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PubMed2006

Measurement of decline of functioning in persons with amyotrophic lateral sclerosis: responsiveness and possible applications of the Functional Independence Measure, Barthel Index, Rehabilitation Activities Profile and Frenchay Activities Index.

It is important not only to monitor the functional change during the course of ALS, but also to determine whether or not the available help is sufficient. This study was performed to determine which generic assessment instrument is most appropriate. A multicentre cohort of patients with ALS was followed for one year. At baseline, six months, and 1 year four instruments were used: Functional Independence Measure (FIM), Rehabilitation Activities Profile (RAP), Barthel Index (BI), and Frenchay Activities Index (FAI). The responsiveness of the measures was examined using effect sizes and standardized response mean statistics. Seventy-three patients at baseline, 63 after six months and 43 after one year were assessed. If calculated on the group that completed all three assessments, the FIM, BI, and RAP showed moderate effect sizes and standardized response means over a period of six months and large effect sizes over 12 months. Based on their responsiveness FIM, BI, and RAP can be used to evaluate limitations in activities and care needs of persons with ALS and to evaluate treatment results in trials. The FIM was the most responsive instrument, although the BI might be easier to use in clinical practice.

Activities of Daily Living↗
PubMed2006

Performance of cervical motion in chronic whiplash patients and healthy subjects: the case of atypical patients.

STUDY DESIGN: A comparative study of cervical motion performance in chronic whiplash (CW) patients and healthy subjects. OBJECTIVES: To examine the efficiency of total cervical range of motion (TCROM), which consists of the combined score of all six primary movements and their mean coefficient of variation (MCV), in differentiating CW patients from healthy subjects as well as typical from atypical patients. Additionally to explore in the patients possible relationships between their cervical motion profile and functional and personality traits. SUMMARY OF BACKGROUND DATA: Previous studies revealed that cervical motion was an efficient discriminator between healthy and CW patients. However, none of these studies provided either guidelines regarding cutoff scores or insight as to what should be considered typical compared with atypical patient with respect to cervical motion performance. METHODS: Cervical motion was measured in 75 healthy subjects and 101 CW patients in each of the six primary movements. In addition, patients filled the functional neck disability index (NDI) and personality symptom check list (SCL-R-90) questionnaire. RESULTS: Total CROM was significantly lower and the MCV was significantly higher in patients compared with healthy subjects. Age and gender affected TCROM significantly in both groups while MCV remained unaffected, respectively. Atypical patients were identified by having a TCROM < 58 degrees and or MCV > 22%, both scores corresponding to 2 SDs below and above group means, respectively. These benchmarks resulted in classifying as atypical 6% of the CW group who also scored drastically higher in the NDI and SCL-R-90 questioners. CONCLUSIONS: Using MCV and TCROM adds new insight regarding what should be considered as atypical cervical motion profile in CW patients. Several aspects of this complex clinical entity are discussed.

Adult↗
PubMed1995

The structural stability of a three-species food chain model.

A three-species food-chain model which was previously shown to exhibit chaotic dynamics was revisited. By exploring the sensitivity of that result this study found that complex behavior depended on the functional form chosen to model the interaction between the two highest species in the food chain. Two separate scenarios were explored: the gradual addition of refugia modeling the escape from predation at low prey densities; and the gradual addition of predator interference modeling territorial behavior. The addition of even a small amount of refugia provided a stabilizing influence as the chaotic dynamics collapsed to stable limit cycles. The results of adding interference to the model were more complex. Although the numerical simulations indicated that a low level of interference provided a stabilizing influence, the analytical results suggest that complex dynamics are possible for a range of parameter values that are biologically relevant. The sensitivity of the stability profile to functional changes in the model suggests two important ecological motivations for structural stability analysis. First, in ecological systems, environmental fluctuations cause continuous changes in the functional relationships between and within species, resulting in potential changes in the complexity of the dynamics over time. Second, slight changes in ecological structure may cause significant bifurcations; however, most ecological data are inadequate to distinguish such phenomena.

