In cells cleared of Ctr infection, average telomere length was slightly increased and immunofluorescence staining of the DNA damage marker gamma H2A.X was reduced after clearance of infection compared with cells that had not been infected. Reduced p53 binding to the promoter of the cell cycle checkpoint regulator p21 was also detected in cells cleared of infection and p21 levels were reduced; moreover, this cell population exhibited increased resistance to etoposide-induced DNA damage. Thus, Ctr infection altered cell aging and survival pathways, which persisted after infection clearance. Cells that survive infection are likely to

exhibit altered physiology, as evidenced by an increased DMH1 resistance to DNA damage-induced

apoptosis, which may support cellular transformation. (C) 2013 Elsevier GmbH. All rights reserved.”
“Concentrated liquid detergent pods are an emerging public health hazard, especially in pediatric patients. Ingestion is a more common route of exposure for liquid detergent pods compared with non-pod detergents and it tends to be associated with more severe adverse effects. We present 3 cases that demonstrate the varied clinical symptoms ML323 in vivo resulting from detergent pod ingestion. These cases not only demonstrate findings such as gastrointestinal and respiratory symptoms but also 5-Fluoracil show more rare neurological symptoms. The cases highlight the dangers of concentrated liquid detergent pod ingestion. To help prevent further life-threatening injuries, there is a need for more consumer information and provider knowledge about the potential adverse complications.”
“A highly efficient

molecular iodine catalyzed oxidative amidation of aryl methyl ketones with formamidine hydrochloride has been developed. This reaction represents a novel strategy for the synthesis of free (N-H) alpha-ketoamides. Based on the experimental results, a self-sequenced iodination/Kornblum oxidation/amidation/oxidation/decarbonylation mechanism was proposed.”
“A new polymorph alpha of indiplon was discovered, initially prepared by two methods, and further characterized by various means including single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), variable temperature powder X-ray diffraction (VT-PXRD), differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), Fourier transform Raman (FT-Raman) spectroscopy and solubility determination. The crystal structure of Form alpha as analyzed by SCXRD differ from the three previously reported polymorphs, Form I, II, and III. In addition, PXRD and solubility measurements could clearly distinguish between Form alpha and Form I. Slight differences between the two forms were also detected by FT-Raman.

Differences

were assessed using the two-sided sign test. All seven HPAs made improvements, with gains in an overall index (P = 0.017) and in the specific dimensions of culture (P = 0.016), operational capacity (P = 0.016), performance (P = 0.03), and functions (P = 0.016). Increased capacity contributed to the ability of each HPA to enhance their credibility and assume leadership in national efforts to improve maternal and newborn health. (C) 2014 International see more Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.”
“Amorphous solid dispersions are an increasingly important formulation approach to improve the dissolution rate and apparent solubility of poorly water soluble compounds. Due to their complex physicochemical properties, there is a need for multi-faceted analytical methods to enable comprehensive characterization, and thermal

techniques are widely employed for this purpose. Key parameters of interest that can influence product performance include the glass transition temperature (T-g), molecular mobility of the drug, miscibility between the drug and excipients, and the rate and extent of drug crystallization. It GW786034 in vivo is important to evaluate the type of information pertaining to the aforementioned properties that can be extracted from thermal analytical measurements, in addition to considering any inherent assumptions or limitations of the various analytical approaches. Although differential scanning calorimetry (DSC) is the most widely used thermal analytical technique applied to the characterization of amorphous solid dispersions, there are many established and emerging techniques which have been shown to provide useful information. Comprehensive characterization of fundamental material descriptors will ultimately lead to the formulation of more robust solid dispersion products. (C) 2011 Elsevier B.V. All rights reserved.”
“Voltage-gated sodium channels initiate electrical signaling in excitable cells such as muscle and neurons. They also are

expressed in non-excitable cells such as macrophages and neoplastic cells. Previously, in LY3023414 macrophages, we demonstrated expression of SCN8A, the gene that encodes the channel NaV1.6, and intracellular localization of NaV1.6 to regions near F-actin bundles, particularly at areas of cell attachment. Here we show that a splice variant of NaV1.6 regulates cellular invasion through its effects on podosome and invadopodia formation in macrophages and melanoma cells. cDNA sequence analysis of SCN8A from THP-1 cells, a human monocyte-macrophage cell line, confirmed the expression of a full-length splice variant that lacks exon 18. Immunoelectron microscopy demonstrated NaV1.6-positive staining within the electron dense podosome rosette structure.

