Metabolic acidosis associated with chronic kidney disease (CKD) may contribute to muscle dysfunction and bone disease. We aimed to test whether treatment with sodium bicarbonate improves muscle and ...bone outcomes.
Multicenter, randomized, placebo-controlled, clinical trial.
149 patients with CKD stages 3 and 4 between July 2011 and April 2016 at 3 centers in Cleveland, OH, and the Bronx, NY.
Sodium bicarbonate (0.4 mEq per kg of ideal body weight per day) (n=74) or identical-appearing placebo (n=75).
Dual primary outcomes were muscle function assessed using sit-to-stand test and bone mineral density. Muscle biopsies were performed at baseline and 2 months. Participants were seen at baseline and 2, 6, 12, and 24 months.
Mean baseline serum bicarbonate level was 24.0±2.2 (SD) mEq/L and mean baseline estimated glomerular filtration rate was 36.3±11.2mL/min/1.73m2. Baseline characteristics did not differ between groups. Mean serum bicarbonate levels in the intervention arm during follow-up were 26.4±2.2, 25.5±2.3, 25.6±2.6, and 24.4±2.8 mEq/L (at 2, 6, 12, and 24 months). These were significantly higher than in the placebo group (P<0.001). Compared to the placebo group, participants randomly assigned to sodium bicarbonate treatment had no significant differences in sit-to-stand time (5 repetitions: P=0.1; and 10 repetitions P=0.07) or bone mineral density (P=0.3). Sodium bicarbonate treatment caused a decrease in serum potassium levels that was of borderline statistical significance (P=0.05). There were no significant differences in estimated glomerular filtration rates, blood pressure, weight, serious adverse events, or levels of muscle gene expression between the randomly assigned groups.
Initial mean serum bicarbonate level was in the normal range.
Sodium bicarbonate therapy in patients with CKD stages 3 and 4 significantly increases serum bicarbonate and decreases potassium levels. No differences were found in muscle function or bone mineral density between the randomly assigned groups. Larger trials are required to evaluate effects on kidney function.
National Institutes of Health grant.
Registered at ClinicalTrials.gov with study number NCT01452412
During cell division, cells form the microtubule-based mitotic spindle, a highly specialized and dynamic structure that mediates proper chromosome transmission to daughter cells. Cancer cells can ...show perturbed mitotic spindles and an approach in cancer treatment has been to trigger cell killing by targeting microtubule dynamics or spindle assembly. To identify and characterize proteins necessary for spindle assembly, and potential antimitotic targets, we performed a proteomic and genetic analysis of 592
mitotic
microtubule
copurifying
proteins (MMCPs). Screening for regulators that affect both mitosis and apoptosis, we report the identification and characterization of STARD9, a kinesin-3 family member, which localizes to centrosomes and stabilizes the pericentriolar material (PCM). STARD9-depleted cells have fragmented PCM, form multipolar spindles, activate the spindle assembly checkpoint (SAC), arrest in mitosis, and undergo apoptosis. Interestingly, STARD9-depletion synergizes with the chemotherapeutic agent taxol to increase mitotic death, demonstrating that STARD9 is a mitotic kinesin and a potential antimitotic target.
Display omitted
► Proteomic and genetic screens identify factors contributing to cell division ► The mitotic kinesin STARD9 is required for pericentriolar matrix cohesion ► Depletion of STARD9 leads to mitotic arrest and apoptosis in multiple types of cancers ► STARD9-depletion synergizes with the chemotherapeutic agent paclitaxel
Paclitaxel efficacy as an antimitotic drug is limited by toxic side effects. Loss of STARD9, a kinesin associated with daughter centrioles and the stability of pericentriolar material, synergizes with the drug to enhance apoptosis and shift Paclitaxel's effective concentration range in cells.
The effects of altered neural processing, defined as altering neural networks responsible for perceptions of pain and function, on chronic pain remains unclear.
To estimate the effect of a graded ...sensorimotor retraining intervention (RESOLVE) on pain intensity in people with chronic low back pain.
This parallel, 2-group, randomized clinical trial recruited participants with chronic (>3 months) nonspecific low back pain from primary care and community settings. A total of 276 adults were randomized (in a 1:1 ratio) to the intervention or sham procedure and attention control groups delivered by clinicians at a medical research institute in Sydney, Australia. The first participant was randomized on December 10, 2015, and the last was randomized on July 25, 2019. Follow-up was completed on February 3, 2020.
Participants randomized to the intervention group (n = 138) were asked to participate in 12 weekly clinical sessions and home training designed to educate them about and assist them with movement and physical activity while experiencing lower back pain. Participants randomized to the control group (n = 138) were asked to participate in 12 weekly clinical sessions and home training that required similar time as the intervention but did not focus on education, movement, and physical activity. The control group included sham laser and shortwave diathermy applied to the back and sham noninvasive brain stimulation.