Animals↗
PubMed1999

Convection and thermodiffusion of colloidal gold tracers by laser light scattering.

In a dynamic light scattering experiment, we have investigated the time intensity correlation function and the profile of the transmitted laser beam for organic dispersions of light absorbing colloidal particles containing tiny gold clusters. The correlation functions have been found to show a superposition of an exponential decay, corresponding to Brownian motion of the tracers, and well-defined oscillations. These oscillations are caused by convection due to local heating of the sample by the incident laser beam, which has been confirmed independently via measurements of the local temperature within the sample. It will be shown how the particle convection velocity, which is the order of 1 mm/s, can be obtained quantitatively from the oscillating correlation functions. The profile of the transmitted beam allowed us to determine the Soret coefficient, which is a measure for the thermal diffusion of the particles. This article shows how tracer diffusion, convection, and thermal diffusion can be determined simultaneously by one single experiment, laser light scattering of light absorbing colloidal particles in dispersion.

Journal Article↗
PubMed2002

(+/-)-Domesticine, a novel and selective alpha1D-adrenoceptor antagonist in animal tissues and human alpha 1-adrenoceptors.

The pharmacological profile of (+/-)-domesticine, a novel alpha(1)-adrenoceptor antagonist, was examined in animal tissues and Chinese hamster ovary (CHO) cells expressing cloned human alpha(1)-adrenoceptor subtypes and compared with the properties of BMY-7378 ([8-(2-[4-(2-methoxy-phenyl)-1-piperazinyl]ethyl)-8-azaspirol [4.5]decane-7,9-dione dihydrochloride], the prototypical alpha(1D)-adrenoceptor antagonist. Both (+/-)-domesticine and BMY-7378 were more potent in inhibiting the phenylephrine-induced contraction in rat thoracic aorta than tail artery or spleen. The selectivity of (+/-)-domesticine to inhibit phenylephrine-induced contraction in rat thoracic aorta was 32- and 17-fold higher than that in tail artery and spleen, respectively, while that of BMY-7378 it was 125- and 11-fold, respectively. The functional affinity profiles of these compounds for the alpha(1)-adrenoceptor subtypes in animal tissues were consistent with the respective binding affinity profiles in cloned human alpha(1)-adrenoceptor subtypes. (+/-)-Domesticine displayed a 34- and 9-fold higher selectivity for alpha(1d)-adrenoceptor than for alpha(1a)- and alpha(1b)-adrenoceptor, respectively, while BMY-7378 showed a selectivity for alpha(1d)-adrenoceptor of 102-fold higher than that of alpha(1a)-adrenoceptor and 21-fold higher than that of alpha(1b)-adrenoceptor. Interestingly, in [3H]8-OH-DPAT (8-hidroxy-2-(di-n-propyl-amino)tetraline hidrobromide) binding to 5-HT(1A) receptors of rat cerebral cortex, (+/-)-domesticine showed a 183-fold higher selectivity for alpha(1D)-adrenoceptor relative to 5-HT(1A) receptor, whereas BMY-7378 displayed a similar affinity at this receptor with respect to the alpha(1D)-adrenoceptor (0.89-fold). Both compounds, however, showed a weak affinity for 5-HT(2A)/5-HT(2C) receptors in rat frontal cortex. These results suggest that (+/-)-domesticine is more potent for alpha(1D)-adrenoceptor than for alpha(1A)- or alpha(1B)-adrenoceptor subtypes and it is highly selective compared to 5-HT(1A) and other receptors.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2006

2-DE proteomic profiling of neuronal stem cells.