(C) 2011 Elsevier Ltd. All rights reserved.”
“Background: Kalihi Valley is a densely populated, low-income community (28,958 residents in approximately 6 square miles) with insufficient sidewalks, bike lanes, and public green space to Support regular physical activity for its residents. Kokua Kalihi Valley (KKV), a community health center formed in 1972, sought to improve Kalihi Valley’s built environment based Oil its history Of community- and partnership-based preventive health initiatives that have focused on the social determinants of health.\n\nIntervention: ACY-1215 Kokua Kalihi Valley used a flexible partnership model and a focus on direct community action to develop an unused 100-acre state park (the Kalihi Valley Nature Park)

and establish a bicycle repair and recycling program that mobilized thousands Of Community Volunteers, attracted widespread media coverage, and established a number of innovative programs for active living. Kokua Kalihi Valley and its partners also contributed to the successful passage of a city charter amendment to prioritize Honolulu as a bicycle- and pedestrian-friendly city.\n\nResults: This initiative was successful in reclaiming a substantial amount of land for active living and in stimulating both public governmental support, and widespread private community involvement in programs and activities.\n\nLessons learned: Projects that engaged Community members in activities with tangible accomplishment were shown

to be most successful.\n\nConclusions: This initiative showed that community health centers may be uniquely, Nutlin-3 research buy positioned to Prexasertib provide leadership and assume responsibility for cross-sectoral active-living health projects. (Am J PreN, Med 2009;37(6S2):S345-S351) (C) 2009 American Journal of Preventive Medicine”
“Trastuzumab (Herceptin), a humanized monoclonal antibody, is a cancer drug developed to target the human epidermal receptor (HER) 2, which is overexpressed in some cancer cells. Cutaneous side effects, such as folliculitis, xerosis, and alopecia have not been reported with therapies targeting HER2, in spite of the

frequent observances of such with the therapies targeting the epidermal growth factor receptor. We experienced a patient in whom psoriasis was triggered by the trastuzumab treatment for breast cancer. She was a 57-year-old woman with erythematous and scaly plaques occurring a few months after starting trastuzumab, with repeated aggravation after the re-administration of trastuzumab for the breast cancer. Histologic examination showed the typical features of psoriasis with parakeratosis, epidermal hyperplasia, elongation of the rete ridges, and a lymphocytic and polymorphonuclear cell infiltrate in the dermis. To the best of our knowledge, this is the first report of psoriasis triggered by trastuzumab treatment for breast cancer.”
“To the Editor: Williams et al. (Nov. 7 issue)(1) reported no increase in the overall cancer risk among British children born after assisted conception.

N-ChIP assays were also able to detect several other types of chromatin interactions including those with Dlx homeodomain factors and nuclear proteins such as Sin3a that lack an intrinsic DNA-binding motif selleckchem and, therefore, bind to chromatin via interactions with other proteins.”
“Purpose: To investigate the heart position variability in deep-inspiration breath-hold (DIBH) radiation therapy (RT) for breast cancer when 3D surface imaging would be

used for monitoring the BH depth during treatment delivery. For this purpose, surface setup data were compared with heart setup data.\n\nMaterials and methods: Twenty patients treated with DIBH-RT after breast-conserving surgery were included. Retrospectively, heart registrations https://www.selleckchem.com/products/xmu-mp-1.html were performed for cone-beam computed tomography (CBCT) to planning CT. Further, breast-surface

