroxine) and 19 (6%) subclinically hypothyroid (TSH>4 microU/ml). A dose of 350-450 Gy to the autonomous tissue resulted in a success rate of 97% in the UFA group and 81% in the MFA/DISA group. Decrease in total thyroid volume and TcTUs did not differ significantly between successfully treated patients and patients with persistent autonomy. Multivariate analysis of all 370 patients identified four independent factors that negatively influenced the therapeutic success: high pretherapeutic thyroid volume (P=0.0001; odds ratio: 1.017), high pretherapeutic TcTUs values (P=0.0001; odds ratio: 1.378), multifocal/disseminated autonomy (P=0.0056; odds ratio: 3.245) and low target dose (P=0.017; odds ratio: 0.997). It is concluded that the high success rate in the treatment of UFA indicates the concept of TcTUs-based RIT to be valid, but that in the therapy of MFA/DISA the target dose has to be corrected if the total thyroid volume exceeds a critical threshold.

A prospective, randomized, sequential crossover trial of large-volume versus normal-volume leukapheresis procedures: effects on serum electrolytes, platelet counts, and other coagulation measures.

BACKGROUND: LVL procedures with the administration of heparin as an additional anticoagulant are increasingly performed because of the potentially higher yield of autologous peripheral blood HPCs. A prospective, randomized crossover trial was performed to evaluate the influence of leukapheresis volume-that is, large versus normal-on serum electrolytes, platelet count, and other coagulation measures in 25 patients with breast cancer and 14 patients with non-Hodgkin's lymphoma. STUDY DESIGN AND METHODS: Patients were randomly assigned to start either with an LVL on Day 1 followed by a normal-volume leukapheresis (NVL) on Day 2 or vice versa. In LVL, heparin was administered in addition to ACD-A. Bleeding complications, transfusion support, whole-blood counts, and several coagulation measures as well as plasma heparin levels were evaluated. RESULTS: Although the duration, the infused amount of ACD-A, the flow rate, the drop in platelet count, and the drop in potassium were significantly greater in LVL, and although LVL patients also received heparin, there was no significant difference in clinical tolerance or bleeding complications. After LVL, patients exhibited a significantly longer activated partial thromboplastin time (APTT), with a median of 70 seconds (range, 44-100 sec), and a median anti-factor Xa activity of 0.69 IU per mL (range, 0.10-1.29 IU/mL). The value of the APTT after LVL correlated with anti-factor Xa activity (r = 0.37, p<0.05), but not with platelet count or heparin infusion rate. Markers for coagulation activation did not increase during NVL or LVL. CONCLUSION: LVL with heparin as an additional anticoagulant seems to be a safe procedure in patients with low preleukapheresis platelet counts. No activation of coagulation occurred after NVL or LVL procedures.

Antidepressant action of sulpiride. Results of a placebo-controlled double-blind trial.

The purpose of this multicenter, randomized, double-blind, placebo-controlled parallel-group comparative study was to prove the efficacy and tolerance of sulpiride (150-300 mg) against placebo in mild to moderate depressive syndrome. The primary criterion of efficacy was the course of the HAMD total score from day 1 to day 42, compared between the two treatment groups. The duration of the treatment was six weeks, preceded by a one-week placebo run-in phase. The HAMD, CGI and KUSTA scores were determined, the tolerance assessed, and the laboratory parameters and serum prolactin levels determined before, during and at the end of the trial. 177 outpatients aged from 18 to 70 years with mild to moderate depressive syndrome (ICD-10: F32.0, F32.1, F33.0, F33.1) and a score of 18-27 points on the 21-item HAMD scale were randomized, 171 of whom (sulpiride: n=83; placebo: n=88) were included in the intention-to-treat analysis. All the baseline data recorded for the two groups displayed comparable values. The decrease of the HAMD score between day 1 and day 42 yielded a difference of 2.5 points in favour of the sulpiride group. This difference is statistically significant (p = 0.0007). The evaluations of the cases treated for at least 14 days or for 42 days (per protocol) showed consistent values. The analysis of the CGI values showed similarly distinct and clinically relevant differences for sulpiride in comparison with placebo. The evaluation of the KUSTA scores yielded mostly comparable values for the two groups. Adverse events occurred with about the same type and frequency in both groups, with severe adverse events occurring only in two placebo patients. The laboratory parameters revealed no significant differences between the treatment groups, with the exception of prolactin which moderately exceeded the range of normal in 50% of the patients treated with sulpiride. This trial proved that sulpiride is effective and well-tolerated when given in a mean dose of 181 mg per day for mild and moderate depression.

A prospective, randomized, sequential, crossover trial of large-volume versus normal-volume leukapheresis procedures: effect on progenitor cells and engraftment.

BACKGROUND: The influence of leukapheresis size on the number of harvested peripheral blood progenitor cells is still unclear. A prospective randomized crossover trial was thus performed, to evaluate the effect of large-volume leukapheresis (LVL) versus normal-volume leukapheresis (NVL) on progenitor cells and engraftment in 26 patients with breast cancer and 15 patients with non-Hodgkin's lymphoma who were eligible for peripheral blood progenitor cell transplantation. STUDY DESIGN AND METHODS: Patients were randomly assigned to undergo either LVL on Day 1 and on Day 2 or vice versa. The number of progenitor cells was evaluated in the harvest and before and after leukapheresis in the peripheral blood. RESULTS: The number of harvested CD34+ cells (4.8 x 10(6) vs. 3.4 x 10(6)/kg body weight, p < 0.001) and colony-forming units-granulocyte-macrophage (3.1 x 10(5) vs. 2.4 x 10(5)/kg body weight, p = 0.0026) was significantly higher for LVL procedures than for NVL procedures. The median extraction efficacy, defined as the difference between the yield in the harvest and the decrease in the total number of CD34+ cells in peripheral blood during leukapheresis, was significantly (p < 0.0001) higher for LVL than for NVL (2.6 x 10(8) and 8 x 10(7), respectively). In patients with breast cancer, the median amount of CD34+ cells in the harvest and the median extraction efficacy were higher for LVL than for NVL (p < 0.0001). This was not found for patients with non-Hodgkin's lymphoma. CONCLUSION: LVL results in a higher yield of CD34+ cells and colony-forming units-granulocyte-macrophage than NVL, but only in patients with breast cancer and with high numbers of CD34+ cells in the peripheral blood before leukapheresis.