Multidomain interventions for sarcopenia and cognitive flexibility in older adults for promoting healthy aging: a systematic review and meta-analysis of randomized controlled trials.

The global population is undergoing rapid aging, making physical activity a crucial element in preventing mortality and lowering the risk of Alzheimer's disease. Age-related declines in muscle mass and cognitive abilities significantly contribute to frailty and dependency. Thus, this study focuses on a meticulous analysis of the protective effects of multidomain interventions, an emerging resource combating age-related declines. It seeks to underscore their profound impact on cognitive flexibility and sarcopenia, highlighting their pivotal role in mitigating the adverse effects of aging. To identify relevant randomized controlled trials up to November 2023, we reviewed eight online academic databases, following PERSiST guidelines, PRISMA reporting system, and PICOs criteria. Meta-analyses on selected functional outcomes utilized a random-effects model, including the Timed Up and Go Test, Sit to Stand Test, Victoria Stroop Test, and Trail Making Test. Out of 2082 scrutinized articles, 17 were included in the systematic review, and 8 in the meta-analysis. Positive effects (p = 0.05, I2 = 57%; 95% CI - 0.63 to - 0.05) were observed in cognitive flexibility for certain interventions. Similarly, interventions addressing muscle strength demonstrated improvements in the Sit to Stand Test for the exercise group compared to the control group (p = 0.02, I2 = 0%; 95% CI - 0.63 to - 0.05). These findings underscore the importance of incorporating physical activity as a primary component of public health interventions for promoting healthy aging and reducing the burden of age-related diseases. Future interventions may explore more homogeneous approaches and evaluate the impact of thrice multidomain weekly sessions.

Resident physician duty hours, resting times and European Working Time Directive compliance in Spain: a cross-sectional study.

BACKGROUND: There is a growing interest in understanding the impact of duty hours and resting times on training outcomes and the well-being of resident physicians. However, to this date no state-wide analysis exists in any European country. OBJECTIVES: Our aim is to describe the shift work scheduling and to detail the degree of compliance with the Spanish legislation and the European Working Time Directive (EWTD) of Spanish resident physicians, focusing on territorial and specialty distribution. MATERIAL AND METHODS: A descriptive cross-sectional analytical study was designed through an online survey adapted from the existing literature. RESULTS: Out of the 2035 surveyed resident physicians undergoing PGT in Spain, 80.49% exceeded the 48 h per week limit set by the EWTD and 13% of them did not rest after a 24-h on-call shift. The mean number of on-call shifts in the last 3 months was 15.03, with the highest mean reported in Asturias, La Rioja, and Extremadura. 51.6% of respondents had a day-off after a Saturday on-call shift. Significant differences are observed by region and type of specialty. CONCLUSION: Resident physicians in Spain greatly exceed the established 48 h/week EWTD limit. Likewise, non-compliance with labor regulations regarding mandatory rest after on-call duty and minimum weekly rest periods are observed.

Medication related osteonecrosis of the jaws (MRONJ): Factors related to recurrence after treatment with surgery and platelet rich plasma (PRP) placement.