The primary outcome was pain intensity at 18 weeks, measured on an 11-point numerical rating scale (range, 0 no pain to 10 worst pain imaginable) for which the between-group minimum clinically important difference is 1.0 point.
Among 276 randomized patients (mean SD age, 46 14.3 years; 138 50% women), 261 (95%) completed follow-up at 18 weeks. The mean pain intensity was 5.6 at baseline and 3.1 at 18 weeks in the intervention group and 5.8 at baseline and 4.0 at 18 weeks in the control group, with an estimated between-group mean difference at 18 weeks of -1.0 point (95% CI, -1.5 to -0.4; P = .001), favoring the intervention group.
In this randomized clinical trial conducted at a single center among patients with chronic low back pain, graded sensorimotor retraining, compared with a sham procedure and attention control, significantly improved pain intensity at 18 weeks. The improvements in pain intensity were small, and further research is needed to understand the generalizability of the findings.
ANZCTR Identifier: ACTRN12615000610538.
Purpose
There has been increased awareness recently of the unique medical and psychosocial needs of adolescents and young adults (AYAs) with cancer. However, the existing AYA literature is mainly ...focused on curative disease or survivorship rather than on advanced disease. Using qualitative methodology, we sought to understand the experience of younger adults with advanced cancer.
Methods
Participants were interviewed using open-ended, discovery-oriented interviews. Data was analyzed using thematic analysis. In total, ten English-speaking advanced cancer patients who were being treated at a comprehensive cancer center in Canada, were interviewed. Participants were between the ages of 18 and 35, and seven of them were female.
Results
The diagnosis of cancer was universally experienced as isolating and unexpected, with serious illness regarded as a problem of older individuals. The core challenge of living in the face of dying was felt to be constantly present yet typically unarticulated. Meaning-making tended to be constructed around future-oriented goals rather than upon the life that had been lived. Individuals felt forcefully removed from the stream of life, with a perceived interruption in the developmental tasks of establishing adult identity, becoming autonomous, and forming new relationships. All cited a need for young adult-specific services, yet none could describe specific services that would be beneficial. Many expressed reluctance to engage in individual psychotherapeutic treatment.
Conclusions
Advanced cancer in younger adults was perceived by them as isolating and as interfering with age-appropriate developmental tasks. Creative and flexible psychosocial support programs are needed to engage this population with limited expected survival.
White Blood Cell Count Is Associated With Macro- and Microvascular Complications in Chinese Patients With Type 2 Diabetes
Peter C. Tong , PHD 1 ,
Ka-Fai Lee , MBCHB 1 ,
Wing-Yee So , MBCHB 1 ,
...Margaret H. Ng , MD 2 ,
Wing-Bun Chan , MBCHB 1 ,
Matthew K. Lo , MBCHB 1 ,
Norman N. Chan , MD 1 and
Juliana C. Chan , MD 1
1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong
Kong
2 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin,
N.T., Hong Kong
Address correspondence and reprint requests to Dr. Peter C.Y. Tong, Department of Medicine and Therapeutics, The Chinese University
of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. E-mail: ptong{at}cuhk.edu.hk
Abstract
OBJECTIVES —There are close associations among raised white blood cell (WBC) count, coronary heart disease, and metabolic syndrome in
the general population. The association between WBC count and vascular complications of diabetes has not been explored. We
carried out a cross-sectional cohort study to determine the association between WBC count and the presence of macro- and microvascular
complications in type 2 diabetes.
RESEARCH DESIGN AND METHODS —In this study, 3,776 patients with type 2 diabetes and normal WBC count (3.5–12.5 × 10 9 /l) underwent a comprehensive assessment of complications and cardiovascular risk factors based on the European DiabCare protocol.
Demographic and anthropometric parameters were recorded. Metabolic profiles, including complete blood picture and urinary
albumin excretion, were measured.
RESULTS —Patients with higher WBC counts (categorized into quintiles) had adverse metabolic profiles as evidenced by higher blood
pressure, BMI, HbA 1c , fasting plasma glucose, LDL cholesterol, triglycerides, and urinary albumin excretion, but lower HDL cholesterol (all P <0.001 for trend). The prevalence of macro- and microvascular complications increased in a dosage-related manner with WBC
count. After adjustments for smoking and other known cardiovascular risk factors, a 1-unit (1 × 10 9 /l) increment of WBC count was associated with a 15.8% (95% CI 9.3–22.6; P < 0.001) and 12.3% increase (5.8–19.1; P < 0.001) in the prevalence of macro- and microvascular complications, respectively.