Proteomics has become a powerful tool in neuroscience studies. Although numerous human neural stem cells are available for research purposes since many years, there exists only limited information on proteomic data from stable neural stem cell lines. Profiling and functional proteome studies of neuronal stem cells will help to describe the protein inventory as well as protein activity and interactions, subcellular localization and posttranslational modifications. The proteomic analysis of neuronal differentiation processes will elucidate the complex events leading to the generation of different phenotypes via distinctive developmental programs that control self-renewal, differentiation, and plasticity. Using the ReNcell VM197 model, a cell line derived from human fetal ventral mesencephalon stem cells, we studied the protein inventory of the stem cells by 2-DE gel electrophoresis and mass spectrometric protein identification and constructed a 2-DE protein map consisting of more than 400 identified protein spots. This proteome reference database constitutes the basis for further investigations of differential protein expression during differentiation. A profiling of the neuronal differentiation-associated changes displayed the large rearrangement of the proteome during this process, and the proteomic techniques proved to be a valuable tool for the elucidation of neuronal differentiation process and for target protein screening.

Animals↗
PubMed2001

Gene expression profiling of lymphomas.

The functional phenotype of a cell results from the simultaneous action of many thousands of genes, which until recently could not be assessed using standard molecular biological techniques. Indeed, molecular genetics and cellular biology inadequately explain the molecular physiology of normal and diseased cells and provide a fragmented view of the role of various genes and their products. Recent advances in techniques of large-scale gene expression allow simultaneous study of thousands of genes of interest in a specific tissue/tumor of interest, and the ability to identify expression signatures associated with functional phenotypes. The application of gene expression profiling to lymphomas has already led to identification of distinct expression signatures associated with a germinal center cell and activated B-cell phenotype, and to the differentiation of tumor cells based on these stages of development. The differentiation of two stages of developmental arrest in large B-cell lymphomas suggests that this subtype is comprised of two diseases, albeit of similar histologic and immunophenotypic character, which were shown to have dramatically different outcomes following chemotherapy. Important information will also be obtained through the association of genes of unknown activity with functional cellular phenotypes and expression signatures, possibly leading to identification of new genes involved in lymphomagenesis and new targets for treatment.

Chromosome Aberrations↗
PubMed1996

CD30 cell expression and abnormal soluble CD30 serum accumulation in Omenn's syndrome: evidence for a T helper 2-mediated condition.

Omenn's syndrome (OS) is a severe immunodeficiency, characterized by clinical and laboratory features reminiscent of a T helper type-2 (Th2) response. CD30, a member of the tumor necrosis factor receptor superfamily, has been found to be preferentially expressed by human T cell clones exhibiting a Th2-line profile and function. We investigated whether there are derangement in CD30 expression in tissues, and/or abnormalities in soluble CD30 (sCD30) levels in the serum, or both, of three children with OS and one child with maternal engraftment and Omenn's-like syndrome (OLS). Large proportions of tissue-infiltrating T lymphocytes from all four patients expressed CD30, whereas in control tissues, including peripheral blood, CD30+ T lymphocytes were extremely few or absent. In addition, levels of sCD30 were abnormally increased in all patients' sera. T cell clones were generated from sorted CD30+ and CD30-peripheral blood T cells of the patient with OLS who showed unusually high numbers of circulating CD30+ T lymphocytes. Most CD4+ T cell clones derived from CD30+ cells showed a Th2-like cytokine profile, whereas the majority of clones generated from CD30-T cells were Th1. These findings support the hypothesis that Th2 cells are involved in the pathogenesis of OS. Moreover, they provide evidence that detection of CD30+ T cells in tissues, increased levels of sCD30 in biological fluids, or both, reflect the presence of immune responses characterized by prevalent activation of T cells producing Th2 cytokines.

Cytokines↗
PubMed2002

Profiling of differential expression of messenger RNA in normal, benign, and metastatic prostate cell lines.