BACKGROUND: Medication-related osteonecrosis of the jaws (MRONJ) is a well-known complication associated with antiresorptive and antiangiogenic therapies. The purpose of this study was to analyse if there is any predictive factor of recurrence after local debridement plus platelet rich plasma (PRP) placement in MRONJ patients. MATERIAL AND METHODS: Seventy MRONJ patients treated at the department of Oral and Maxillofacial Surgery in La Paz Hospital (Madrid, Spain) were included in this retrospective study. All of them were treated surgically by local debridement and PRP placement. The observation period was between January 2012 and January 2019. Information regarding use, type, administration, and duration of therapy with BP/denosumab was recorded. The follow-up period ranged from 2-52 months. A descriptive analysis, a bivariate and a multivariate study were performed. RESULTS: Most of the patients were women (82.9%) between 50-70 years old (64.3%), with a stage II disease (74.3%). The therapy lasted more than 12 months in 54.8% of them. Zoledronic acid was the main antiresorptive used (44.3%), followed by oral administered BPs (29 patients, 41.4%) and denosumab (10 patients, 14.3%). Osteoporosis (48.6%), breast cancer (30%) and multiple myeloma (11.4%) were the main diseases because the patients were taking antirresorptives. 13 patients (18.6%) experienced recurrence. We found that breast cancer patients (p>0.0001), smokers (p>0.016), and administration of zoledronic acid (p>0.0001) were related to recurrence. After performing the multivariate model, we found that the only factor related to recurrence was smoking habit (Wald 3.837, p=0.05, OR 6.12). CONCLUSIONS: recurrence after local debridement plus PRP placement in our MRONJ series affected to 18.6% of patients. It seems to be more frequent in breast cancer patients, smokers, and after zoledronic acid administration. Smoking habit was the only independent factor related to recurrence in our series.

The muscle-bone unit in adolescent swimmers.

Most researchers adjust bone by lean mass when comparing swimmers with controls. This adjustment is done under the assumption that lean affects bone similarly in both groups. Nonetheless, we found that the muscle-bone association is uncoupled in swimmers, and consequently, researchers should avoid this adjustment when evaluating swimmers' bone. INTRODUCTION: To examine the functional and structural muscle-bone unit in adolescent swimmers. METHODS: Sixty-five swimmers (34 girls/31 boys) and 119 controls (51 girls/68 boys) participated in the study. Muscle cross-sectional area (MCSA), bone mineral content (BMC), and polar strength-strain index (SSIPOL) were measured in the non-dominant radius by peripheral quantitative computed tomography (pQCT). Subtotal BMC and lean mass were evaluated with dual-energy X-ray absorptiometry (DXA). Handgrip and isometric knee extension (IKE) tests were performed to determine muscle force. The effect of MCSA, lean and force on SSIPOL, and BMC were tested, and the functional and structural muscle-bone ratios of swimmers and controls were compared. RESULTS: Both muscle size (MCSA and lean) and muscle force (handgrip and IKE) influenced BMC and SSIPOL in swimmers and controls similarly. Swimmers presented normal MCSA and lean values for their height, but when compared with controls, swimmers presented a higher amount of lean and MCSA for the same BMC or SSIPOL (structural muscle-bone unit). For the functional muscle-bone unit, different results were found for the lower and upper limbs, as no differences were found for the upper limbs, while for the lower limbs, swimmers presented higher muscle force for the same amount of BMC. CONCLUSIONS: The contradictory results regarding BMC in swimmers found in previous studies could partly be explained with the findings of the present study that reinforce the idea that swimming is not an effective sport to practice regarding bone mass and that the muscle-bone unit is different in swimmers than in controls.

The unusual γ-ray burst GRB 101225A from a helium star/neutron star merger at redshift 0.33.

Long γ-ray bursts (GRBs) are the most dramatic examples of massive stellar deaths, often associated with supernovae. They release ultra-relativistic jets, which produce non-thermal emission through synchrotron radiation as they interact with the surrounding medium. Here we report observations of the unusual GRB 101225A. Its γ-ray emission was exceptionally long-lived and was followed by a bright X-ray transient with a hot thermal component and an unusual optical counterpart. During the first 10 days, the optical emission evolved as an expanding, cooling black body, after which an additional component, consistent with a faint supernova, emerged. We estimate its redshift to be z = 0.33 by fitting the spectral-energy distribution and light curve of the optical emission with a GRB-supernova template. Deep optical observations may have revealed a faint, unresolved host galaxy. Our proposed progenitor is a merger of a helium star with a neutron star that underwent a common envelope phase, expelling its hydrogen envelope. The resulting explosion created a GRB-like jet which became thermalized by interacting with the dense, previously ejected material, thus creating the observed black body, until finally the emission from the supernova dominated. An alternative explanation is a minor body falling onto a neutron star in the Galaxy.