CONCLUSIONS —Elevated WBC count, even within the normal range, is associated with both macro- and microvascular complications in type
2 diabetes. Chronic inflammation, as indicated by a higher WBC count, may play a linkage role in the development of macro-
and microvascular complications in diabetes.
TG, triglyceride
TGF-β1, transforming growth factor-β1
UAE, urinary albumin excretion
WBC, white blood cell
WHR, waist-to-hip ratio
Footnotes
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Accepted October 5, 2003.
Received July 6, 2003.
DIABETES CARE
Cell size is specific to each species and impacts cell function. Various phenomenological models for cell size regulation have been proposed, but recent work in bacteria has suggested an 'adder' ...model, in which a cell increments its size by a constant amount between each division. However, the coupling between cell size, shape and constriction remains poorly understood. Here, we investigate size control and the cell cycle dependence of bacterial growth using multigenerational cell growth and shape data for single Caulobacter crescentus cells. Our analysis reveals a biphasic mode of growth: a relative timer phase before constriction where cell growth is correlated to its initial size, followed by a pure adder phase during constriction. Cell wall labelling measurements reinforce this biphasic model, in which a crossover from uniform lateral growth to localized septal growth is observed. We present a mathematical model that quantitatively explains this biphasic 'mixer' model for cell size control.
Prostate cancer displays a wide spectrum of clinical behaviour from biological indolence to rapidly lethal disease, but we remain unable to accurately predict an individual tumor’s future clinical ...course at an early curable stage. Beyond basic dimensions and volume calculations, tumor morphometry is an area that has received little attention, as it requires the analysis of the prostate gland and tumor foci in three-dimensions. Previous efforts to generate three-dimensional prostate models have required specialised graphics units and focused on the spatial distribution of tumors for optimisation of biopsy strategies rather than to generate novel morphometric variables such as tumor surface area. Here, we aimed to develop a method of creating three-dimensional models of a prostate’s pathological state post radical prostatectomy that allowed the derivation of surface areas and volumes of both prostate and tumors, to assess the method’s accuracy to known clinical data, and to perform initial investigation into the utility of morphometric variables in prostate cancer prognostication. Serial histology slides from 21 prostatectomy specimens covering a range of tumor sizes and pathologies were digitised. Computer generated three-dimensional models of tumor and prostate space filling models were reconstructed from these scanned images using Rhinoceros 4.0 spatial reconstruction software. Analysis of three-dimensional modelled prostate volume correlated only moderately with weak concordance to that from the clinical data (r = 0.552, θ = 0.405), but tumor volume correlated well with strong concordance (r = 0.949, θ = 0.876). We divided the cohort of 21 patients into those with features of aggressive tumor versus those without and found that larger tumor surface area (32.7 vs 3.4cc, p = 0.008) and a lower tumor surface area to volume ratio (4.7 vs 15.4, p = 0.008) were associated with aggressive tumor biology.
Purpose Chemotherapy is the mainstay treatment for advanced non-small cell lung cancer (NSCLC). Gefitinib, an epidermal growth factor receptor—tyrosine kinase inhibitor (EGFR-TKI), has been recently ...shown to be effective as a first-line treatment in Asian patients with advanced NSCLC, especially for those with favourable clinical features such as female, non-smoker and adenocarcinoma. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment. The purpose of this study is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib. Method Retrospective review of NSCLC patients with favourable clinical features who received gefitinib as first-line treatment and subsequent salvage treatment with erlotinib. Results A total of 21 patients with NSCLC were included in the study. Among them, 18 (85.7%) patients had disease control with gefitinib and 12 (57.1%) patients with salvage erlotinib. There was an association between the disease control with gefitinib and erlotinib (p = 0.031). The disease control rate of erlotinib was independent of the chemotherapy use between the two EGFR-TKIs. Conclusion For NSCLC patients with favourable clinical features, erlotinib was effective in those who had prior disease control with first-line gefitinib.
Summary
This study evaluated patterns of response as discerned by comprehensive metastasis‐specific analysis in metastatic melanoma patients receiving anti‐PD‐1 antibodies. Bi‐dimensional ...measurements of every metastasis in patients enrolled in the KEYNOTE‐001 trial at a single institution were obtained at baseline and throughout treatment. Twenty‐seven evaluable patients had 399 baseline metastases measurable on CT imaging. Complete response (CR) which occurred in 52.6% of metastases was smaller (mean 223 mm2 versus 760 mm2, p < .01) and occurred more frequently in the lungs (65% versus 39.4%, p < .01). Response was heterogenous (new/progressing metastases alongside CR metastases) at first assessment in 4/14 patients with objective response (OR) as opposed to 7/13 patients with non‐OR. CR of individual metastases is common and influenced by site and size. Most patients with OR demonstrate homogenous regression in all metastases at the first assessment. In contrast, patients with early heterogeneity had a poor outcome.
PDF