registrations were performed for a surface, captured concurrently with CBCT, to planning CT. The resulting setup errors were compared with linear regression analysis. Furthermore, geometric uncertainties of the heart (systematic [Sigma] and random [sigma]) were estimated relative to the surface registration. Based on these uncertainties planning organ at risk volume (PRV) margins for the heart were calculated: 1.3 Sigma – 0.50 sigma.\n\nResults: Moderate correlation between surface and heart setup errors was found: R-2 = 0.64, 0.37, 0.53 in left-right (LR), cranio-caudal (CC), and in anterior-posterior (AP) direction, respectively. When surface imaging would be used for monitoring, the geometric uncertainties of the heart (cm) are [Sigma = 0.14, sigma = 0.14]; [Sigma = 0.66, sigma = 0.38]; [Sigma = 0.27, sigma = 0.19] in LR; CC; AP. This results in PRV margins of 0.11; 0.67; this website 0.25 cm in LR; CC; AP.\n\nConclusion: When DIBH-RT after breast-conserving surgery is guided by the breast-surface position then PRV margins should be used to take into account the heart-position variability relative to the breast-surface. (C) 2013 Elsevier

Ireland Ltd. All rights reserved.”
“Objective: the partograph is a tool used globally to record labour progress. Although it has the potential to improve maternal and neonatal outcomes, some midwives struggle with using it in practice. Training in partograph use is limited, and the theory is often divorced from practice. Innovative ways of improving training are urgently required. We therefore aimed to determine whether the use of an e-learning tool is beneficial for learning partograph skills.\n\nDesign: an uncontrolled before-and-after study was conducted, informed by Kirkpatrick’s four-stage model of evaluation; we report on the first two stages. We included a cohort of third and fourth year midwifery students who were studying at one university in Nairobi.

035). In multivariate logistic-regression analysis, individuals with the

CG or GG genotypes were significantly more likely to have had a stroke than individuals with the CC genotype (vs. CG; OR 2.99, P = 0.024, vs. GG; OR 4.49, P = 0.010). These data suggested that the genotyping of resistin polymorphism. at -420(C>G) can be a risk marker for stroke susceptibility in Japanese type 2 diabetic patients. (C) 2009 Elsevier Ireland Ltd. All rights reserved.”
“Background. Disparity between patient report and physician perception of pain from radiotracer injection for sentinel node biopsy is thought to center on the severity of the intervention, ethnic composition of population queried, and socioeconomic factors. Objective. The objectives of this study were, first, to explore agreement between physicians’ THZ1 chemical structure and their breast cancer patients’ pain assessment during subareolar radionucleotide injection; and second, to evaluate potential ethnic differences in ratings. Methods. A trial was conducted, from January 2006 to April 2009, where 140 breast cancer patients were randomly assigned to standard topical lidocaine-4% cream and 99mTc-sulfur colloid

injection, or to one of three other groups: placebo cream and 99mTc-sulfur colloid injection containing NaHCO3, 1% lidocaine, or NaHCO3 + 1% lidocaine. Providers Torin 2 manufacturer and patients completed numeric pain scales Stattic manufacturer (010) immediately after injection. Results. Patients

and providers rated pain similarly over the entire cohort (median, 3 vs 2, P = 0.15). Patients rated pain statistically significantly higher than physicians in the standard (6 vs 5, P = 0.045) and placebo + NaHCO3 (5 vs 4, P = 0.032) groups. No significant difference in scores existed between all African Americans and their physicians (3 vs 4, P = 0.27). Conclusion. Patientphysician pain assessment congruence over the less painful injections and their statistically similar scores with the more painful methods suggests the importance of utilizing the least painful method possible. Providers tended to underestimate patients with the highest pain ratingsthose in the greatest analgesic need. Lack of statistical difference between African American and physician scores may reflect the equal-access-to-care over the entire patient cohort, supporting the conclusion that socioeconomic factors may lie at the heart of previously reported discrepancies.”
“The influence of flow limitation on the magnitude of the cardiorespiratory response to arousal from sleep is of interest in older people, because they experience considerable flow limitation and frequent arousals from sleep. We studied older flow-limiting subjects, testing the hypothesis that the cardiorespiratory activation response would be larger when arousal occurred during flow limitation, compared to no flow limitation, and chemical stimuli were controlled.

coli SlyD, SlyD155. Ni(II) binding to SlyD155 was investigated by using isothermal titration calorimetry, NMR and electrospray ionization mass spectrometry measurements.