To understand the phenotypic changes associated with prostate cancer development and metastasis, we investigated differential gene expression in primary and established prostate cell lines used as models. We have used a differential display of messenger RNA (DDRT-PCR) technique using 168 primer combinations and total RNA from BPH-1, LNCaP, and PC3 cells to identify filter-based cDNA microarrays containing 18,376 nonredundant clones of genes and expressed sequence tags (EST) using mRNA from PrEC and MDAPCa2a cells to identify genes that are differentially expressed in normal, benign, and cancerous prostate cell lines. Twenty-five cDNA with a significant difference in expression of 76 candidate cDNA, as identified by DDRT-PCR and confirmed by slot-blot analysis, were selected for sequence analysis. Of these, 14 cDNA were further confirmed by Northern blot analysis. Analysis of the cDNA microarray data showed that a variety of genes/EST were up- or down-regulated in the metastatic prostate tumor cells and a majority of these genes encode cytoskeletal proteins and proteins with regulatory function. Expression profile of two EST was confirmed by reverse transcription polymerase chain reaction. We also have identified a number of genes exhibiting differential expression in prostate cancer cells, which were not known earlier to be involved in prostate cancer. This report provides a comparative analysis of differential gene expression between normal prostatic epithelial cells and prostate cancer cells, and a foundation to facilitate in-depth studies on the mechanism of prostate cancer development and metastasis.

Adenocarcinoma↗
PubMed1990

A double-blind placebo-controlled trial of zopiclone 7.5 mg and temazepam 20 mg in insomnia.

Zopiclone, a cyclopyrrolone with hypnotic properties was compared with temazepam and placebo in the treatment of insomnia. After a week's washout period, suitable subjects were allocated at random to zopiclone 7.5 mg or temazepam 20 mg or placebo for 2 weeks. Measurements of psychomotor function using the Leed's psychomotor tester and letter cancellation were carried out on day 0, 7 and 14. Sleep latency, duration of sleep and number of times waking during the night were recorded on a sleep diary filled by the subjects nightly. Forty-four subjects completed the trial, 15 taking zopiclone, 16 taking temazepam and 10 taking placebo. Both zopiclone and temazepam had significant hypnotic properties when compared to placebo. Zopiclone increased total sleep time in both weeks of the trial while temazepam increased sleep time in the first week only. There was no significant deterioration in psychomotor performance at the end of both weeks for zopiclone. Critical flicker fusion was significantly increased in subjects on temazepam. There were no abnormalities for both zopiclone and temazepam subjects in the blood picture, renal profile, liver function, urine and ECG before and after the study. Zopiclone is an effective hypnotic comparable to temazepam.

Adult↗
PubMed2026

Metagenomic insights into antibiotic resistance genes and virulence factors in sediments of river Yamuna.

Riverine sediments serve as critical reservoirs of microbial diversity and functional genes, reflecting both natural ecological processes and anthropogenic impacts. In the present study, we employed a shotgun metagenomic approach to investigate microbial community composition, antimicrobial resistance (AMR) genes, and virulence factors in sediments collected from three environmentally distinct locations of the Yamuna River near Agra, India, representing BSA, TGY, and YEA. The sediment DNA was subjected to high-throughput Illumina sequencing, followed by quality control, assembly, and open reading frame prediction. Taxonomic classification and diversity analyses were performed using MEGAN6 and R-based statistical tools, while AMR genes were identified from predicted metagenomic proteins using the Resistance Gene Identifier (RGI) against the CARD database, with high-confidence perfect and strict hits retained; ARGs were interpreted independently of species-level host assignment. Virulence factors were assessed through presence-absence profiling of functionally relevant gene categories. The results revealed pronounced spatial heterogeneity in microbial communities, with increasing taxonomic diversity, functional complexity, and evenness from BSA to TGY and YEA. TGY and YEA composite samples showed greater observed representation of high-confidence AMR gene predictions spanning multiple drug classes and resistance mechanisms, alongside a diverse repertoire of virulence-associated genes linked to motility, adhesion, and secretion systems. In contrast, the BSA site harbored a comparatively simpler resistome and virulome. Overall, this study highlights Yamuna River sediments as important reservoirs of resistance and virulence determinants and underscores the need for long-term genomic surveillance to inform risk assessment, pollution control, and sustainable river management strategies.

AMR↗
PubMed2003

The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation.