Swimming and bone: Is low bone mass due to hypogravity alone or does other physical activity influence it?

UNLABELLED: Swimming during adolescence has shown neutral or even negative effects on bone mass. Nevertheless, it is still unknown if these effects are due to swimming or to other factors, such as sedentary behaviors. INTRODUCTION: Three objectives were described (1) to measure objective physical activity (PA) additional to swimming performed by adolescent swimmers (SWI) and compare it to that performed by normo-active controls (CG), (2) to describe the relationship between objectively measured PA and bone mass, and (3) to compare bone mass of swimmers that meet the World Health Organization PA guidelines (active) WHO and those that do not (inactive). METHODS: A total of 71 SWI (33 females) and 41 CG (17 females) wore an accelerometer for at least 4 days. PA was expressed as the amount of time (minutes/day) in each intensity [sedentary/light/moderate or vigorous (VPA), and the sum of moderate and vigorous (MVPA)]. Using the cutoff points proposed by Vanhelst et al. SWI were classified as active or inactive according to whether they reached 60 min of weight-bearing MVPA per day or not. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry, and bone strength values were calculated with peripheral quantitative computed tomography. Differences in PA intensities were calculated between SWI and CG. The relation of VPA to bone mass was studied in the SWI. RESULTS: Male-SWI spend less time in VPA and MVPA than male-GC, which partly explains the lower BMD values in SWI than CG. CONCLUSION: Swimming may displace weight-bearing VPA with serious implications on bone health.

Effect of whole-body vibration training on bone mass in adolescents with and without Down syndrome: a randomized controlled trial.

UNLABELLED: Whole-body vibration training (WBV) attracts great interest as osteoporosis prevention strategy. Twenty-six adolescents with and without Down syndrome (DS) (13 DS; 12-18 years) performed 20 weeks of WBV. The results indicate that WBV seems to provoke a lesser response in adolescents with DS than in those without DS. INTRODUCTION: This study aims to observe the differences between adolescents with and without DS in the effects of 20 weeks of WBV training, on bone mineral content (BMC) and density (BMD). METHODS: Twenty-six adolescents (13 DS; 12-18 years) were measured with dual-energy X-ray absorptiometry before and after the intervention (3/week, 10 repetitions (30-60 s) and 1-min rest, frequency 25-30 Hz and peak-to-peak displacement of 2 mm (peak acceleration 2.5-3.6 g)). Both, an intention-to-treat (ITT) analysis designed to assess the effects on bone mass and a per-protocol analysis, designed to compare poor and high compliers, were performed. RESULTS: The ITT analysis revealed significant increases in all BMC and BMD parameters (dz = 0.66 to 1.64; all p < 0.05) in the non-DS group, whilst DS group improved whole-body, subtotal (whole-body less head), upper limbs (ULIMBS), pelvis, lower limbs (LLIMBS) and spine BMC (dz = 0.75 to 1.76; all p < 0.05) and subtotal, pelvis, LLIMBS and spine BMD (dz = 0.73 to 1.28; all p < 0.05). Significantly greater increases were evident in the absolute and percent changes of the non-DS group over DS group (d = 0.88 to 3.85; all p < 0.05). ULIMBS BMD showed a tendency towards an interaction (f = 0.41 and p = 0.086) with higher increase for non-DS group. When a per-protocol analysis was considered, high-complier adolescents had 8.1 versus 5.3 % of gains in the spine BMC over poor-complier adolescents (d = 0.93; p < 0.05). CONCLUSIONS: Twenty weeks of WBV training may improve BMC and BMD in clinically relevant skeletal sites in both groups. Nevertheless, this type of training seems to provoke a lesser response in adolescents with DS than in those without DS.