This in vitro characterization revealed that Selleckchem NVP-BSK805 SlyD155 contains a single metal-binding motif with high affinity for nickel. Structural characterization by X-ray absorption spectroscopy and NMR indicated that nickel was coordinated in an octahedral geometry with at least two histidines as ligands. Heterodimerization between SlyD and another hydrogenase accessory protein, HypB, is essential for optimal hydrogenase maturation and was confirmed for SlyD155 via cross-linking experiments and NMR titrations, as were conserved chaperone and peptidyl-prolyl isomerase activities. Although these properties of SlyD

are preserved in the truncated version, it does not modulate nickel binding to HypB in vitro or contribute to the maturation of [NiFe]-hydrogenases in vivo, unlike the full-length protein. This study highlights the importance of the unusual metal-binding domain of E. coli SlyD in hydrogenase biogenesis. (C) 2012 Elsevier Ltd. All rights reserved.”
“Many ion channels have Pevonedistat cell line been shown to be regulated by the membrane signaling phospholipid phosphatidylinositol 4,5-bisphosphate (PIP(2)). Here, we demonstrate that the binding of PIP(2) to SpIH, a sea urchin hyperpolarization-activated cyclic nucleotide-gated ion channel (HCN), has a dual effect: potentiation and inhibition. The potentiation is observed as a shift in the voltage dependence of activation to more depolarized voltages. The inhibition is observed as a reduction in the currents elicited by the partial agonist cGMP. These two effects were separable and arose from PIP(2) binding to two different regions. Deletion of the C-terminal region of SpIH removed PIP(2)-induced inhibition but not the PIP(2)-induced shift in voltage dependence. Mutating key positively charged amino acids in the C-terminal region

adjacent to the membrane selectively disrupted PIP(2)-induced inhibition, suggesting a direct interaction between PIP(2) in the membrane and amino acids in the C-terminal region that stabilizes the closed state relative to CCI-779 mw the open state in HCN channels.”
“As a result Of an increasing life expectancy, the incidence of colon cancer in the older population is rising. As a consequence oncologists and their older patients commonly face the dilemma of whether or not to give/receive treatment for colon cancer. However. the Paucity of large, well conducted prospective trials makes it difficult to provide evidence-based clinical recommendations for these patients. The Current evidence supports the safety and efficacy of treatment for colon cancer in fit older patients and demonstrates that treatment outcome can be similar to that of their younger Counterparts.

Transcranial Doppler was used to monitor cerebral blood flow. EEG recordings were used to

detect seizures. Immunocytochemical detection (Cresyl Violet, anti-human CD8 for TALL-104, Evans Blue for BBB damage, GFAP and NEUN) was performed.\n\nResults: At the concentration used TALL-104 cells were tolerated. Incomplete BBBD did not allow cell entry into the brain. MRI scans at 24 and 48 hours post-injection 5-Fluoracil in vivo allowed visualization of topographically segregated cells in the hemisphere that underwent successful BBBD. Perivascular location of TALL-104 was confirmed in the BBBD hemisphere by Cresyl violet and CD8 immunocytochemistry. No significant alteration in CBF or EEG activity was recorded during cell injections.\n\nConclusions: Our data show that targeted CNS cell therapy requires blood-brain barrier Vistusertib in vivo disruption. MRI-detectable cytotoxic anti-neoplastic cells can be forced to transverse the BBB and accumulate in the perivascular space. The virtual absence of toxicity, the high anti-tumor activity of TALL-104, and the clinical feasibility of human osmotic BBBD suggest that this approach may be adopted to treat brain or spinal cord tumors. In addition, BBBD may favor CNS entry of other cells that normally lack CNS tropism.”
“The frequency for movements along the longitudinal axis during running peaks at approximately