A functional motor scale was devised for use in children with spinal muscular atrophy type 2 and type 3, in particular those with limited mobility, to give objective information on motor ability and clinical progression. The scale, which has 20 scored activities, was designed to be self-explanatory, quick, easy to use, reproducible and reliable. In this paper we describe the development of the scale, reporting the criteria used to choose the items to be included, their application in a normal cohort and in a cohort of children with SMA and how we arrived to a final version of the scale in which the items are arranged in order of difficulty. The analysis of 120 assessments over 2 years from 51 children with type 2 and type 3 SMA also led to a more accurate profile of functional achievements in both type 2 and 3 SMA and to a more detailed sub-classification of type 2 SMA.

Adolescent↗
PubMed2026

Enteral Nutrition Is Associated with a Distinct Gut Microbiome Composition and Fermentation Capacity Profile After Acute Colonic Injury in Rats.

Enteral nutrition (EN) is known to promote mucosal healing in inflammatory bowel disease, and multi-omics data suggest that the gut microbiome mediates its therapeutic effects. However, the impact of EN and its components on the gut community during recovery from acute epithelial injury remains incompletely understood. We used whole-genome metagenomic sequencing to investigate the effect of an EN formula based on extruded amaranth flour and pea protein on the gut microbiome in a dextran sulfate sodium (DSS) rat model of acute colonic injury. Three groups were compared, as follows: an unchallenged control (n = 9) with standard chow, a colonic injury (5% DSS; n = 9) group with standard chow, and a colonic injury (5% DSS; n = 9) group with EN. Injury was confirmed histologically (median MCHI score was 2, indicating epithelial damage without inflammation). DSS caused significant weight loss. Animals receiving EN regained baseline weight faster, by day 14, whereas animals on standard chow achieved recovery only by day 21. Differences in energy intake should be further investigated to validate the effect of EN on body weight recovery. At day 21, both injury groups demonstrated higher relative abundances of Bacteroidaceae and Erysipelotrichaceae, including the mucin-degrader Allobaculum mucilyticum, compared with the control group. Conversely, Lactobacillus abundance, notably Lactobacillus acidophilus, was higher in the EN group than in both other groups, as was the inferred capacity for lactate-producing fermentation. These findings suggest that EN is associated with a distinct microbial composition and inferred metabolic profile during the post-injury period, with lactobacilli as one of the potential mediators of its effects.

Animals↗
PubMed2005

Human TRPV4 channel splice variants revealed a key role of ankyrin domains in multimerization and trafficking.

The TRPV4 cation channel exhibits a topology consisting of six predicted transmembrane domains (TM) with a putative pore loop between TM5 and TM6 and intracellular N- and C-tails, the former containing at least three ankyrin domains. Functional transient receptor potential (TRP) channels are supposed to result following the assembly of four subunits. However, the rules governing subunit assembly and protein domains implied in this process are only starting to emerge. The ankyrin, TM, and the C-tail domains have been identified as important determinants of the oligomerization process. We now describe the maturation and oligomerization of five splice variants of the TRPV4 channel. The already known TRPV4-A and TRPV4-B (delta384-444) variants and the new TRPV4-C (delta237-284), TRPV4-D (delta27-61), and TRPV4-E (delta237-284 and delta384-444) variants. All alternative spliced variants involved deletions in the cytoplasmic N-terminal region, affecting (except for TRPV4-D) the ankyrin domains. Subcellular localization, fluorescence resonance energy transfer, co-immunoprecipitation, glycosylation profile, and functional analysis of these variants permitted us to group them into two classes: group I (TRPV4-A and TRPV4-D) and group II (TRPV4-B, TRPV4-C, and TRPV4-E). Group I, unlike group II variants, were correctly processed, homo- and heteromultimerized in the endoplasmic reticulum, and were targeted to the plasma membrane where they responded to typical TRPV4 stimuli. Our results suggest that: 1) TRPV4 biogenesis involves core glycosylation and oligomerization in the endoplasmic reticulum followed by transfer to the Golgi apparatus for subsequent maturation; 2) ankyrin domains are necessary for oligomerization of TRPV4; and 3) lack of TRPV4 oligomerization determines its accumulation in the endoplasmic reticulum.