Effect of whole body vibration training on bone mineral density and bone quality in adolescents with Down syndrome: a randomized controlled trial.

UNLABELLED: Adolescents with Down syndrome (DS) have poorer bone health than their peers without DS. Twenty-five adolescents with DS were randomly assigned to whole-body vibration training (WBV) or control groups. The results indicate that a 20-week WBV might be useful to improve subtotal bone mineral content and density in adolescents with DS. INTRODUCTION: This study aims to determine the effects of 20 weeks of whole body vibration training (WBV) on bone mineral content (BMC), density (BMD), and structure variables in adolescents with Down syndrome (DS). METHODS: This randomized controlled trial of 25 adolescents (12-18 years) with DS (8 females) generated 2 non-equal groups, WBV group (n = 11) and CON group (n = 14). Using an efficacy analysis, the primary outcomes were BMC and BMD by dual-energy X-ray absorptiometry and the secondary were bone structure variables by peripheral quantitative computed tomography. A synchronous vibration platform (PowerPlate®) was used (3/week, 10 repetitions (30-60 s) 1-min rest, frequency of 25-30 Hz, and peak-to-peak displacement of 2 mm (peak acceleration 2.5-3.6 g)). RESULTS: WBV group improved whole body BMC 2.8%, 95% CI [3.5, 2.1], subtotal area, BMC, and BMD by 2.8, 4.8, and 2%, respectively, 95% confidence intervals (CIs) [3.4, 2.1], [6.5, 3.1], and [2.8, 1.1], respectively (all, p < 0.05), showing group by time interactions in BMC and BMD (both p < 0.05). Lumbar spine BMC and BMD also increased in the WBV group by 6.6 and 3.3% both p < 0.05, 95 % CIs [8.6, 4.7], and [4.9, 1.7], respectively. Regarding bone structure, WBV group showed improvements in tibial BMC at 4 % (2.9 %, 95 % CI [3.0, 2.8]) and in volumetric BMD (vBMD), cortical vBMD, and cortical thickness at 66% of the radius (by 7.0, 2.4, and 10.9%; 95% CIs [7.4, 6.7], [2.6, 2.3], and [12.4, 9.3], respectively) (all, p < 0.05). CONCLUSIONS: A 20-week WBV, with this protocol, might be useful to improve subtotal BMC and BMD in adolescents with DS.

The effects of swimming training on bone tissue in adolescence.

The aim was to analyze bone mineral content (BMC) and density (BMD) in regular swimming trained adolescents and the interaction that weigh-bearing sports may have on these values. Bone mass was evaluated by dual energy x-ray absorptiometry (DXA) and quantitative ultrasound (QUS) in 77 swimmers (34 females/43 males) and 52 normoactive controls (CG; 23 females/29 males) from 11 to 18 years. Swimmers who had performed or were performing other sports (OSP; 11 females/20 males) were compared with pure swimmers (PSW; 23 females/23 males). Both groups were compared with CG. Bone values were compared using analyses of covariance adjusting for height, calcium intake, subtotal lean (whole body lean minus head), and pubertal status. Male PSW showed lower BMD and BMC at several sites than male CG. However, for male OSP, only lumbar spine BMC was lower in OSP than male CG. Male PSW showed lower BMD and BMC when compared with male OSP. Female PSW showed higher arm BMD and lower leg BMC than female CG, while female OSP only presented lower leg BMC than female CG. Contrary to males, female-PSW presented higher BMD and BMC than female OSP. No differences in QUS values were found between swimmers and CG. To summarize, although more information is needed for females, it seems that for males, swimming is associated with lower BMC and BMD.

Neutrophil CD64: diagnostic accuracy and prognostic value in patients presenting to the emergency department.