3Hz. Other physiological systems (e.g. heart rate and brain cortical activity) are known to show a dominant frequency of 3Hz connected to exercise. As recent studies have proposed a clear correlation between musical tempo, mood, and performance output, we wished to ascertain whether peak locomotion frequency of 3Hz during running is synchronized with different intrinsic and extrinsic frequencies. Eighteen healthy regular runners performed three outdoor running sessions

at different intensities. Oscillations along the longitudinal axis were recorded using an accelerometer (ActiBelt selleck compound (R)). Electrocortical activity was recorded using electroencephalography before and after exercise and analysed in the delta frequency range (2-4Hz). In addition, the frequency spectra of the participants’ favourite musical pieces were analysed. Data revealed a peak frequency at around 2.7 to 2.8Hz for the vertical acceleration during running. Similar oscillation patterns were found for heart rate and musical pieces. Electroencephalographic delta activity increased after running. Results of this study give reason to speculate that a strong relationship exists between intrinsic and extrinsic oscillation patterns during exercise. A frequency of approximately 3Hz seems to be dominant in different physiological systems and seems to be rated as pleasurable when choosing the appropriate music for exercising. This is in line with previous research showing that an adequate choice of music during exercise enhances performance output and mood.

These results underscore the contribution of visual-spatial abilities to the reading acquisition process and identify WS as a potential source of valuable information regarding the role of visual-spatial processing in reading development.”
“Introduction: We present our technique of laparoscopic nephrectomy for massive polycystic kidneys in patients with autosomal dominant polycystic kidney disease (ADPKD) and review the outcome Rigosertib concentration analysis of our experience. Methods: We retrospectively reviewed all transperitoneal laparoscopic nephrectomies done for polycystic kidneys at a university hospital. Our technique included three 12-mm ports with additional one or two 5-mm ports, with usage

of retraction devices, such as the Jarit PEER retractor (J. Jamner Surgical Instruments, Inc, Hawthorne, NY). Results: In total, 39 (left 14, right 25) laparoscopic nephrectomies were performed in 32 patients (male 21, female 11). Surgical indications were varied: to create space for future renal transplant in 21 (54%), to alleviate pain in 16 (41%), to prevent recurrent urosepsis in 2 (5%), to prevent recurrent bleeding which would require transfusions in 2 (5%) and to remove a renal tumour in 1 kidney (2.5%). Four patients had surgery for more than one reason.

The mean age and body mass index were 52.2 years (range: 29-72) and 26.9 MK-4827 kg/m(2) (range: 21.6-34.0), respectively. The mean preoperative hemoglobin and serum creatinine levels were 131.6 g/L (range: SBE-β-CD 107-171) and 514 mu mol/L (range: 84-923), respectively; 26 (81%) patients were on dialysis. The mean operative time and estimated blood loss were 185 minutes (range: 113-287) and 94 mL (range: 10-350), respectively.

No patient required open conversion. The mean specimen size was 24.2 cm (range: 15-38); weight 1515 g (range: 412-4590) and the length of extraction incision was 9.2 cm (range: 6-13). There were 1 Grade 2 2 (2.5%), 2 Grade 3b (5%) and 1 Grade 4a-d (2.5%) complications. The mean length of stay was 4.5 days (range: 3-8). Conclusions: Our technique of laparoscopic nephrectomy for massively enlarged polycystic kidneys in ADPKD is safe and offers all the advantages of minimal access surgery, such as smaller incision, decreased estimated blood loss, excellent cosmesis and faster recovery.”
“In vivo T cell depletion with 100mg alemtuzumab prevents graft-versus-host disease (GVHD) in reduced intensity conditioned transplants but is associated with delayed immune reconstitution, a higher risk of infection and relapse. De-escalation studies have shown that a reduced dose of 30mg is as effective as 100mg in preventing GVHD in matched related donor (MRD) transplants. Dose reduction in matched unrelated donor (MUD) transplants is feasible but the comparative efficacy of alemtuzumab in this setting is not known and opinions vary widely concerning the optimal level of GVHD prophylaxis that should be achieved.