Alternative Splicing↗
PubMed1978

Skeletal muscle fibre types, enzyme activities and physical performance in young males and females.

Differences in skeletal muscle characteristics, metabolic profiles and functional performance between males and females were investigated using young (15--24 yrs) male and female twins as subjects. The comparison included such variables as anthropometry, muscle strength, mechanical power, maximum oxygen uptake, electrical activation of muscle, muscle fibre composition (m. vastus lateralis), and activities of several skeletal muscle enzymes. The results disclosed the following primary differences between males and females: In the various functional tests the performance of females was from 61.1 to 84.6% of that in males; distribution of slow twitch fibres in m. vastus lateralis of the females (49.1 +/- 7.7%) was lower (p less than .05) than that of the males (55.9 +/- 11.9); activities of enzymes Ca2+ stimulated ATPase, CPK, phosphorylase and LDH1a leads to py were higher (p less than .05--0.1) in the males, whereas the distribution pattern of LDH-1 isozyme was higher (p less than .05) in the females. A pronounced difference between the two groups was a almost 100% longer rise time of isometric force in females. It is concluded that the males as compared to the females demonstrate higher aerobic and strength performance capacity, more efficient neuromotoric output during contraction, more slow twitch muscle fibres and more pronounced contractile and glycolytic profiles in the skeletal muscles.

Adenosine Triphosphatases↗
PubMed2006

Assessing 1-h plasma glucose and shape of the glucose curve during oral glucose tolerance test.

OBJECTIVE: To assess the cutoff values at different time points for impaired glucose regulation (IGR) and diabetes, the glucose curve and isolated 1-h hyperglycemia were monitored during an oral glucose tolerance test (OGTT). METHODS: Two thousand eight hundred and eighty-six subjects (1300 men and 1586 women) were recruited to have an OGTT. Plasma was collected at 0, 30, 60, 120, and 180 min to analyze glucose and insulin. The diagnosis of impaired fasting glucose, impaired glucose tolerance, and diabetes was based on World Health Organization and American Diabetes Association's criteria. Those with fasting plasma glucose (FPG) < 5.6 and 2-h plasma glucose (PG) < 7.8, but 1-h PG > or = 7.8 and < 11.1 mmol/l were defined as 1h-High7.8, and those with FPG < 7.0 and 2-h PG < 11.1, but 1-h PG > or =11.1 mmol/l as 1h-High11.1. The cutoff values were calculated by receiver operating characteristic (ROC) curve. The correlation between beta-cell function and the area under the curve of glucose (AUCg) and the shape index was analyzed with linear regression. RESULTS: The cutoff values for IGR were 5.6, 9.7, 10.1, 7.8 and 6.1 mmol/l for blood glucose at 0, 30, 60, 120 and 180 min, 24 for AUCg and 1.3 mmol/l for the shape index. The cutoff values for diabetes were 6.8, 11.2, 13, 11.1 and 7 mmol/l for 0, 30, 60, 120 and 180 min, 30.9 for AUCg and 2 mmol/l for the shape index. Both AUCg and the shape index were inversely related to beta-cell function. The profiles of glucose and insulin in the subgroup with isolated 1-h hyperglycemia were very different from those seen in subjects with normal glucose tolerance or IGR. CONCLUSIONS: The present study provides new information on measures other than the fasting and 2-h PG to evaluate glucose metabolism in vivo and stimulates further research aimed at assessing the value of the OGTT 1-h PG concentration prospectively.

Adult↗
PubMed2006

Advanced molecular profiling in vivo detects novel function of dickkopf-3 in the regulation of bone formation.