The purpose of this study was to evaluate the diagnostic accuracy and prognostic value of neutrophil CD64 expression for bacterial infection in febrile adult patients presenting to our hospital emergency department. We prospectively included 132 patients with fever ≥ 38ºC (≥ 100.4ºF) during the last 24 hours and we measured CD64 expression on neutrophils the day after admission at the emergency department. We followed the patients until full recovery or death. There were 115 (87%) patients with bacterial infection and 108 (94%) of them survived. There were 17 (13%) patients without bacterial infection and 12 (71%) of them survived. Patients with bacterial infection and patients who survived showed a CD64 index higher when compared with patients without bacterial infection and patients who died, respectively (3.7 ± 3.2 vs. 2.5 ± 2.3; p = 0.03; and 3.7 ± 3.1 vs. 1.7 ± 0.6; p = 0.002; Mann-Whitney U test). The receiver operating characteristic (ROC) curve analysis for detecting bacterial infection and predicting survival with the CD64 index showed an area under curve (AUC) of 0.66 (95% CI, 0.52-0.8; p = 0.03) and 0.71 (95% CI, 0.57-0.85; p = 0.01), respectively. Diagnostic accuracy and prognostic value of CD64 expression was good in adult patients with fever.

A 3-Case Series of Autoimmune Haemolytic Anaemia and COVID-19: Is Plasma Exchange an Alternative?

COVID-19 has rarely been associated with immune-mediated phenomena such as autoimmune haemolytic anaemia (AIHA). Both cold hemolysis with cold agglutinin detection and warm haemolysis have been described with variable prognoses. Current treatment regimens are based on experience with other case series and case reports, which still represent a clinical challenge. Corticosteroids, red cell transfusions and rituximab have been successfully employed. We present 3 cases of AIHA in the context of COVID-19 disease, the first case successfully treated with plasma exchange and long-term follow-up of the 3 cases showing complete remission of anaemia.

Associations between Physical Fitness, Bone Mass, and Structure in Older People.

The main aim was to analyse the associations between several physical fitness variables and bone parameters in a sample of elderly people. 129 participants (94 females and 35 males, 76.2 ± 5.4 y) from the EXERNET cohort of Zaragoza (Spain) were included in the study. Physical fitness was assessed using the Senior Fitness Test Battery. Peripheral quantitative computed tomography (pQCT) at the tibia and dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine were used to assess bone and muscle parameters. Partial correlations were used to describe the associations between fitness and bone parameters. A stepwise regression analysis was used to determine the influence of fitness variables on bone parameters. In males, significant correlations were found between lower body strength and agility with bone total mineral density (Tt.BMD) (r = 0.41 and -0.50) and cortical thickness (r = 0.40 and -0.50, respectively) and walking speed with total and cortical density (r = -0.41 and -0.40, respectively), all measured at tibia (all p < 0.05). Regarding DXA, neck areal bone mineral density (aBMD) correlated with flexibility (r = -0.37) and walking speed (r = 0.39) and Ward's triangle with walking speed (r = 0.39). Agility predicted Tt.BMD and cortical thickness (r 2 change = 24.8% and 23.0%), while walking speed predicted cortical bone mineral density (r 2 change = 19.5%) (all p < 0.05). Females showed correlations between balance and total hip aBMD (r = 0.27) and trochanter aBMD (r = 0.25). Balance predicted trochanter (r 2 change = 4.2%) and total hip aBMD (r 2 change = 4.9%) (both p < 0.05). In conclusion, bone mass in elderly males seems to be more influenced by physical fitness than in females, being agility and walking speed the variables showing greater associations. Other variables should be taken into account in females for future research.

Endothelial dysfunction is an early indicator of sepsis and neutrophil degranulation of septic shock in surgical patients.