However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3 alpha and 9 of GSK-3 beta respectively, required for inactivation by upstream kinases.\n\nBetween 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility,

accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, selleck ISO-treated KI hearts demonstrated reversible PS-095760 physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts.\n\nExpression of inactivation-resistant GSK-3 alpha/beta does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation,

maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent

phosphorylation of Ser-21/9, and consequent inactivation of GSK-3 alpha/beta, may enable a sustained cardiac response to chronic beta-agonist stimulation while preventing pathological remodelling.”
“Breast AZD2014 cancer is the leading cause of cancer-related deaths in women worldwide. Tanshinone IIA (Tan-IIA) is one of the pure compounds from Salviae miltiorrhizae radix (Danshen). Tan-IIA can inhibit human breast cancer cells but the molecular mechanisms are not well understood. Our previous study showed that Tan-IIA can inhibit hep-J5 human hepatocellular carcinoma cells through the endoplasmic reticulum (ER) stress-induced apoptotic pathway. In the present study, we evaluated the effects of Tan-IIA on BT-20 human breast cancer cells and assessed the involvement of the ER-stress-apoptotic pathway. The cytotoxicity of Tan-IIA in BT-20 cells was measured by the MTT assay. The cell cycles were analyzed by flow cytometry. The expression of ER stress-related proteins in BT-20 cells treated with Tan-IIA were evaluated by western blotting and immunocytochemical staining. These results showed that Tan-IIA can inhibit BT-20 cells and increase the sub-GI phase in a time- and dose-dependent manner. Tan-IIA could increase the protein expression of caspase 12, CADD153. caspase 3, phospho-JNK, phospho-p38 and Bax, but decreased Bcl-xl and phospho-ERK expression in BT-20 cells.

Sequence alignment showed 95 SNPs in alpha-Phs and 83 in PvFRO1, but diversity

along the nucleotide Dinaciclib mw sequences was not evenly distributed in both genes. Accessions from the same gene pool showed greater similarity than those from different gene pools, and the cluster patterns obtained in this study were consistent with the hierarchical organization into two P. vulgaris gene pools. The polymorphisms detected in the alpha-Phs gene allowed better discrimination among the accessions within each cluster than the PvFRO1 polymorphisms. Furthermore, some variations within exons changes amino acids in both predicted protein sequences. In an unprecedented result, the phaseolin-predicted amino acid variation allowed most of the accessions to be typified.”
“The resolution

of inflammation is central to the maintenance of good health and immune homeostasis. Recently, several intracellular stress proteins have been described as having extracellular properties that are anti-inflammatory or favour the resolution of inflammation. We propose that these molecules should be defined as resolution-associated molecular patterns (RAMPs). RAMPs are released at times of cellular stress and help to counterbalance the inflammatory effects of pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns. We propose that heat shock protein 10 (HSP10), alpha B-crystallin (alpha BC), HSP27 and binding immunoglobulin protein Anlotinib purchase (BiP) should be considered founding members of the RAMP family. A greater understanding of RAMP biology may herald the development of novel

immunotherapies.”
“Background\n\nPhosphate binders are widely used to lower serum phosphorus levels in people with chronic kidney disease (CKD) but their impact AZD1480 concentration in CKD remains controversial.\n\nObjectives\n\nTo review the effects of various phosphate binders on biochemical and patient-level end-points in CKD stages 3 to 5D.\n\nSearch strategy\n\nIn March 2010 we searched MEDLINE, EMBASE, the Cochrane Renal Group’s Specialised Register and CENTRAL for relevant studies.\n\nSelection criteria\n\nRandomised controlled trials (RCTs) or quasi-RCTs that assessed the effects of various phosphate binders in adults with CKD.\n\nData collection and analysis\n\nTwo authors independently reviewed search results and extracted data. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model.\n\nMain results\n\nSixty studies (7631 participants) were included. There was no significant reduction in all-cause mortality (10 studies, 3079 participants: RR 0.73, 95% CI 0.46 to 1.16), or serum calcium by phosphorus (Ca x P) product with sevelamer hydrochloride compared to calcium-based agents.