UNLABELLED: A bioinformatics-based analysis of endochondral bone formation model detected several genes upregulated in this process. Among these genes the dickkopf homolog 3 (Dkk3) was upregulated and further studies showed that its expression affects in vitro and in vivo osteogenesis. This study indicates a possible role of Dkk3 in regulating bone formation. INTRODUCTION: Endochondral bone formation is a complex biological process involving numerous chondrogenic, osteogenic, and angiogenic proteins, only some of which have been well studied. Additional key genes may have important roles as well. We hypothesized that to identify key genes and signaling pathways crucial for bone formation, a comprehensive gene discovery strategy should be applied to an established in vivo model of osteogenesis. MATERIALS AND METHODS: We used in vivo implanted C3H10T1/2 cells that had been genetically engineered to express human bone morphogenetic protein-2 (BMP2) in a tetracycline-regulated system that controls osteogenic differentiation. Oligonucleotide microarray data from the implants (n = 4 repeats) was analyzed using coupled two-way clustering (CTWC) and statistical methods. For studying the effects of dickkopf homolog 3 (Dkk3) in chondrogenesis and osteogenesis, C3H10T1/2 mesenchymal progenitors were used. RESULTS: The CTWC revealed temporal expression of Dkk3 with other chondrogenesis-, osteogenesis-, and Wnt-related genes. Quantitative RT-PCR confirmed the expression of Dkk3 in the implants. C3H10T1/2 cells that expressed Dkk3 in the presence of BMP2 displayed lower levels of alkaline phosphatase and collagen I mRNA expression than control C3H10T1/2 cells that did not express Dkk3. Interestingly, the levels of collagen II mRNA expression, Alcian blue staining, and glucose aminoglycans (GAGs) production were not influenced by Dkk3 expression. In vivo microCT and bioluminescence imaging revealed that co-expression of Dkk3 and BMP2 by implanted C3H10T1/2 cells induced the formation of significantly lower quantities of bone than cells expressing only BMP2. CONCLUSIONS: A bioinformatics analysis enabled the identification of Dkk3 as a pivotal gene with a novel function in endochondral bone formation. Our results showed that Dkk3 might have inhibitory effects on osteogenesis, but no effect on chondrogenesis, indicating that Dkk3 plays a regulatory role in endochondral bone formation. Further mechanistic studies are required to reveal the mechanism of action of Dkk3 in endochondral bone formation.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal function.

BACKGROUND: Bortezomib is a potent, reversible proteasome inhibitor that has been approved for the treatment of recurrent and/or refractory multiple myeloma, but its activity in patients with renal impairment has not been studied to date. METHODS: Response rates, safety, and 20S proteasome activity were assessed in relation to baseline creatinine clearance (CrCl) among patients with recurrent and/or refractory myeloma (n = 256 patients) who were treated with bortezomib in 2 Phase II trials. Bortezomib was administered by intravenous bolus on Days 1, 4, 8, and 11 of a 21-day cycle at 2 doses, 1.0 mg/m2 (n = 28 patients) and 1.3 mg/m2 (n = 228 patients). RESULTS: Of 10 patients with CrCl < or = 30 mL/minute, 7 patients completed the protocol-specified 8 cycles of treatment; 4 patients received the 1.3 mg/m2 bortezomib dose, and 3 patients received the 1.0 mg/m2 bortezomib dose. Using the European Group for Blood and Marrow Transplantation criteria, responses were assigned by an independent committee to 3 of the 10 patients (2 partial responses and 1 minimal response), a response rate similar to that of the overall treated population. Patients with CrCl > 80 mL/minute (n = 105 patients), 51-80 mL/minute (n = 99 patients), and < or = 50 mL/minute (n = 52 patients) had similar rates of discontinuation and similar adverse event profiles. Renal function did not appear to affect the 1-hour postdose proteasome inhibition or its recovery. CONCLUSIONS: Clinical experience in a limited number of patients with impaired renal function suggests that bortezomib provides clinical benefit with manageable toxicities in this high-risk population.

Adult↗