BACKGROUND: Stratification of the severity of infection is currently based on the Sequential Organ Failure Assessment (SOFA) score, which is difficult to calculate outside the ICU. Biomarkers could help to stratify the severity of infection in surgical patients. METHODS: Levels of ten biomarkers indicating endothelial dysfunction, 22 indicating emergency granulopoiesis, and six denoting neutrophil degranulation were compared in three groups of patients in the first 12 h after diagnosis at three Spanish hospitals. RESULTS: There were 100 patients with infection, 95 with sepsis and 57 with septic shock. Seven biomarkers indicating endothelial dysfunction (mid-regional proadrenomedullin (MR-ProADM), syndecan 1, thrombomodulin, angiopoietin 2, endothelial cell-specific molecule 1, vascular cell adhesion molecule 1 and E-selectin) had stronger associations with sepsis than infection alone. MR-ProADM had the highest odds ratio (OR) in multivariable analysis (OR 11·53, 95 per cent c.i. 4·15 to 32·08; P = 0·006) and the best area under the curve (AUC) for detecting sepsis (0·86, 95 per cent c.i. 0·80 to 0·91; P < 0·001). In a comparison of sepsis with septic shock, two biomarkers of neutrophil degranulation, proteinase 3 (OR 8·09, 1·34 to 48·91; P = 0·028) and lipocalin 2 (OR 6·62, 2·47 to 17·77; P = 0·002), had the strongest association with septic shock, but lipocalin 2 exhibited the highest AUC (0·81, 0·73 to 0·90; P < 0·001). CONCLUSION: MR-ProADM and lipocalin 2 could be alternatives to the SOFA score in the detection of sepsis and septic shock respectively in surgical patients with infection.

ANTECEDENTES: La estratificación de la gravedad de una infección se basa actualmente en la puntuación SOFA (Sequential Organ Failure Assessment), que es difícil de calcular fuera de la unidad de cuidados intensivos. Los biomarcadores podrían ayudar a estratificar la gravedad de la infección en pacientes quirúrgicos. MÉTODOS: Se compararon las concentraciones de 10 biomarcadores que denotan disfunción endotelial, 22 que indican granulopoyesis de emergencia y 6 que expresan la degranulación de neutrófilos en tres grupos de pacientes de tres hospitales españoles (100 con infección, 95 con sepsis y 57 con shock séptico) en las primeras doce horas después del diagnóstico. RESULTADOS: Siete biomarcadores que expresan disfunción endotelial (proadrenomedulina, sindecan-1, trombomodulina, angiopoyetina-2, endocan-1, molécula de adhesión endotelial 1 y E-selectina) mostraron una fuerte asociación con la sepsis en comparación con la infección aislada. La proadrenomedulina presentó el valor más alto de la razón de oportunidades (odds ratio, OR) en el análisis multivariable (OR 11,53, i.c. del 95% 4,15-32,08, P = 0,006) y la mejor área bajo la curva para detectar sepsis (AUC 0,86, i.c. del 95% 0,80-0,91, P < 0,001). En la comparación entre sepsis y shock séptico, los biomarcadores que mostraron la asociación más estrecha con el shock séptico fueron dos biomarcadores de degranulación de neutrófilos (proteinasa-3 y lipocalina-2) (OR 8,09, i.c. del 9% 1,34-48,91, P = 0,028; OR 6.62, i.c. del 95% 2,47-17,77, P = 0,002), pero la lipocalina-2 presentó la mejor AUC (0,81, i.c. del 95% 0,73-0,90, P < 0,001). CONCLUSIÓN: la proadrenomedulina y la lipocalina-2 podrían representar alternativas a la puntuación SOFA para detectar sepsis y shock séptico en pacientes quirúrgicos con infección.

Expression of mutant dynamin inhibits toxicity and transport of endocytosed ricin to the Golgi apparatus.

Endocytosis and intracellular transport of ricin were studied in stable transfected HeLa cells where overexpression of wild-type (WT) or mutant dynamin is regulated by tetracycline. Overexpression of the temperature-sensitive mutant dynG273D at the nonpermissive temperature or the dynK44A mutant inhibits clathrin-dependent endocytosis (Damke, H., T. Baba, A.M. van der Blieck, and S.L. Schmid. 1995. J. Cell Biol. 131: 69-80; Damke, H., T. Baba, D.E. Warnock, and S.L. Schmid. 1994. J. Cell Biol. 127:915-934). Under these conditions, ricin was endocytosed at a normal level. Surprisingly, overexpression of both mutants made the cells less sensitive to ricin. Butyric acid and trichostatin A treatment enhanced dynamin overexpression and increased the difference in toxin sensitivity between cells with normal and mutant dynamin. Intoxication with ricin seems to require toxin transport to the Golgi apparatus (Sandirg, K., and B. van Deurs. 1996. Physiol. Rev. 76:949-966), and this process was monitored by measuring the incorporation of radioactive sulfate into a modified ricin molecule containing a tyrosine sulfation site. The sulfation of ricin was much greater in cells expressing dynWT than in cells expressing dynK44A. Ultrastructural analysis using a ricin-HRP conjugate confirmed that transport to the Golgi apparatus was severely inhibited in cells expressing dynK44A. In contrast, ricin transport to lysosomes as measured by degradation of 125I-ricin was essentially unchanged in cells expressing dynK44A. These data demonstrate that although ricin is internalized by clathrin-independent endocytosis in cells expressing mutant dynamin, there is a strong and apparently selective inhibition of ricin transport to the Golgi apparatus. Also, in cells with mutant dynamin, there is a redistribution of the mannose-6-phosphate receptor.

Efficacy of transfusion of platelet concentrates obtained by manual pooling or by semiautomated pooling of buffy-coats: a retrospective analysis of count increment, corrected count increment and transfusion interval.

BACKGROUND AND OBJECTIVE: The preparation of platelet concentrates from pooling buffy-coats can be done manually or semiautomatically with the OrbiSac BC System. The objective of this study was to compare the clinical outcome of platelet transfusions prepared by these two methods in terms of 1-h count increment (1-h CI), 1-h corrected count increment (1-h CCI) and transfusion interval. MATERIALS AND METHODS: Platelet transfusions were identified retrospectively for inclusion in the control group (manual pooling) or the test group (automated pooling). Transfusion outcome variables were 1-h CI, 1-h CCI and transfusion interval. The impact of 16 patient- and platelet concentrate-related variables on transfusion efficacy was investigated by multiple regression analysis. RESULTS: The database analysed consisted of 205 control transfusions given to 36 patients and 219 test transfusions given to 36 patients. Mean platelet content and mean 1-h CI were statistically higher in the test group when compared to the control group (P < 0.05), but mean 1-h CCI and transfusion interval were not. Multiple regression analysis resulted in models explaining 13% of the variance of 1-h CI, 8% of the variance of 1-h CCI and 17% of the variance of transfusion interval (P < 0.05). CONCLUSION: There are no significant differences between the two preparation methods regarding the clinical outcome of platelet transfusions, as the difference in 1-h CI is explained by differences in platelet content.

Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)].

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.

Role for dynamin in late endosome dynamics and trafficking of the cation-independent mannose 6-phosphate receptor.

It is well established that dynamin is involved in clathrin-dependent endocytosis, but relatively little is known about possible intracellular functions of this GTPase. Using confocal imaging, we found that endogenous dynamin was associated with the plasma membrane, the trans-Golgi network, and a perinuclear cluster of cation-independent mannose 6-phosphate receptor (CI-MPR)-containing structures. By electron microscopy (EM), it was shown that these structures were late endosomes and that the endogenous dynamin was preferentially localized to tubulo-vesicular appendices on these late endosomes. Upon induction of the dominant-negative dynK44A mutant, confocal microscopy demonstrated a redistribution of the CI-MPR in mutant-expressing cells. Quantitative EM analysis of the ratio of CI-MPR to lysosome-associated membrane protein-1 in endosome profiles revealed a higher colocalization of the two markers in dynK44A-expressing cells than in control cells. Western blot analysis showed that dynK44A-expressing cells had an increased cellular procathepsin D content. Finally, EM revealed that in dynK44A-expressing cells, endosomal tubules containing CI-MPR were formed. These results are in contrast to recent reports that dynamin-2 is exclusively associated with endocytic structures at the plasma membrane. They suggest instead that endogenous dynamin also plays an important role in the molecular machinery behind the recycling of the CI-MPR from endosomes to the trans-Golgi network, and we propose that dynamin is required for the final scission of vesicles budding from endosome tubules.

Endosome to Golgi transport of ricin is independent of clathrin and of the Rab9- and Rab11-GTPases.

The plant toxin ricin is transported to the Golgi and the endoplasmic reticulum before translocation to the cytosol where it inhibits protein synthesis. The toxin can therefore be used to investigate pathways leading to the Golgi apparatus. Except for the Rab9-mediated transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network (TGN), transport routes between endosomes and the Golgi apparatus are still poorly characterized. To investigate endosome to Golgi transport, we have used here a modified ricin molecule containing a tyrosine sulfation site and quantified incorporation of radioactive sulfate, a TGN modification. A tetracycline-inducible mutant Rab9S21N HeLa cell line was constructed and characterized to study whether Rab9 was involved in transport of ricin to the TGN and, if not, to further investigate the route used by ricin. Induced expression of Rab9S21N inhibited Golgi transport of mannose 6-phosphate receptors but did not affect the sulfation of ricin, suggesting that ricin is transported to the TGN via a Rab9-independent pathway. Moreover, because Rab11 is present in the endosomal recycling compartment and the TGN, studies of transient transfections with mutant Rab11 were performed. The results indicated that routing of ricin from endosomes to the TGN occurs by a Rab11-independent pathway. Finally, because clathrin has been implicated in early endosome to TGN transport, ricin transport was investigated in cells with inducible expression of antisense to clathrin heavy chain. Importantly, endosome to TGN transport (sulfation of endocytosed ricin) was unchanged when clathrin function was abolished. In conclusion, ricin is transported from endosomes to the Golgi apparatus by a Rab9-, Rab11-, and clathrin-independent pathway.

Do 6 months of whole-body vibration training improve lean mass and bone mass acquisition of adolescent swimmers?

Swimming has little effect on bone mass. Therefore, adolescent swimmers should complement their water training with a short and intense weight-bearing training, aiming to increase their bone acquisition. Forty swimmers performed a six-month whole-body vibration (WBV) training. WBV had no effect on adolescent swimmers' bone mass or lean mass. PURPOSE: The aims of the present study were to evaluate the effects of a whole-body vibration (WBV) intervention on bone mineral density (BMD), bone mineral content (BMC) and lean mass (LM) in adolescent swimmers. METHODS: Forty male and female adolescent swimmers (VIB; mean age 14.2 ± 1.9 years) completed the WBV protocol that consisted of 15 min of training 3 days per week during a 6-month period (ranging from 3.6 to 11.6 g), while 23 swimmers (SWI; mean age 15.0 ± 2.2 years) continued with their regular swimming training alone. VIB were divided into tertiles according to training compliance in order to evaluate if any dose-effect relation existed. BMD, BMC and LM were measured longitudinally by dual energy X-ray at the whole body, lumbar-spine and hip. RESULTS: No group by time interactions and no differences in change percentage were found for BMD, BMC or LM in any of the measured variables. The mean change percentage of the subtotal body (whole body minus the head) for VIB and SWI, respectively, was 2.3 vs. 2.4% for BMD, 5.7 vs 5.7% for BMC and 7.3 vs. 8.0% for lean mass. Moreover, no indication for dose-response was observed. CONCLUSIONS: The proposed WBV protocol had no effect on BMD, BMC and LM in adolescent swimmers. Other types of training should be used in this population to improve both bone and lean mass.

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.